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January 11, 2023
The characteristics of antibodies that broadly neutralize coronaviruses are poorly understood. Here, Dacon et al.identify a class of stem helix-specific monoclonal antibodies from COVID-19 convalescent donors that neutralize diverse betacoronaviruses, use an IGHV1-46/IGKV3-20 gene signature, and bind in a conserved manner to the spike protein.
November 29, 2022
Post-COVID syndrome remains poorly studied in children and adolescents. Here, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status. Children from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), aged 6 months to 17 years, were tested for anti-SARS-CoV-2 N antibodies (December 2021-February 2022) and parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID. Of 1034 children tested, 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). Stratifying per age group, only adolescents displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%, 95%CI: 3.5;13.5). Identified risk factors for post-COVID syndrome were older age, having a lower socioeconomic status and suffering from chronic health conditions, especially asthma. Our findings show that a significant proportion of seropositive children, particularly adolescents, experienced persistent COVID symptoms. While there is a need for further investigations, growing evidence of pediatric post-COVID urges early screening and primary care management.
In conclusion, a shift in COVID-19 mortality to relatively younger people in the second pandemic year contributed to markedly elevated YLL from this increasingly preventable cause of death.
November 28, 2022
Understanding immune determinants of vaccine-mediated immunogenicity could further provide rational vaccine design. Two research groups revealed pre-existing and early innate immune signatures associated with better vaccine-mediated antibody responses.
The SARS-CoV-2 Omicron variant continues to evolve, with new BQ and XBB subvariants now rapidly expanding in Europe/US and Asia, respectively. As these new subvariants have additional spike mutations, they may possess altered antibody evasion properties. Here, we report that neutralization of BQ.1, BQ.1.1, XBB, and XBB.1 by sera from vaccinees and infected persons was markedly impaired, including sera from individuals who were boosted with a WA1/BA.5 bivalent mRNA vaccine. Compared to the ancestral strain D614G, serum neutralizing titers against BQ and XBB subvariants were lower by 13-81-fold and 66-155-fold, respectively, far beyond what had been observed to date. A panel of monoclonal antibodies capable of neutralizing the original Omicron variant, including those with Emergency Use Authorization, were largely inactive against these new subvariants. The spike mutations that conferred antibody resistance were individually studied and structurally explained. Finally, the ACE2-binding affinities of the spike proteins of these novel subvariants were found to be similar to those of their predecessors. Taken together, our findings indicate that BQ and XBB subvariants present serious threats to the efficacy of current COVID-19 vaccines, render inactive all authorized monoclonal antibodies, and may have gained dominance in the population because of their advantage in evading antibodies.
People with acute COVID-19 due to SARS-CoV-2 infection experience a range of symptoms, but major factors contributing to severe clinical outcomes remain to be understood. Emerging evidence suggests associations between the gut microbiome and the severity and progression of COVID-19. To better understand the host-microbiota interactions in acute COVID-19, we characterized the intestinal microbiome of patients with active SARS-CoV-2 infection in comparison to recovered patients and uninfected healthy controls. We performed 16S rRNA sequencing of stool samples collected between May 2020 and January 2021 from 20 COVID-19-positive patients, 20 COVID-19-recovered subjects and 20 healthy controls. COVID-19-positive patients had altered microbiome community characteristics compared to the recovered and control subjects, as assessed by both α- and β-diversity differences. In COVID-19-positive patients, we observed depletion of Bacteroidaceae, Ruminococcaceae, and Lachnospiraceae, as well as decreased relative abundances of the genera Faecalibacterium, Adlercreutzia, and the Eubacterium brachy group. The enrichment of Prevotellaceae with COVID-19 infection continued after viral clearance; antibiotic use induced further gut microbiota perturbations in COVID-19-positive patients. In conclusion, we present evidence that acute COVID-19 induces gut microbiota dysbiosis with depletion of particular populations of commensal bacteria, a phenomenon heightened by antibiotic exposure, but the general effects do not persist post-recovery.
November 24, 2022
Viral infection is facilitated by the molecular recognition of specific receptors and host factors at the plasma membrane, which provides a gateway into host cells (1). These factors act as “locks” that control access to the intracellular environment, to which viruses have evolved cognate molecular “keys” to gain entry and replicate. In the evolutionary arms race between viruses and their hosts, the development of effective antiviral therapeutic strategies to inhibit this process poses a crucial public health challenge, recently emphasized by the COVID-19 pandemic.
November 23, 2022
Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimers disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD.
November 22, 2022
In this study of vaccine effectiveness of the U.S.-authorized bivalent mRNA booster formulations, bivalent boosters provided significant additional protection against symptomatic SARS-CoV-2 infection in persons who had previously received 2, 3, or 4 monovalent vaccine doses. Due to waning immunity of monovalent doses, the benefit of the bivalent booster increased with time since receipt of the most recent monovalent vaccine dose.
Among U.S. adults diagnosed with COVID-19, including those with previous infection or vaccination, persons who were prescribed Paxlovid within 5 days of diagnosis had a 51% lower hospitalization rate within 30 days after diagnosis than those who were not prescribed Paxlovid.
November 21, 2022
Although absolute rates of myocarditis were low, vaccine type, age and sex are important factors to consider when strategizing vaccine administration to reduce the risk of postvaccination myocarditis. Our findings support the preferential use of the BNT162b2 vaccine over the mRNA-1273 vaccine for people aged 18–29 years.
November 20, 2022
Importance: While a substantial fraction of the US population was infected with SARS-CoV-2 during December 2021-February 2022, the subsequent evolution of population immunity against SARS-CoV-2 Omicron variants reflects the competing influences of waning protection over time and acquisition or restoration of immunity through additional infections and vaccinations. Objective: To estimate changes in population immunity against infection and severe disease due to circulating SARS-CoV-2 Omicron variants in the United States from December 2021 to October 2022, and to quantify the protection against a potential 2022-2023 winter SARS-CoV-2 wave. Design, setting, participants: Bayesian evidence synthesis of reported COVID-19 data (diagnoses, hospitalizations), vaccinations, and waning patterns for vaccine- and infection-acquired immunity, using a mathematical model of COVID-19 natural history. Main Outcomes and Measures: Population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States, by location (national, state, county) and week. Results: By November 10, 2022, 94% (95% CrI, 79%-99%) of the US population were estimated to have been infected by SARS-CoV-2 at least once. Combined with vaccination, 97% (95%-99%) were estimated to have some prior immunological exposure to SARS-CoV-2. Between December 1, 2021 and November 10, 2022, protection against a new Omicron infection rose from 22% (21%-23%) to 63% (51%-75%) nationally, and protection against an Omicron infection leading to severe disease increased from 61% (59%-64%) to 89% (83%-92%). Increasing first booster uptake to 55% in all states (current US coverage: 34%) and second booster uptake to 22% (current US coverage: 11%) would increase protection against infection by 4.5 percentage points (2.4-7.2) and protection against severe disease by 1.1 percentage points (1.0-1.5). Conclusions and Relevance: Effective protection against SARS-CoV-2 infection and severe disease in October 2022 was substantially higher than in December 2021. Despite this high level of protection, a more transmissible or immune evading (sub)variant, changes in behavior, or ongoing waning of immunity could lead to a new SARS-CoV-2 wave.
Background The emergence of SARS-CoV-2 variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5μg SARS-CoV-2 rS + 50μg Matrix-M™ adjuvant) was evaluated to determine induction of cross-reactive antibodies to variants of concern. Methods A phase 2 randomized study assessed a fourth dose of NVX-CoV2373 in adults 18-84 years of age (2-dose primary series followed by third and fourth doses at 6-month intervals). Local/systemic reactogenicity was assessed the day of vaccination and for 6 days thereafter. Unsolicited adverse events (AEs) were reported. Immunogenicity was measured before, and 14 days after, fourth dose administration using anti-spike neutralization assays against the ancestral SARS-CoV-2 strain and Omicron sublineages. Antigenic cartography assessed antigenic distances between ancestral and variant strains. Results Among 1283 enrolled participants, 258 were randomized to receive the 2-dose primary series, of whom 104 received a third dose, and 45 received a fourth dose of NVX-CoV2373. The incidence of local/systemic reactogenicity events increased after the first three doses of NVX-CoV2373, and leveled off after dose four. Unsolicited AEs were reported in 9% of participants after dose 4 (none severe or serious). Neutralization antibody titers increased following booster doses. Antigenic cartography demonstrated reductions in antigenic distance between ancestral and variant SARS-CoV-2 strains with increased number of NVX-CoV2373 doses. Conclusions A fourth dose of NVX-CoV2373 enhanced immunogenicity without increasing reactogenicity. Antigenic cartography demonstrated a more universal-like response against SARS-CoV-2 variants after a fourth dose of NVX-CoV2373, indicating that updates to the vaccine composition may not be warranted. Trial registration number: NCT04368988
November 19, 2022
Remember the pandemic? Barely. Economist Impact, a policy research team within The Economist Group, supported by The Lancet's publisher Elsevier, last week launched Confidence in Research—a report exploring attitudes of scientists to the practice and communication of science during the pandemic. Based on a survey of over 3000 researchers worldwide, Economist Impact identified important actions that should be considered if mistakes are not to be repeated during future health emergencies.
November 18, 2022
One half of adults surveyed during June–July 2022 who had recently received a positive SARS-CoV-2 test result in metropolitan Detroit, Michigan and DuPage County, Illinois perceived local COVID-19 transmission when surveyed to be low or moderate, despite documented sustained high transmission. Higher perceived local COVID-19 transmission was associated with more use of preventive behaviors, overall and in response to high local COVID-19 transmission.
Four percent of children aged 6 months–4 years had received ≥1 doses of COVID-19 vaccine based on interviews conducted during July 2022; 59% were unvaccinated, but the parent was open to vaccinating their child; and 37% were unvaccinated and the parent was reluctant to vaccinate. Among parents open to vaccination, 25% reported receiving a provider recommendation, and 57% were confident of the vaccine’s safety; confidence of vaccine safety varied by race or ethnicity and household income.
Introduction In addition to the original monovalent vaccines available for SARS-CoV-2, bivalent vaccines covering wild-type (WT) and Omicron BA.1 are also available. However, there is a lack of real-world data on the effectiveness of bivalent vaccines as second boosters on the dominant Omicron sublineages, including BA.2 and BA.5. Methods This prospective longitudinal cohort study was conducted at Toyama University Hospital, a tertiary medical center in Japan. Participants (n = 565) who received the first booster vaccination were followed up until 2 weeks after the second booster dose of the monovalent mRNA-1273 (WT group, n = 168) and bivalent BNT162b2 (WT+BA.1 group, n = 23) vaccines. Participants with previous SARS-CoV-2 infections were excluded from the study. Anti-receptor-binding domain (RBD) antibody levels and neutralizing activity were measured. Vaccine-related symptoms were also assessed using a questionnaire after the second booster dose. Results The anti-RBD antibody levels after the second booster dose in the WT and WT+BA.1 group were similar (median [inter quartile], 26262.0 [16951.0-38137.0] U/mL vs. 24840.0 [14828.0-41460.0] U/mL, respectively). Although the neutralization activity of the pooled sera of the WT+BA.1 group was the lowest against BA.5, the activities against BA.2 and BA.5 were higher than those of the WT group in both pseudotyped and live virus assays. Vaccine-related symptoms, including systemic and local symptoms, were strongly correlated with anti-RBD antibody levels and neutralizing titers with significant differences. Conclusion The second booster dose of the bivalent (WT/Omicron BA.1) vaccine induced higher neutralizing activity against BA.2 and BA.5 than that of the original.
In this cross-sectional study of NFL games attended by a total 1.3 million fans, the presence of large numbers of fans at NFL games was associated with increases in the incidence of COVID-19 cases both in the counties in which these venues were located and contiguous counties. Specifically, NFL games that had 20 000 fans in attendance had 2.23 times the rate of spikes in COVID-19, but NFL games with fewer than 5000 fans in attendance did not generate any spikes.
In 5-11-year-old children mRNA-vaccines are moderately effective against infections with the Omicron variant, but probably still protect well against COVID-19 hospitalisations. Vaccines were reactogenic but generally safe.
November 17, 2022
The BNT162b2 bivalent BA.4/5 COVID-19 vaccine has been authorized to mitigate COVID-19 due to current Omicron and potentially future variants. New sublineages of SARS-CoV-2 Omicron continue to emerge and have acquired additional mutations, particularly in the spike protein, that may lead to improved viral fitness and immune evasion. The present study characterized neutralization activities against new Omicron sublineages BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 after a 4th dose (following three doses of BNT162b2) of either the original monovalent BNT162b2 or the bivalent BA.4/5 booster in individuals >55 years of age. For all participants, the 4th dose of monovalent BNT162b2 vaccine induced a 3.0, 2.9, 2.3, 2.1, 1.8, and 1.5 geometric mean neutralizing titer fold rise (GMFR) against USA/WA1-2020 (a strain isolated in January 2020), BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1, respectively; the bivalent vaccine induced 5.8, 13.0, 11.1, 6.7, 8.7, and 4.8 GMFRs. For individuals without SARS-CoV-2 infection history, BNT162b2 monovalent induced 4.4, 3.0, 2.5, 2.0, 1.5, and 1.3 GMFRs, respectively; the bivalent vaccine induced 9.9, 26.4, 22.2, 8.4, 12.6, and 4.7 GMFRs. These data suggest the bivalent BA.4/5 vaccine is more immunogenic than the original BNT162b2 monovalent vaccine against circulating Omicron sublineages, including BQ.1.1 that is becoming prevalent globally.
Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariants BA.2.75.2 and BQ.1.1 are expected to become predominant in many countries in November 2022. They carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lost any antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remained weakly active. BQ.1.1 was also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals were low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increased these titers, which remained about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increased more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitated their spread in immunized populations and raises concerns about the efficacy of most currently available mAbs.
Background and objective Ecological studies indicate ambient particulate matter ≤2.5mm (PM2.5) air pollution is associated with poorer COVID-19 outcomes. However, these studies cannot account for individual heterogeneity and often have imprecise estimates of PM2.5 exposure. We review evidence from studies using individual-level data to determine whether PM2.5 increases risk of COVID-19 infection, severe disease, and death. Methods Systematic review of case-control and cohort studies, searching Medline, Embase, and WHO COVID-19 up to 30 June 2022. Study quality was evaluated using the Newcastle-Ottawa Scale. Results were pooled with a random effects meta-analysis, with Egger′s regression, funnel plots, and leave-one-out and trim-and-fill analyses to adjust for publication bias. Results N=18 studies met inclusion criteria. A 10μg/m3 increase in PM2.5 exposure was associated with 66% (95% CI: 1.31-2.11) greater odds of COVID-19 infection (N=7) and 127% (95% CI: 1.41-3.66) increase in severe illness (hospitalisation or worse) (N=6). Pooled mortality results (N=5) were positive but non-significant (OR 1.40; 0.94 to 2.10). Most studies were rated "good" quality (14/18 studies), though there were numerous methodological issues; few used individual-level data to adjust for confounders like socioeconomic status (4/18 studies), instead using area-based indicators (12/18 studies) or not adjusting for it (3/18 studies). Most severity (9/10 studies) and mortality studies (5/6 studies) were based on people already diagnosed COVID-19, potentially introducing collider bias. Conclusion There is strong evidence that ambient PM2.5 increases the risk of COVID-19 infection, and weaker evidence of increases in severe disease and mortality.
November 16, 2022
Globally, the spread and severity of COVID-19 have been distinctly non-uniform. Seasonality was suggested as a contributor to regional variability, but the relationship between weather and COVID-19 remains unclear and the focus of attention has been on outdoor conditions. Because humans spend most of their time indoors and because most transmission occurs indoors, we here, instead, investigate the hypothesis that indoor climate—particularly indoor relative humidity (RH)—may be the more relevant modulator of outbreaks. To study this association, we combined population-based COVID-19 statistics and meteorological measurements from 121 countries. We rigorously processed epidemiological data to reduce bias, then developed and experimentally validated a computational workflow to estimate indoor conditions based on outdoor weather data and standard indoor comfort conditions. Our comprehensive analysis shows robust and systematic relationships between regional outbreaks and indoor RH. In particular, we found intermediate RH (40–60%) to be robustly associated with better COVID-19 outbreak outcomes (versus RH < 40% or >60%). Together, these results suggest that indoor conditions, particularly indoor RH, modulate the spread and severity of COVID-19 outbreaks.
November 15, 2022
After COVID-19, patients of all ages and genders had an elevated incidence and relative risk for a new diagnosis of diabetes. Particular attention should be paid during the first 3 months of follow-up after COVID-19 for new-onset diabetes.
Introduction: The uptake of Paxlovid in individuals infected with COVID-19 has been significantly limited by concerns around the Paxlovid rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of Paxlovid rebound in treated and untreated participants with acute COVID-19 infection Methods: We designed a digital, prospective observational study, which included participants who tested positive for COVID-19 and were clinically eligible for Paxlovid. Participants were assigned to a Paxlovid or control group based on their decision to take the medication. Both groups were provided 12 rapid antigen tests and asked to test and answer symptom surveys on a regular frequent schedule for 16 days. Viral rebound based on test results and COVID-19 symptom rebound based on patient reported symptoms were evaluated. Results: Viral rebound incidence was 14.2% in the Paxlovid group (n=127) and 9.3% in the control group (n=43). COVID-19 symptom rebound incidence was higher in the Paxlovid group (18.9%) compared to the control group (7.0%). There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval. Conclusion: This preliminary report of our prospective study suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, we observed a similar rate of rebound in both in the Paxlovid and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.
In this study, contradictions to nirmatrelvir-ritonavir were prevalent in individuals hospitalized with COVID-19, as previously suggested. These findings also alert researchers to the risk of confounding by contraindication in observational studies focused on nirmatrelvir-ritonavir, which may overestimate treatment efficacy if not excluding patients with contraindications to this treatment. In addition, some of the contraindicated medications listed here could be temporarily held in the context of using nirmatrelvir-ritonavir.
November 11, 2022
Although population-based COVID-19–associated hospitalization rates among infants aged <6 months increased in the Omicron variant–predominant periods compared with the Delta variant–predominant period, indicators of the most severe disease among hospitalized infants aged <6 months did not.
Bivalent COVID-19 vaccine booster doses might improve protection against SARS-CoV-2 Omicron sublineages and, along with completion of a primary series in persons who remain unvaccinated, are important to protect against COVID-19, particularly among those persons who are at increased risk for severe illness and death.
November 10, 2022
Messenger RNA (mRNA) is an emerging class of therapeutic agent for the prevention and treatment of a wide range of diseases. The recent success of the two highly efficacious mRNA vaccines produced by Moderna and Pfizer–BioNTech to protect against COVID-19 highlights the huge potential of mRNA technology for revolutionizing life science and medical research. Challenges related to mRNA stability and immunogenicity, as well as in vivo delivery and the ability to cross multiple biological barriers, have been largely addressed by recent progress in mRNA engineering and delivery. In this Review, we present the latest advances and innovations in the growing field of mRNA nanomedicine, in the context of ongoing clinical translation and future directions to improve clinical efficacy.
Numerous safe and effective COVID-19 vaccines have been developed worldwide that utilize various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S, as compared to vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by RBD-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.
Long-term health sequelae of the Coronavirus Disease 2019 (COVID-19) are a major public health concern. However, evidence on post-acute COVID-19 syndrome (post-COVID-19) is still limited, particularly for children and adolescents. Utilizing comprehensive healthcare data on approximately 46% of the German population, we investigated post-COVID-19-associated morbidity in children/adolescents and adults.
Wildlife reservoirs of broad-host-range viruses have the potential to enable evolution of viral variants that can emerge to infect humans. In North America, there is phylogenomic evidence of continual transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to white-tailed deer (Odocoileus virginianus) through unknown means, but no evidence of transmission from deer to humans. We carried out an observational surveillance study in Ontario, Canada during November and December 2021 (n = 300 deer) and identified a highly divergent lineage of SARS-CoV-2 in white-tailed deer (B.1.641). This lineage is one of the most divergent SARS-CoV-2 lineages identified so far, with 76 mutations (including 37 previously associated with non-human mammalian hosts). From a set of five complete and two partial deer-derived viral genomes we applied phylogenomic, recombination, selection and mutation spectrum analyses, which provided evidence for evolution and transmission in deer and a shared ancestry with mink-derived virus. Our analysis also revealed an epidemiologically linked human infection. Taken together, our findings provide evidence for sustained evolution of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission.
First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.
Some patients who have recovered from an infection have reported transient or even lasting cognitive dysfunction. This includes patients who have been infected with SARS-CoV-2, many of whom, including those with mild disease, have reported deficits in attention, executive functioning, language, processing speed, and memory — symptoms collectively referred to as “brain fog.” Together with increased incidence of anxiety, depression, sleep disorder, and fatigue, this syndrome of cognitive impairment contributes substantially to the morbidity of post–Covid-19 conditions (also called “long Covid”).
November 9, 2022
In this prospective cohort study, a third dose of the BNT162b2 vaccine led to an improved and sustained immunologic response as compared with two doses, but the additional immunologic advantage of the fourth dose was much smaller and had waned completely by 13 weeks after vaccination. This finding correlated with waning vaccine effectiveness among recipients of a fourth dose, which culminated in no substantial additional effectiveness over a third dose at 15 to 26 weeks after vaccination. These results suggest that the fourth dose, and possibly future boosters, should be timed wisely to coincide with disease waves or to be available seasonally, similar to the influenza vaccine. Whether multivalent booster doses will result in longer durability remains to be seen.
Among school districts in the greater Boston area, the lifting of masking requirements was associated with an additional 44.9 Covid-19 cases per 1000 students and staff during the 15 weeks after the statewide masking policy was rescinded.
In this cohort study of 585 maternal-newborn dyads, maternal and cord blood IgG antibody levels were higher after vaccination compared with after infection. An association was observed between time from infection or vaccination to delivery and transfer ratio.
November 8, 2022
The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.
November 1, 2022
The emergence of the highly divergent SARS-CoV-2 Omicron variant has jeopardized the efficacy of vaccines based on the ancestral spike. The bivalent COVID-19 mRNA booster vaccine within the United States is comprised of the ancestral and the Omicron BA.5 spike. Since its approval and distribution, additional Omicron subvariants have been identified with key mutations within the spike protein receptor binding domain that are predicted to escape vaccine sera. Of particular concern is the R346T mutation which has arisen in multiple subvariants, including BA.2.75.2 and BQ.1.1. Using a live virus neutralization assay, we evaluated serum samples from individuals who had received either one or two monovalent boosters or the bivalent booster to determine neutralizing activity against wild-type (WA1/2020) virus and Omicron subvariants BA.1, BA.5, BA.2.75.2, and BQ.1.1. In the one monovalent booster cohort, relative to WA1/2020, we observed a reduction in neutralization titers of 9-15-fold against BA.1 and BA.5 and 28-39-fold against BA.2.75.2 and BQ.1.1. In the BA.5-containing bivalent booster cohort, the neutralizing activity improved against all the Omicron subvariants. Relative to WA1/2020, we observed a reduction in neutralization titers of 3.7- and 4-fold against BA.1 and BA.5, respectively, and 11.5- and 21-fold against BA.2.75.2 and BQ.1.1, respectively. These data suggest that the bivalent mRNA booster vaccine broadens humoral immunity against the Omicron subvariants.
Background: Epidemiological evidence for immune imprinting was investigated in immune histories related to vaccination in Qatar from onset of the omicron wave, on December 19, 2021, through September 15, 2022. Methods: Matched, retrospective, cohort studies were conducted to investigate differences in incidence of SARS-CoV-2 reinfection in the national cohort of persons who had a primary omicron infection, but different vaccination histories. History of primary-series (two-dose) vaccination was compared to that of no vaccination, history of booster (three-dose) vaccination was compared to that of two-dose vaccination, and history of booster vaccination was compared to that of no vaccination. Associations were estimated using Cox proportional-hazards regression models. Results: The adjusted hazard ratio comparing incidence of reinfection in the two-dose cohort to that in the unvaccinated cohort was 0.43 (95% CI: 0.38-0.48). The adjusted hazard ratio comparing incidence of reinfection in the three-dose cohort to that in the two-dose cohort was 1.38 (95% CI: 1.16-1.65). The adjusted hazard ratio comparing incidence of reinfection in the three-dose cohort to that in the unvaccinated cohort was 0.53 (95% CI: 0.44-0.63). All adjusted hazard ratios appeared stable over 6 months of follow-up. Divergence in cumulative incidence curves in all comparisons increased markedly when incidence was dominated by BA.4/BA.5 and BA.2.75*. No reinfection in any cohort progressed to severe, critical, or fatal COVID-19. Conclusions: History of primary-series vaccination enhanced immune protection against omicron reinfection, but history of booster vaccination compromised protection against omicron reinfection. These findings do not undermine the short-term public health utility of booster vaccination.
Durable spike-specific T-cell responses after different COVID-19 vaccination regimens are not further enhanced by booster vaccination
Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
October 31, 2022
Importance: The origin of highly divergent "cryptic" SARS-CoV-2 Spike sequences, which appear in wastewater but not clinical samples, is unknown. These wastewater sequences have harbored many of the same variants that later emerged in Omicron. If these enigmatic sequences are human-derived and transmissible, they could both be a source of future variants and a valuable tool for forecasting sequences that should be incorporated into vaccines and therapeutics. Objective: To determine whether enigmatic SARS-CoV-2 lineages detected in wastewater have a human or non-human (i.e., animal) source. Design: On January 11, 2022, an unusual Spike sequence was detected in municipal wastewater from a metropolitan area. Over the next four months, more focused wastewater sampling resolved the source of this variant. Setting: This study was performed in Wisconsin, United States, which has a comprehensive program for detecting SARS-CoV-2 in wastewater. Participants: Composite wastewater samples were used for this study; therefore, no individuals participated. Main Outcome(s) and Measure(s): The primary outcome was to determine the host(s) responsible for shedding this variant in wastewater. Both human and non-human hosts were plausible candidates at the study's outset. Results: The presence of the cryptic virus was narrowed from a municipal wastewater sample (catchment area >100,000 people) to an indoor wastewater sample from a single facility (catchment area ~30 people), indicating the human origin of this virus. Extraordinarily high concentrations of viral RNA (~520,000,000 genome copies / L and ~1,600,000,000 genome copies / L in June and August 2022, respectively) were detected in the indoor wastewater sample. The virus sequence harbored a combination of fixed nucleotide substitutions previously observed only in Pango lineage B.1.234, a variant that circulated at low levels in Wisconsin from October 2020 to February 2021. Conclusions and Relevance: High levels of persistent SARS-CoV-2 shedding from the gastrointestinal tract of an infected individual likely explain the presence of evolutionarily advanced, "cryptic variants" observed in some wastewater samples.
October 30, 2022
Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA. 5. Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such convergent evolution and its impact on humoral immunity remain unclear. Here, we demonstrate that these convergent mutations can cause striking evasion of neutralizing antibody (NAb) drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability. BQ.1.1.10, BA.4.6.3, XBB, and CH. 1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents. Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of NAbs and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted convergent evolution. Moreover, we showed that the convergent RBD mutations could be accurately inferred by integrated deep mutational scanning (DMS) profiles, and the evolution trends of BA.2.75/BA.5 subvariants could be well-simulated through constructed convergent pseudovirus mutants. Together, our results suggest current herd immunity and BA.5 vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be highly prioritized, and the constructed mutants could help to examine their effectiveness in advance.
October 26, 2022
A primary focus of research on conspiracy theories has been understanding the psychological characteristics that predict people’s level of conspiracist ideation. However, the dynamics of conspiracist ideation—i.e., how such tendencies change over time—are not well understood. To help fill this gap in the literature, we used data from two longitudinal studies (Study 1 N = 107; Study 2 N = 1,037) conducted during the COVID-19 pandemic. We find that greater belief in COVID-19 conspiracy theories at baseline predicts both greater endorsement of a novel real-world conspiracy theory involving voter fraud in the 2020 American Presidential election (Study 1) and increases in generic conspiracist ideation over a period of several months (Studies 1 and 2). Thus, engaging with real-world conspiracy theories appears to act as a gateway, leading to more general increases in conspiracist ideation. Beyond enhancing our knowledge of conspiracist ideation, this work highlights the importance of fighting the spread of conspiracy theories.
Our findings in two high-risk populations suggest that mRNA vaccination and previous infection were effective against omicron infection, with lower estimates among those infected before the period of delta predominance. Three vaccine doses offered significantly more protection than two doses, including among previously infected persons.
October 25, 2022
Our results suggest that two doses of BNT162b2 offered little protection against all BA.4/5 outcomes measured, including hospital admission. A booster (third or fourth dose) did provide protection against BA.4/5, but this protection probably wanes after 3 months against milder outcomes like outpatient, urgent care, or emergency department encounters and after roughly 6 months against BA.4/5-related hospitalisation.
Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.
Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.
October 24, 2022
Regular physical activity was associated with improved vaccine effectiveness against COVID-19 hospitalisation, with higher levels of physical activity associated with greater vaccine effectiveness. Physical activity enhances vaccine effectiveness against severe COVID-19 outcomes and should be encouraged by greater public health messaging.
The SARS-CoV-2 Omicron variant and its numerous sub-lineages have exhibited a striking ability to evade humoral immune responses induced by prior vaccination or infection. The Food and Drug Administration (FDA) has recently granted Emergency Use Authorizations (EUAs) to new bivalent formulations of the original Moderna and Pfizer mRNA SARS-CoV-2 vaccines that target both the ancestral strain as well as the Omicron BA.4/BA.5 variant. Despite their widespread use as a vaccine boost, little is known about the antibody responses induced in humans. Here, we collected sera from several clinical cohorts: individuals after three or four doses of the original monovalent mRNA vaccines, individuals receiving the new bivalent vaccines as a fourth dose, and individuals with BA.4/BA.5 breakthrough infection following mRNA vaccination. Using pseudovirus neutralization assays, these sera were tested for neutralization against an ancestral SARS-CoV-2 strain, several Omicron sub-lineages, and several related sarbecoviruses. At ~3-5 weeks post booster shot, individuals who received a fourth vaccine dose with a bivalent mRNA vaccine targeting BA.4/BA.5 had similar neutralizing antibody titers as those receiving a fourth monovalent mRNA vaccine against all SARS-CoV-2 variants tested, including BA.4/BA.5. Those who received a fourth monovalent vaccine dose had a slightly higher neutralizing antibody titers than those who received the bivalent vaccine against three related sarbecoviruses: SARS-CoV, GD-Pangolin, and WIV1. When given as a fourth dose, a bivalent mRNA vaccine targeting Omicron BA.4/BA.5 and an ancestral SARS-CoV-2 strain did not induce superior neutralizing antibody responses in humans, at the time period tested, compared to the original monovalent vaccine formulation.
October 23, 2022
For now, the best defense we have against the BQ.1.1-led wave is to get a booster. It will markedly raise neutralizing antibodies and our cellular immune response, and just-in-time to broaden our immunity to be ready for BQ.1.1 and related variants with marked immune evasiveness. As you well know, it takes a couple of weeks to get the immune response built, so this is the right time to get it done. It will help prevent severe Covid for at least 4-5 months ahead. Be ready. The pandemic isn’t over—yet. Preserve your health and that of your family, friends, and network.
Immune memory develops during primary infections to protect from future exposures to the same pathogen. Vaccines mimic this response and induce immune memory that protects from severe disease, and in some cases, from symptomatic infection. If the pathogen is eliminated before it can replicate, natural and vaccine-induced immune memory can prevent the establishment of the infection, mediating sterilizing immunity. Sterilizing immunity protects the individual and prevents transmission to new hosts thereby contributing to protection at a population level. Here, we describe the basic concepts of sterilizing immunity and discuss its relevance for protection in the context of SARS-CoV-2.
October 22, 2022
Previous infection with pre-Omicron variants was the strongest risk factor for reporting PASC symptoms in this HCW cohort. A definite influence of prior vaccination on the prevention of PASC after Omicron BA.1 infection was not measurable.
October 17, 2022
Over 2 years have passed since the start of the COVID-19 pandemic, which has claimed millions of lives. Unlike the early days of the pandemic, when management decisions were based on extrapolations from in vitro data, case reports and case series, clinicians are now equipped with an armamentarium of therapies based on high-quality evidence. These treatments are spread across seven main therapeutic categories: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin–angiotensin–aldosterone system and vitamins. For each of these treatments, the patient population characteristics and clinical settings in which they were studied are important considerations. Although few direct comparisons have been performed, the evidence base and magnitude of benefit for anti-inflammatory and antiviral agents clearly outweigh those of other therapeutic approaches such as vitamins. The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies. Importantly, patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. Here, we examine the clinical evidence for these therapies through a kidney medicine lens.
Salivary glands act as virus reservoirs in various infectious diseases and have been reported to be targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the mechanisms underlying infection and replication in salivary glands are still enigmatic due to the lack of proper in vitro models. Here, we show that human induced salivary glands (hiSGs) generated from human induced pluripotent stem cells can be infected with SARS-CoV-2. The hiSGs exhibit properties similar to those of embryonic salivary glands and are a valuable tool for the functional analysis of genes during development. Orthotopically transplanted hiSGs can be engrafted at a recipient site in mice and show a mature phenotype. In addition, we confirm SARS-CoV-2 infection and replication in hiSGs. SARS-CoV-2 derived from saliva in asymptomatic individuals may participate in the spread of the virus. hiSGs may be a promising model for investigating the role of salivary glands as a virus reservoir.
The COVID-19 pandemic triggered an unprecedented rise in mortality that translated into life expectancy losses around the world, with only a few exceptions. We estimate life expectancy changes in 29 countries since 2020 (including most of Europe, the United States and Chile), attribute them to mortality changes by age group and compare them with historic life expectancy shocks. Our results show divergence in mortality impacts of the pandemic in 2021. While countries in western Europe experienced bounce backs from life expectancy losses of 2020, eastern Europe and the United States witnessed sustained and substantial life expectancy deficits. Life expectancy deficits during fall/winter 2021 among people ages 60+ and <60 were negatively correlated with measures of vaccination uptake across countries (r60+ = −0.86; two-tailed P < 0.001; 95% confidence interval, −0.94 to −0.69; r<60 = −0.74; two-tailed P < 0.001; 95% confidence interval, −0.88 to −0.46). In contrast to 2020, the age profile of excess mortality in 2021 was younger, with those in under-80 age groups contributing more to life expectancy losses. However, even in 2021, registered COVID-19 deaths continued to account for most life expectancy losses.
October 14, 2022
Adverse Childhood Experiences During the COVID-19 Pandemic and Associations with Poor Mental Health and Suicidal Behaviors Among High School Students — Adolescent Behaviors and Experiences Survey, United States, January–June 2021
The prevalences of poor current mental health and past-year suicide attempts among adolescents reporting four or more ACEs during the COVID-19 pandemic were four and 25 times as high as those without ACEs, respectively. Exposure to specific ACE types (e.g., emotional abuse) were associated with higher prevalences of poor mental health and suicidal behaviors.
October 12, 2022
With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29–3.58), palpitations (OR 2.51, OR 2.36–2.66), chest pain (OR 2.09, 95% CI 1.96–2.23), and confusion (OR 2.92, 95% CI 2.78–3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.
October 11, 2022
Booster mRNA vaccination was highly effective in preventing death and moderately effective in preventing infection and hospitalization for up to 4 months after administration in the Omicron era. Increased uptake of booster vaccination, which is currently suboptimal, should be pursued to limit the morbidity and mortality of SARS-CoV-2 infection, especially in persons with high comorbidity burden.
Some countries are now offering COVID vaccines for children as young as six months. Nature looks at how effective they are and why more kids haven’t had them.
October 10, 2022
Daily use of lateral flow devices by contacts of confirmed COVID-19 cases to enable exemption from isolation compared with standard self-isolation to reduce onward transmission of SARS-CoV-2 in England: a randomised, controlled, non-inferiority trial
DCT with 24 h exemption from self-isolation for essential activities appears to be non-inferior to self-isolation. This study, which provided evidence for the UK Government's daily lateral flow testing policy for vaccinated contacts of COVID-19 cases, indicated that daily testing with LFDs could allow individuals to reduce the risk of onward transmission while minimising the adverse effects of self-isolation. Although contacts in England are no longer required to isolate, the findings will be relevant for future policy decisions around COVID-19 or other communicable infections.
In this cross-sectional study of 63 277 participants conducted at a walk-up community testing site, patients more commonly reported COVID-19 upper respiratory tract symptoms during the Omicron BA.1 period than the pre-Delta and Delta periods, with differences by vaccination status and age. During the Omicron BA.1 period, 5 days after symptom onset, 80% of participants remained positive via a rapid antigen test.
This observational analysis involved bayesian meta-regression and pooling of 54 studies and 2 medical record databases with data for 1.2 million individuals (from 22 countries) who had symptomatic SARS-CoV-2 infection. The modeled estimated proportion with at least 1 of the 3 self-reported Long COVID symptom clusters 3 months after symptomatic SARS-CoV-2 infection was 6.2%, including 3.7% for ongoing respiratory problems, 3.2% for persistent fatigue with bodily pain or mood swings, and 2.2% for cognitive problems after adjusting for health status before COVID-19.
October 7, 2022
Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation, and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme 2 (ACE2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized patients with COVID-19 developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or receptor-binding domain (RBD), to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.
October 6, 2022
Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impacts on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.
October 5, 2022
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins, particularly those containing post-translational modifications required for transcriptional regulation. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation. ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.
Overall, our results show that serum from COVID-19 patients with delirium can negatively affect hippocampal-dependent neurogenic processes, and that this effect is mediated by IL6-induced production of the downstream inflammatory cytokines IL12 and IL13, which are ultimately responsible for the detrimental cellular outcomes.
October 4, 2022
Continuous evolution of Omicron has led to numerous subvariants that exhibit growth advantage over BA.5. Such rapid and simultaneous emergence of variants with enormous advantages is unprecedented. Despite their rapidly divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots, including R346, K356, K444, L452, N460K and F486. The driving force and destination of such convergent evolution and its impact on humoral immunity established by vaccination and infection remain unclear. Here, we demonstrate that these convergent mutations can cause striking evasion of convalescent plasma, including those from BA.5 breakthrough infection, and existing antibody drugs, including Evusheld and Bebtelovimab. BR.2, CA.1, BQ.1.1, and especially XBB, are the most antibody-evasive strain tested, far exceeding BA.5 and approaching SARS-CoV-1 level. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from BA.2 and BA.5 breakthrough-infection convalescents. Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions in the epitope diversity of neutralizing antibodies and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted the convergent RBD evolution. Additionally, the precise convergent RBD mutations and evolution trends of BA.2.75/BA.5 subvariants could be inferred by integrating the neutralization-weighted DMS profiles of mAbs from various immune histories (3051 mAbs in total). Moreover, we demonstrated that as few as five additional convergent mutations based on BA.5 or BA.2.75 could completely evade most plasma samples, including those from BA.5 breakthrough infection, while retaining sufficient hACE2-binding affinity. These results suggest that current herd immunity and BA.5 vaccine boosters may not provide sufficiently broad protection against infection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be of high priority, and the constructed convergent mutants could serve to examine their effectiveness in advance.
Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is the first protease inhibitor against the SARS-CoV-2 protease 3CLpro that has been licensed for clinical use. To identify mutations that confer resistance to this protease inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) that expressed a polyprotein composed of the VSV glycoprotein G, the SARS-CoV-2 3CLpro, and the VSV polymerase L. Viral replication was thus dependent on the autocatalytic processing of this precursor protein by 3CLpro and release of the functional viral polymerase L, and replication of this chimeric VSV was effectively inhibited by nirmatrelvir. Using this system, we applied nirmatrelvir to select for resistance mutations. Resistance was confirmed by retesting nirmatrelvir against the selected mutations in an additional VSV-based systems, in an independently developed cellular system, in a biochemical assay, and in a recombinant SARS-CoV-2 system. We demonstrate that some mutants are cross-resistant to ensitrelvir and GC376, whereas others are less resistant to these compounds. Furthermore, we found that most of these resistance mutations already existed in SARS-CoV-2 sequences that have been deposited in the NCBI and GISAID databases, indicating that these mutations were present in circulating SARS-CoV-2 strains.
In this population-based surveillance, we found that myocarditis/pericarditis 0 to 7 days after mRNA vaccination in persons aged 5 to 39 years occurred in approximately 1 in 200 000 doses after the first dose and 1 in 30 000 doses after second dose of the primary series, and 1 in 50 000 doses after the first booster. The incidence varied markedly by age and sex, however, with a disproportionate number of cases occurring in male persons, notably among adolescents after dose 2 and first boosters.
October 3, 2022
The Coronavirus Disease 2019 (COVID-19) pandemic has threatened global mental health, both indirectly via disruptive societal changes and directly via neuropsychiatric sequelae after SARS-CoV-2 infection. Despite a small increase in self-reported mental health problems, this has (so far) not translated into objectively measurable increased rates of mental disorders, self-harm or suicide rates at the population level. This could suggest effective resilience and adaptation, but there is substantial heterogeneity among subgroups, and time-lag effects may also exist. With regard to COVID-19 itself, both acute and post-acute neuropsychiatric sequelae have become apparent, with high prevalence of fatigue, cognitive impairments and anxiety and depressive symptoms, even months after infection. To understand how COVID-19 continues to shape mental health in the longer term, fine-grained, well-controlled longitudinal data at the (neuro)biological, individual and societal levels remain essential. For future pandemics, policymakers and clinicians should prioritize mental health from the outset to identify and protect those at risk and promote long-term resilience.
There are currently many more questions than answers regarding long COVID and the evolving role of rheumatology in treating this patient population. Overall, given the many unknowns surrounding the syndrome, rheumatologists are well positioned to contribute to basic and clinical research, as well as to care pathways for patients with long COVID, including patients with underlying rheumatic diseases and those with rheumatic complaints. At present, rheumatologists and other subspecialists are limited to some of the foremost tools in our armamentarium (ones that we have long offered to legions of patients with incurable chronic diseases): careful listening, providing validation, and offering empathy. These tools, although in themselves not curative, for now could help patients with long COVID.
October 1, 2022
Studies have reported reduced natural SARS-CoV-2 infection- and vaccine-induced neutralization against Omicron BA.4/BA.5 compared with earlier Omicron subvariants. We conducted a test-negative case–control study evaluating mRNA-1273 vaccine effectiveness (VE) against infection and hospitalization with Omicron subvariants. The study included 30,809 SARS-CoV-2 positive and 92,427 SARS-CoV-2 negative individuals aged ≥18 years tested during 1/1/2022-6/30/2022. While 3-dose VE against BA.1 infection was high and waned slowly, VE against BA.2, BA.2.12.1, BA.4, and BA.5 infection was initially moderate to high (61.0%-90.6% 14-30 days post third dose) and waned rapidly. The 4-dose VE against infection with BA.2, BA.2.12.1, and BA.4 ranged between 64.3%-75.7%, and was low (30.8%) against BA.5 14-30 days post fourth dose, disappearing beyond 90 days for all subvariants. The 3-dose VE against hospitalization for BA.1, BA.2, and BA.4/BA.5 was 97.5%, 82.0%, and 72.4%, respectively; 4-dose VE against hospitalization for BA.4/BA.5 was 88.5%. Evaluation of the updated bivalent booster is warranted.
September 28, 2022
Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at the time of seroconversion has the potential to identify which individuals are more likely to suffer from persistent symptoms related to SARS-CoV-2 infection.
September 26, 2022
Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC. A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fcγ receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.
In a cohort study of 10.6 million North Carolina residents from March 2020 to June 2022, receipt of a primary COVID-19 vaccine series compared with being unvaccinated, receipt of a booster compared with primary vaccination, and prior SARS-CoV-2 infection compared with no prior infection were all significantly associated with lower risk of SARS-CoV-2 infection and resulting hospitalization and death. The estimates for the associated protection decreased over time, especially for the outcome of infection, and varied by type of circulating variant. Receipt of COVID-19 vaccines and boosters, as well as prior SARS-CoV-2 infection, were associated with protection against SARS-CoV-2 infection (including Omicron) and severe COVID-19 outcomes, although the associated protection waned over time.
September 23, 2022
In this study, new T1D diagnoses were more likely to occur among pediatric patients with prior COVID-19 than among those with other respiratory infections (or with other encounters with health systems). Respiratory infections have previously been associated with onset of T1D,6 but this risk was even higher among those with COVID-19 in our study, raising concern for long-term, post–COVID-19 autoimmune complications among youths. Study limitations include potential biases owing to the observational and retrospective design of the electronic health record analysis, including the possibility of misclassification of diabetes as type 1 vs type 2, and the possibility that additional unidentified factors accounted for the association. Results should be confirmed in other populations. The increased risk of new-onset T1D after COVID-19 adds an important consideration for risk-benefit discussions for prevention and treatment of SARS-CoV-2 infection in pediatric populations.
Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.
September 21, 2022
Severity of COVID-19 shows an extraordinary correlation with increasing age. We generated a mouse model for severe COVID-19 and show that the age-dependent disease severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) immunity. Aggravated disease in aged mice was characterized by a diminished IFN-γ response and excessive virus replication. Accordingly, adult IFN-γ receptor-deficient mice phenocopied the age-related disease severity, and supplementation of IFN-γ reversed the increased disease susceptibility of aged mice. Further, we show that therapeutic treatment with IFN-λ in adults and a combinatorial treatment with IFN-γ and IFN-λ in aged Ifnar1−/− mice was highly efficient in protecting against severe disease. Our findings provide an explanation for the age-dependent disease severity and clarify the nonredundant antiviral functions of type I, II, and III IFNs during SARS-CoV-2 infection in an age-dependent manner. Our data suggest that highly vulnerable individuals could benefit from immunotherapy combining IFN-γ and IFN-λ.
September 20, 2022
BNT162b2-vaccinated individuals after Omicron BA.1 breakthrough infection have strong serum neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 variants of concern (VOCs), yet less against the highly contagious Omicron sublineages BA.4 and BA.5 that have displaced previous variants. As the latter sublineages are derived from Omicron BA.2, we characterized serum neutralizing activity of COVID-19 mRNA vaccine triple-immunized individuals who experienced BA.2 breakthrough infection. We demonstrate that sera of these individuals have broadly neutralizing activity against previous VOCs as well as all tested Omicron sublineages, including BA.2 derived variants BA.2.12.1, BA.4/BA.5. Furthermore, applying antibody depletion we showed that neutralization of BA.2 and BA.4/BA.5 sublineages by BA.2 convalescent sera is driven to a significant extent by antibodies targeting the N-terminal domain (NTD) of the spike glycoprotein. However, neutralization by Omicron BA.1 convalescent sera depends exclusively on antibodies targeting the receptor binding domain (RBD). These findings suggest that exposure to Omicron BA.2, in contrast to BA.1 spike glycoprotein, triggers significant NTD specific recall responses in vaccinated individuals and thereby enhances the neutralization of BA.4/BA.5 sublineages. Given the current epidemiology with a predominance of BA.2 derived sublineages like BA.4/BA.5 and rapidly ongoing evolution, these findings helped to inform development of our Omicron BA.4/BA.5-adapted vaccine.
High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.
September 19, 2022
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires fusion of viral and host membranes, mediated by the viral spike glycoprotein (S). Due to the importance of viral membrane fusion, S has been a popular target for developing vaccines and therapeutics. We discovered a simple peptide that inhibits infection by all major variants of SARS-CoV-2 with nanomolar efficacies. In marked contrast, widely used shorter peptides that lack a key N-terminal extension are about 100 times less potent than this peptide. Our results suggest that a simple peptide with a suitable sequence can be a potent and cost-effective therapeutic against coronavirus disease 2019, and they provide new insights into the virus entry mechanism.
September 16, 2022
The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns.
Several sublineages of omicron have emerged with additional mutations that may afford further antibody evasion. Here, we characterise the sensitivity of emerging omicron sublineages BA.2.75.2, BA.4.6, and BA.2.10.4 to antibody-mediated neutralisation, and identify extensive escape by BA.2.75.2. BA.2.75.2 was resistant to neutralisation by Evusheld (tixagevimab + cilgavimab), but remained sensitive to bebtelovimab. In recent serum samples from blood donors in Stockholm, Sweden, BA.2.75.2 was neutralised, on average, five-fold less potently than BA.5, representing the most neutralisation resistant variant evaluated to date. These data raise concerns that BA.2.75.2 may effectively evade humoral immunity in the population.
In-hospital mortality among patients hospitalized primarily for COVID-19 decreased from 15.1% (Delta period) to 4.9% (later Omicron period; April–June 2022), despite high-risk patient groups representing a larger proportion of hospitalizations. During the later Omicron period, the majority of in-hospital deaths occurred among adults aged ≥65 years (81.9%) and persons with three or more underlying medical conditions (73.4%).
September 15, 2022
Older people who were infected with COVID-19 show a substantially higher risk – as much as 50% to 80% higher than a control group – of developing Alzheimer’s disease within a year, according to a study of more than 6 million patients 65 and older. In a study published in the Journal of Alzheimer’s Disease, researchers report that people 65 and older who contracted COVID-19 were more prone to developing Alzheimer’s disease in the year following their COVID diagnosis. And the highest risk was observed in women at least 85 years old.
These findings suggest that prolonged symptoms may persist in a proportion of COVID-19 survivors for 2 years after SARS-CoV-2 infection.
Overall, we have identified immune profiles of severe COVID-19 patients associated with full recovery from disease or increased risk of mortality. We propose that these differences in COVID Group 1 and Group 2 patients could be employed to better allocate healthcare resources and design targeted treatment plans to better care for individuals who are at the greatest risk of worse outcomes. Whereas optimal medical care and appropriate ventilator management may be sufficient in patients with immune profiles similar to COVID Group 1, patients with immune profiles similar to COVID Group 2 could benefit from more aggressive therapeutic intervention targeting the dysregulated innate immune response. In particular, drugs targeting Type I IFNs, cytokines, such as IL6 or TNF, or myeloid chemokines such as IP-10 or MCP1 could be effective treatments for these individuals. Our work highlights the heterogeneity among severe cases of COVID-19 and the need for better characterization of hospitalized individuals to determine effective strategies to mitigate pathogenic immune processes that are dysregulated in the most at-risk patients. Furthermore, infected individuals with the potential to progress to severe disease should be identified as early as possible to allow for better resource allocation and early individualized therapies.
Although our results await confirmation with authentic virus and primary cells, BA.2.75 might be more adept than BA.2 at infecting the lower airways and inducing cell–cell fusion, which could indicate an elevated intrinsic pathogenic potential. Moreover, we identified bebtelovimab (also known as LYCoV-1404) and the cilgavimab–tixagevimab antibody combination as treatments for BA.2.75-infected individuals. The observation that BA.2.75 and BA.4/BA.5 display lower neutralisation sensitivity compared with BA.2 suggests that this trait might enable them to outcompete BA.2 in subpopulations with vaccination or infection-induced immunity. Finally, our data confirm and extend the findings of two recent studies and provide evidence that three vaccine doses are required to induce potent neutralising activity against BA.2.75, similar to what has been shown for other omicron sublineages.
In the EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) trial of nirmatrelvir–ritonavir, which was conducted during a period when the B.1.617.2 (delta) variant was predominant in the United States, investigators noted the occurrence of virologic rebound in some patients regardless of whether they had received antiviral treatment. In contrast, in a study involving National Basketball Association personnel who were under infection surveillance and who were not treated with nirmatrelvir–ritonavir, Ct values of less than 30 were not detected for the omicron variant between day 11 and day 15. Here, our evaluation includes a convenience sample in which 5 of 13 cases occurred within two families, which suggests that rebound after nirmatrelvir–ritonavir therapy is not uncommon. Additional data are needed to determine the cause, frequency, duration, and spectrum of rebound symptoms along with the relation to antiviral treatment. During rebound, the findings of a higher viral load, the ease of viral culture, and possible viral transmission suggest that patients are likely to be contagious during the rebound period.
September 14, 2022
We observed a high burden of long COVID and substantial variability in prevalence of SARS-CoV-2. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.
SARS-CoV-2 has extensively mutated creating variants of concern (VOC) resulting in global infection surges. The Omicron VOC reinfects individuals exposed to earlier variants of SARS-CoV-2 at a higher frequency than previously seen for non-Omicron VOC. An analysis of the sub-lineages associated with an Omicron primary infection and Omicron reinfection reveals that the incidence of Omicron-Omicron reinfections is occurring over a shorter time interval than seen after a primary infection with a non-Omicron VOC. Our analysis suggests that a single infection from SARS-CoV-2 may not generate the protective immunity required to defend against reinfections from emerging Omicron lineages. This analysis was made possible by Next-generation sequencing (NGS), specifically of a Danish cohort with clinical metadata on both infections occurring in the same individual. We suggest that the continuation of COVID-19 NGS and inclusion of clinical metadata is necessary to ensure effective surveillance of SARS-CoV-2 genomics, assist in treatment and vaccine development, and guide public health recommendations.
As of May 31, 2022, there were 6·9 million reported deaths and 17·2 million estimated deaths from COVID-19, as reported by the Institute for Health Metrics and Evaluation (IHME; throughout the report, we rely on IHME estimates of infections and deaths; note that the IHME gives an estimated range, and we refer to the mean estimate). This staggering death toll is both a profound tragedy and a massive global failure at multiple levels. Too many governments have failed to adhere to basic norms of institutional rationality and transparency, too many people—often influenced by misinformation—have disrespected and protested against basic public health precautions, and the world's major powers have failed to collaborate to control the pandemic.
Thus, after either two doses or three doses of the BNT162b2 vaccine, we found rapid waning of vaccine effectiveness against the current sublineages of the omicron variant with respect to protection against hospitalization. Our data indicate that boosting maintains vaccine effectiveness against severe disease caused by the current omicron sublineages, although the evidence of rapid waning of durability indicates the need for regular boosting as early as 4 months after the last dose or the need for vaccines to incorporate variants of concern to maintain protection.
Taken together, these findings suggest that wild-type SARS-CoV-2 spike-specific mucosal IgA is protective against omicron infection. Further studies are warranted to determine whether vaccines that induce a combination of mucosal and systemic immune responses would confer stronger protection than intramuscular vaccines.
As additional SARS-CoV-2 variants evolve, vaccines that maintain efficacy across these variants become increasingly important. Here, Hajnik et al. tested whether an mRNA vaccine encoding the more conserved nucleocapsid (N) protein of SARS-CoV-2 can elicit responses that protect against SARS-CoV-2 challenge in vivo. mRNA-N vaccination alone elicited immune responses that could control SARS-CoV-2. Furthermore, combining mRNA-N vaccination with an mRNA vaccine encoding the spike protein (mRNA-S+N) induced better viral control than mRNA-S vaccination alone, including against the Omicron variant. Thus, incorporating the N protein into SARS-CoV-2 vaccines may promote protection against existing and future variants.
September 13, 2022
After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4 and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.
The emergence of SARS-CoV-2 variants in the Omicron lineage with large numbers of substitutions in the spike protein that can evade antibody neutralization has resulted in diminished vaccine efficacy and persistent transmission. One strategy to broaden vaccine-induced immunity is to administer bivalent vaccines that encode for spike proteins from both historical and newly-emerged variant strains. Here, we evaluated the immunogenicity and protective efficacy of two bivalent vaccines that recently were authorized for use in Europe and the United States and contain two mRNAs encoding Wuhan-1 and either BA.1 (mRNA-1273.214) or BA.4/5 (mRNA-1273.222) spike proteins. As a primary immunization series in BALB/c mice, both bivalent vaccines induced broader neutralizing antibody responses than the constituent monovalent vaccines (mRNA-1273 [Wuhan-1], mRNA-1273.529 [BA.1], and mRNA-1273-045 [BA.4/5]). When administered to K18-hACE2 transgenic mice as a booster at 7 months after the primary vaccination series with mRNA-1273, the bivalent vaccines induced greater breadth and magnitude of neutralizing antibodies compared to an mRNA-1273 booster. Moreover, the response in bivalent vaccine-boosted mice was associated with increased protection against BA.5 infection and inflammation in the lung. Thus, boosting with bivalent Omicron-based mRNA-1273.214 or mRNA-1273.222 vaccines enhances immunogenicity and protection against currently circulating SARS-CoV-2 strains.
This study, based on comprehensive health care administrative data, provides evidence that a fourth mRNA vaccine dose confers additional sustained protection against hospitalization and severe disease from COVID-19 in an elderly Asian population during Omicron variant epidemic.
September 12, 2022
Immunocompromised individuals and particularly those with hematologic malignancies are at increased risk for SARS-CoV-2-associated morbidity and mortality due to immunologic deficits that limit prevention, treatment, and clearance of the virus. Understanding the natural history of viral infections in people with impaired immunity due to underlying conditions, immunosuppressive therapy, or a combination thereof has emerged as a critical area of investigation during the COVID-19 pandemic. Studies focused on these individuals have provided key insights into aspects of innate and adaptive immunity underlying both the anti-viral immune response and excess inflammation in the setting of COVID-19. This review presents what is known about distinct states of immunologic vulnerability to SARS-CoV-2 and how this information can be harnessed to improve prevention and treatment strategies for immunologically high-risk populations.
September 9, 2022
Studying 446 people hospitalised for COVID-19, we show durable nasal and plasma IgG responses to ancestral (B.1 lineage) SARS-CoV-2, Delta and Omicron (BA.1) variants up to 12 months after infection. Nasal antibody induced by infection with pre-Omicron variants, bind Omicron virus in vitro better than plasma antibody. Although nasal and plasma IgG responses were enhanced by vaccination, Omicron binding responses did not reach levels equivalent to responses for ancestral SARS-CoV-2. Using paired plasma and nasal samples collected approximately 12 months after infection, we show that nasal IgA declines and shows a minimal response to vaccination whilst plasma antibody responses to S antigen are well maintained and boosted by vaccination.
COVID-19 vaccines used in humans are highly effective in limiting disease and death caused by the SARS-CoV-2 virus, yet improved vaccines that provide greater protection at mucosal surfaces, which could reduce break-through infections and subsequent transmission, are still needed. Here we show that intranasal (I.N.) vaccination with the receptor binding domain of Spike antigen of SARS-CoV-2 (S-RBD) in combination with the mucosal adjuvant mastoparan-7 improved systemic T cell responses compared to an equivalent dose of antigen delivered by the sub-cutaneous (S.C.) route, adjuvanted by either M7 or the gold-standard adjuvant, alum. T cell phenotypes induced by I.N. vaccine administration included enhanced polyfunctionality (combined IFN-γ and TNF expression) and greater numbers of T central memory (TCM) cells. These phenotypes were T cell-intrinsic and could be recalled in the lungs and/or brachial LNs upon antigen challenge after adoptive T cell transfer to naïve recipients. Furthermore, mucosal vaccination induced antibody responses that were similarly effective in neutralizing the binding of the parental strain of S-RBD to its ACE2 receptor, but showed greater cross-neutralizing capacity against multiple variants of concern (VOC), compared to S.C. vaccination. These results highlight the role of nasal vaccine administration in imprinting an immune profile associated with long-term T cell retention and diversified neutralizing antibody responses, which could be applied to improve vaccines for COVID-19 and other infectious diseases.
September 8, 2022
There has been substantial research on adult COVID-19 and how to treat it. But how do severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections afflict children? The COVID-19 pandemic has yielded many surprises, not least that children generally develop less severe disease than older adults, which is unusual for a respiratory disease. However, some children can develop serious complications from COVID-19, such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid, even after mild or asymptomatic COVID-19. Why this occurs in some and not others is an important question. Moreover, when children do contract COVID-19, understanding their role in transmission, especially in schools and at home, is crucial to ensuring effective mitigation measures. Therefore, in addition to nonpharmaceutical interventions, such as improved ventilation, there is a strong case to vaccinate children so as to reduce possible long-term effects from infection and to decrease transmission. But questions remain about whether vaccination might skew immune responses to variants in the long term. As the experts discuss below, more is being learned about these important issues, but much more research is needed to understand the long-term effects of COVID-19 in children.
SARS-CoV-2 whole genome sequencing has played an important role in documenting the emergence of polymorphisms in the viral genome and its continuing evolution during the COVID-19 pandemic. Here we present data from over 360 patients to characterize the complex sequence diversity of individual infections identified during multiple variant surges (e.g., Alpha and Delta). Across our survey, we observed significantly increasing SARS-CoV-2 sequence diversity during the pandemic and frequent occurrence of multiple biallelic sequence polymorphisms in all infections. This sequence polymorphism shows that SARS-CoV-2 infections are heterogeneous mixtures. Convention for reporting microbial pathogens guides investigators to report a majority consensus sequence. In our study, we found that this approach would under-report sequence variation in all samples tested. As we find that this sequence heterogeneity is efficiently transmitted from donors to recipients, our findings illustrate that infection complexity must be monitored and reported more completely to understand SARS-CoV-2 infection and transmission dynamics. Many of the nucleotide changes that would not be reported in a majority consensus sequence have now been observed as lineage defining SNPs in Omicron BA.1 and/or BA.2 variants. This suggests that minority alleles in earlier SARS-CoV-2 infections may play an important role in the continuing evolution of new variants of concern.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) presents as a range of symptoms that affect multiple organ systems. Enteric dysbiosis, neurological and immune dysfunction, as well as impaired mitochondrial function are implicated in the pathomechanism of ME/CFS. These symptoms also occur in Long Covid, although with differing prevalence.
September 7, 2022
This study suggests that parenteral-prime mucosal boost is an effective strategy for protecting against SARS-CoV-2 infection and highlights that protection against virus transmission may be obtained despite incomplete clearance of virus from the upper respiratory tract. It should be noted that protection against onward transmission was not compared to standard parenteral prime-boost, which should be a focus for future studies.
The decrease in booster durability appeared to be slower than the decrease that was previously reported for two doses of mRNA vaccine alone. Although the rate of booster neutralizing-antibody decay was similar among variants, the omicron subvariants, especially BA.4/5, had substantial neutralization resistance. Our observed trends are consistent with the waning of vaccine protection and natural immunity, and our data suggest that both SARS-CoV-2 variant evolution and waning neutralizing-antibody titers reduce booster-induced immune protection. Our anecdotal experience in two participants indicates that a fourth dose of vaccine may be effective. A variant-specific booster may become necessary as new variants evolve.
September 6, 2022
SARS-CoV-2 Omicron subvariants BA.4.6, BA.4.7, and BA.5.9 have recently emerged, and BA.4.6 appears to be expanding even in the presence of BA.5 that is globally dominant. Compared to BA.5, these new subvariants harbor a mutation at R346 residue in the spike glycoprotein, raising concerns for further antibody evasion. We compared the viral receptor binding affinity of the new Omicron subvariants with BA.5 by surface plasmon resonance. We also performed VSV-based pseudovirus neutralization assays to evaluate their antigenic properties using sera from individuals who received three doses of a COVID-19 mRNA vaccine (boosted) and patients with BA.1 or BA.2 breakthrough infection, as well as using a panel of 23 monoclonal antibodies (mAbs). Compared to the BA.5 subvariant, BA.4.6, BA.4.7, and BA.5.9 showed similar binding affinities to hACE2 and exhibited similar resistance profiles to boosted and BA.1 breakthrough sera, but BA.4.6 was slightly but significantly more resistant than BA.5 to BA.2 breakthrough sera. Moreover, BA.4.6, BA.4.7, and BA.5.9 showed heightened resistance over to a class of mAbs due to R346T/S/I mutation. Notably, the authorized combination of tixagevimab and cilgavimab completely lost neutralizing activity against these three subvariants. The loss of activity of tixagevimab and cilgavimab against BA.4.6 leaves us with bebtelovimab as the only therapeutic mAb that has retained potent activity against all circulating forms of SARS-CoV-2. As the virus continues to evolve, our arsenal of authorized mAbs may soon be depleted, thereby jeopardizing the wellbeing of millions of immunocompromised persons who cannot robustly respond to COVID-19 vaccines.
An estimated 17.3% (95% CI 14.9, 19.8) of respondents had SARS-CoV-2 infection during the two-week study period–equating to 44 million cases as compared to 1.8 million per the CDC during the same time period. SARS-CoV-2 prevalence was higher among those 18-24 years old (aPR 2.2, 95% CI 1.8, 2.7) and among non-Hispanic Black (aPR 1.7, 95% CI 1.4, 2.2) and Hispanic (aPR 2.4, 95% CI 2.0, 2.9). SARS-CoV-2 prevalence was also higher among those with lower income (aPR 1.9, 95% CI 1.5, 2.3), lower education (aPR 3.7 95% CI 3.0,4.7), and those with comorbidities (aPR 1.6, 95% CI 1.4, 2.0). An estimated 21.5% (95% CI 18.2, 24.7) of respondents with a SARS-CoV-2 infection more than 4 weeks prior reported long COVID symptoms. The inequitable distribution of SARS-CoV-2 prevalence during the BA.5 surge will likely drive inequities in the future burden of long COVID.
Variants of SARS-CoV-2 with reduced sensitivity to neutralising antibodies can pose a challenge to immunity induced by vaccination or infection and can render therapeutic monoclonal antibodies ineffective. Our results suggest that the mutations in the spike protein of the BA.2.75 sublineage decrease susceptibility to vaccine-induced neutralising activity compared with BA.2, albeit to a lesser extent than the mutations present in BA.4/5. Moreover, BA.2.75 showed an overall higher sensitivity to SARS-CoV-2 neutralising monoclonal antibodies in advanced development, including antibodies currently in clinical use. Although our analysis of vaccinee sera was limited to a single post-booster timepoint, our results and those of others suggest that antibody escape is an overall less pronounced characteristic of BA.2.75 compared with BA.4/5. Thus, additional features favouring viral expansion beyond vaccine escape might be required for BA.2.75 to gain a growth advantage over BA.4/5.
September 5, 2022
Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2.75 emerged recently and appears to be spreading. It has nine mutations in spike compared with the currently circulating BA.2, raising concerns that it may further evade vaccine-elicited and therapeutic antibodies. We found BA.2.75 to be moderately more neutralization resistant to sera from vaccinated/boosted individuals than BA.2 (1.8-fold), similar to BA.2.12.1 (1.1-fold), but more neutralization sensitive than BA.4/5 (0.6-fold). Relative to BA.2, BA.2.75 showed heightened resistance to class 1 and class 3 monoclonal antibodies targeting the spike-receptor-binding domain while gaining sensitivity to class 2 antibodies. Resistance was largely conferred by G446S and R460K mutations. BA.2.75 was slightly resistant (3.7-fold) to bebtelovimab, a therapeutic antibody with potent activity against all Omicron subvariants. BA.2.75 also exhibited a higher binding affinity to host receptor ACE2 than other Omicron subvariants. BA.2.75 provides further insight into SARS-CoV-2 evolution as it gains transmissibility while incrementally evading antibody neutralization.
September 1, 2022
Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.
Most of these trials found that the updated vaccines — based not only on Omicron, but also on older variants, including Beta — performed a bit better in terms of this measure than the original vaccines did. “This is a clearly superior booster,” Stephen Hoge, the president of pharmaceutical firm Moderna, told investors on 8 June when touting such results from the company’s BA.1-based bivalent vaccine.
We show that Covid-19 illnesses persistently reduce labor supply. Using an event study, we estimate that workers with week-long Covid-19 work absences are 7 percentage points less likely to be in the labor force one year later compared to otherwise-similar workers who do not miss a week of work for health reasons. Our estimates suggest Covid-19 illnesses have reduced the U.S. labor force by approximately 500,000 people (0.2 percent of adults) and imply an average forgone earnings per Covid-19 absence of at least $9,000, about 90 percent of which reflects lost labor supply beyond the initial absence week.
The onset, progression, and symptom profile of post COVID-19 condition patients have considerable overlap with ME/CFS. Considering the large scope and range of pro-inflammatory effects of this virus, it is reasonable to expect development of post COVID-19 clinical complications in a proportion of the affected population. There are reports of a later debilitating syndrome onset three months post COVID-19 infection (often described as long-COVID-19), marked by the presence of fatigue, headache, cognitive dysfunction, post-exertional malaise, orthostatic intolerance, and dyspnoea. Acute inflammation, oxidative stress, and increased levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), have been reported in SARS-CoV-2 infected patients. Longitudinal monitoring of post COVID-19 patients is warranted to understand the long-term effects of SARS-CoV-2 infection and the pathomechanism of post COVID-19 condition.
August 30, 2022
A subset of patients has long-lasting symptoms after mild to moderate Coronavirus disease 2019 (COVID-19). In a prospective observational cohort study, we analyze clinical and laboratory parameters in 42 post-COVID-19 syndrome patients (29 female/13 male, median age 36.5 years) with persistent moderate to severe fatigue and exertion intolerance six months following COVID-19. Further we evaluate an age- and sex-matched postinfectious non-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome cohort comparatively. Most post-COVID-19 syndrome patients are moderately to severely impaired in daily live. 19 post-COVID-19 syndrome patients fulfill the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome. Disease severity and symptom burden is similar in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome and non-COVID-19/myalgic encephalomyelitis/chronic fatigue syndrome patients. Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.
August 26, 2022
Laboratory-Confirmed COVID-19–Associated Hospitalizations Among Adults During SARS-CoV-2 Omicron BA.2 Variant Predominance — COVID-19–Associated Hospitalization Surveillance Network, 14 States, June 20, 2021–May 31, 2022
Increased hospitalization rates among adults aged ≥65 years compared with rates among younger adults were most pronounced during the Omicron BA.2–predominant period. Among hospitalized nonpregnant patients, 44.1% had received primary vaccination and ≥1 booster or additional dose. Hospitalization rates among unvaccinated adults were approximately triple those of vaccinated adults.
August 22, 2022
In this systematic review and meta-analysis of 141 articles, the pooled incubation period was 6.57 days. The incubation periods of COVID-19 caused by the Alpha, Beta, Delta, and Omicron variants were 5.00, 4.50, 4.41, and 3.42 days, respectively.
Regular physical activity seems to be related to a lower likelihood of adverse COVID-19 outcomes. Our findings highlight the protective effects of engaging in sufficient physical activity as a public health strategy, with potential benefits to reduce the risk of severe COVID-19. Given the heterogeneity and risk of publication bias, further studies with standardised methodology and outcome reporting are now needed.
he emergent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants complicate the battle to halt the coronavirus disease 2019 (COVID-19) pandemic. The currently approved vaccines typically express native full-length S or preS-2P. Here, we show that HexaPro is superior to 2P or the native full-length S protein as a SARS-CoV-2 vaccine immunogen. HexaPro is expressed more efficiently and induces more robust SARS-CoV-2 specific antibody and Th1-biased T cell immune responses. Antibodies induced by HexaPro also neutralize SARS-CoV-2 variants two- to fourfold more efficiently than those induced by preS-2P. By comparing different immunization doses, we found that HexaPro is more immunogenic and protective than 2P. This work highlights the importance of using HexaPro in the development of next generation COVID-19 vaccines because of its broad protection against SARS-CoV-2 variants.
August 20, 2022
Treatment with NMV-r in non-hospitalized vaccinated patients with Covid-19 was associated with a reduced likelihood of emergency room visits, hospitalization, or death. Complications and overall resource utilization were also decreased.
August 19, 2022
Among children aged 5–11 years, local and systemic reactions were reported to v-safe with similar frequency after doses 2 and 3; specific reactions differed in severity. Vaccine administration errors were the most common events reported to the Vaccine Adverse Event Reporting System. No reports of myocarditis or death after receipt of dose 3 were received.
Public transportation industries in California experienced cumulative COVID-19 outbreak incidence and mortality rates 1.5 times as high as that for all industries; outbreak incidence was 5.2 times as high, and mortality was 1.8 times as high in bus and urban transit industries as in all industries.
August 18, 2022
A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P=0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P=0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P=0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19.
Prescribing nonefficacious treatments is not a neutral or harmless option. In addition to denying patients the appropriate treatment, such prescribing can lead to side effects without any therapeutic benefit and to drug shortages for patients who need the medications for other conditions. Hence, it is important to have reliable evidence of nonefficacy and to have journals publish such studies. It is also important that multiple rigorous randomized, controlled trials be performed to provide unequivocal evidence on the efficacy of new treatments, as the Covid-19 experience has shown.
August 17, 2022
People infected with the highly transmissible Alpha, Delta and Omicron variants of SARS-CoV-2 spew out higher amounts of virus than do those infected with other variants, according to a study1. Furthermore, individuals who contract COVID-19 after vaccination, and even after a booster dose, still shed virus into the air.
This analysis of 2-year retrospective cohort studies of individuals diagnosed with COVID-19 showed that the increased incidence of mood and anxiety disorders was transient, with no overall excess of these diagnoses compared with other respiratory infections. In contrast, the increased risk of psychotic disorder, cognitive deficit, dementia, and epilepsy or seizures persisted throughout. The differing trajectories suggest a different pathogenesis for these outcomes. Children have a more benign overall profile of psychiatric risk than do adults and older adults, but their sustained higher risk of some diagnoses is of concern. The fact that neurological and psychiatric outcomes were similar during the delta and omicron waves indicates that the burden on the health-care system might continue even with variants that are less severe in other respects. Our findings are relevant to understanding individual-level and population-level risks of neurological and psychiatric disorders after SARS-CoV-2 infection and can help inform our responses to them.
In the general population, individuals who have had COVID-19 have been found to have substantial deficits on computerised cognitive batteries. Taquet and colleagues found that this deficit does indeed seem to translate into an increased risk of a diagnosis of dementia. However, dementia has an insidious onset and the cohort is likely to have had some participants with undiagnosed or subclinical cases at baseline. Although concerning, the findings regarding psychosis and dementia need replication in a cohort in which there is more thorough ascertainment of case status.
SARS-CoV-2 omicron subvariants BA.1 and BA.2 became dominant in many countries in early 2022. These subvariants are now being displaced by BA.4 and BA.5. While natural infection with BA.1/BA.2 provides some protection against BA.4/BA.5 infection, the duration of this protection remains unknown. We used the national Portuguese COVID-19 registry to investigate the waning of protective immunity conferred by prior BA.1/BA.2 infection towards BA.5. We divided the individuals infected during the period of BA.1/BA.2 dominance (>90% of sample isolates) in successive 15-day intervals and determined the risk of subsequent infection with BA.5 over a fixed period. Compared with uninfected people, one previous infection conferred substantial protection against BA.5 re-infection at 3 months (RR=0.12; 95% CI: 0.11-0.12). However, although still significant, the protection was reduced by two-fold at 5 months post-infection (RR=0.24; 0.23-0.24). These results should be interpreted in the context of vaccine breakthrough infections, as the vaccination coverage in the individuals included in the analyses is >98% since the end of 2021. This waning of protection following BA.1/BA.2 infection highlights the need to assess the stability and durability of immune protection induced with the adapted vaccines (based on BA.1) over time.
Despite the remarkable efficacy of COVID-19 vaccines, waning immunity and the emergence of SARS-CoV-2 variants such as Omicron represents a global health challenge. Here, we present data from a study in nonhuman primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, which was recently authorized for use in individuals 18 years or older. Vaccination induced neutralizing antibody (nAb) titers that were maintained at high concentrations for at least 1 year after two doses, with a pseudovirus nAb geometric mean titer (GMT) of 1978 and a live virus nAb GMT of 1331 against the ancestral strain but not against the Omicron BA.1 variant. However, a booster dose at 6 to 12 months with RBD-Wu or RBD-β (RBD from the Beta variant) displayed on I53-50 elicited high neutralizing titers against the ancestral and Omicron variants. In addition, we observed persistent neutralization titers against a panel of sarbecoviruses, including SARS-CoV. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Vaccination resulted in protection against Omicron infection in the lung and suppression of viral burden in the nares at 6 weeks after the final booster immunization. Even at 6 months after vaccination, we observed protection in the lung and rapid control of virus in the nares. These results highlight the durable and cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine.
August 16, 2022
In this retrospective cohort study that included 93 906 patients, hospitalization with COVID-19 before vaccine availability and during vaccine availability was significantly associated with higher 90-day risk of venous thromboembolism (adjusted hazard ratios, 1.60 and 1.89, respectively) vs hospitalization with influenza in 2018-2019, but there was no significant difference in the risk of arterial thromboembolism among those hospitalized with COVID-19 during either period (adjusted hazard ratios, 1.04 and 1.07) vs those hospitalized with influenza.
Long Covid is far from uniform, the new study makes clear—for example, only about 20% to 30% of the study’s patients had very high levels of exhausted T cells. But, “The level of consistency is great” among recent studies probing Long Covid biology, says James Heath, president of the Institute for Systems Biology, an author of the Cell paper that found low cortisol and virus reactivation. He notes that his group’s study examined patients about 3 months after SARS-CoV-2 infection, whereas Iwasaki and Putrino’s cohort was on average more than a year out from their COVID-19.
August 15, 2022
There is a need for safe and effective platform vaccines to protect against COVID-19 and other infectious diseases. In this randomized, double-blinded, placebo-controlled Phase 2/3 trial, we evaluate the safety and efficacy of multi-dose Bacillus Calmette-Guerin (BCG) vaccine for prevention of COVID-19 and other infectious disease in a COVID-19-unvaccinated, at-risk-community-based cohort. The at-risk population are adults with type 1 diabetes. We enrolled 144 subjects and randomized 96 to BCG and 48 to placebo. There were no drop-outs over the 15-month trial. A cumulative incidence of 12.5% of placebo-treated and 1% of BCG-treated participants meets criteria for confirmed COVID-19, yielding an efficacy of 92%. The BCG group also displays fewer infectious disease symptoms and lesser severity, and fewer infectious disease events per patient, including COVID-19. There were no BCG-related systemic adverse events. BCG’s broad-based infection protection suggests that it may provide platform protection against new SARS-CoV-2 variants and other pathogens.
Genetic differences between SARS-CoV-2 variants raise concerns about reinfection. Public health authorities monitored the incidence of suspected reinfection in Clark County, Nevada, USA, during March 2020–March 2022. Suspected reinfections, defined as a second positive PCR test collected >90 days after an initial positive test, were monitored through an electronic disease surveillance system. We calculated the proportion of all new cases per week that were suspected reinfections and rates per 1,000 previously infected persons by demographic groups. The rate of suspected reinfection remained <2.7% until December 2021, then increased to ≈11%, corresponding with local Omicron variant detection. Reinfection rates were higher among adults 18–50 years of age, women, and minority groups, especially persons identifying as American Indian/Alaska Native. Suspected reinfection became more common in Clark County after introduction of the Omicron variant, and some demographic groups are disproportionately affected. Public health surveillance could clarify the SARS-CoV-2 reinfection burden in communities.
We included 2919 HCWs (median age, 43 years (range, 18-73 years); 749 participants (26%) were infected with SARS-CoV-2. SARS-CoV-2 positivity was 13% in HCWs without patient exposure. For those exposed to patients, positivity was 21% for HCWs using respirator masks and 35% for those using surgical/mixed masks (OR, 0.49; 95% CI, 0.39-0.61), showing an increase for surgical/mixed mask users (OR, 1.21; 95% CI, 1.15-1.28) and respirator mask users (OR, 1.15; 95% CI, 1.05-1.27) across categories of patient exposure (Figure). Variables associated with SARS-CoV-2 infection in multivariable analysis included a positive household contact (OR, 7.79; 95% CI, 5.98-10.15), exposure to patients (OR, 1.20 per category of cumulative contact; 95% CI, 1.14-1.26), respirator use (OR, 0.56; 95% CI, 0.43-0.74), and SARS-CoV-2 vaccination (OR, 0.55; 95% CI, 0.41-0.74) (Table). Similar results were obtained in sensitivity analysis.
The nightlife setting was the driver of COVID-19 spread, while household and healthcare settings were in the lower course of transmission chains. Surveillance and countermeasures targeting the nightlife setting should be prioritized to disrupt COVID-19 transmission, especially in the early stage of an epidemic.
August 12, 2022
During October 31, 2021–June 11, 2022, 10.7 million test results were voluntarily reported by users of four manufacturers’ self-tests; during that period, 361.9 million laboratory-based and point-of-care test results were reported. Completeness of reporting demographic variables and trends in percent positivity were similar across test types. Self-tests are a valuable risk-reduction tool that can guide individual actions, but they currently offer limited utility in enhancing public health surveillance. Laboratory-based and point-of-care test result data, in combination with other COVID-19 surveillance information, continue to provide strong situational awareness.
By April 29, 2022, a total of 702,686 COVID-19 cases were reported among children and adolescents aged 5–17 years in the state of New York.* Pediatric COVID-19 cases and hospitalizations increased during the 2021–22 school year, driven by transmission of the Omicron variant† (1). In late 2021, during the surge in Omicron BA.1 variant cases, state§ and federal¶ authorities expanded access to self-administered, at-home rapid antigen tests, which can increase a person’s knowledge of their COVID-19 status and guide risk-reduction behaviors. New York government agencies sent millions of these tests to schools for distribution to teachers, students, and staff members. Because results of self-administered, at-home tests are not captured by electronic laboratory reporting (in contrast to health care provider–administered tests at a physician’s office or laboratory that are reported through electronic health records or other means), expanded use of these tests might affect interpretation of trends in reported COVID-19 cases; however, this has yet to be assessed** (2). Furthermore, understanding changes in testing behavior before and after the Omicron variant surge might help public health officials better use available COVID-19 data to guide future policy.
August 11, 2022
To prevent medically significant COVID-19 illness and death, persons must understand their risk, take steps to protect themselves and others with vaccines, therapeutics, and nonpharmaceutical interventions when needed, receive testing and wear masks when exposed, receive testing if symptomatic, and isolate for ≥5 days if infected. Medically significant illness, death, and health care system strain can be reduced through vaccination and therapeutics to prevent severe illness, complemented by use of multiple prevention methods to reduce exposure risk and an emphasis on protecting persons at high risk for severe illness.
As of Nov 4, 2021, 191 360 women aged 15–49 years with known pregnancy status had completed the first vaccine dose survey and 94 937 had completed the second dose survey. 180 388 received one dose and 94 262 received a second dose of an mRNA vaccine, with 5597 pregnant participants receiving dose one and 3108 receiving dose two, and 174 765 non-pregnant participants receiving dose one and 91 131 receiving dose two. Of 6179 included unvaccinated control participants, 339 were pregnant and 5840 were not pregnant. Overall, 226 (4·0%) of 5597 vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227 (7·3%) of 3108 after dose two, compared with 11 (3·2%) of 339 pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event within 7 days of the vaccine after dose two of mRNA-1273 (adjusted odds ratio [aOR] 4·4 [95% CI 2·4–8·3]) compared with pregnant unvaccinated controls within the past 7 days, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant vaccinated females had decreased odds of a significant health event compared with non-pregnant vaccinated females after both dose one (aOR 0·63 [95% CI 0·55–0·72]) and dose two (aOR 0·62 [0·54–0·71]) of any mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention.
Neurological symptoms are among the most prevalent of the extrapulmonary complications of COVID-19, affecting more than 30% of patients. In this study, we provide evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in the human brain, where it infects astrocytes and to a lesser extent, neurons. We also show that astrocytes are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction and respond to the infection by remodeling energy metabolism, which in turn, alters the levels of metabolites used to fuel neurons and support neurotransmitter synthesis. The altered secretory phenotype of infected astrocytes then impairs neuronal viability. These features could explain the damage and structural changes observed in the brains of COVID-19 patients.
August 10, 2022
ARS-CoV-2, the causative agent of COVID-19 disease has resulted in the death of millions worldwide since the beginning of the pandemic in December 2019. While much progress has been made to understand acute manifestations of SARS-CoV-2 infection, less is known about post-acute sequelae of COVID-19 (PASC). We investigated the levels of circulating SARS-CoV-2 components, Spike protein and viral RNA, in patients hospitalized with acute COVID-19 and in patients with and without PASC. In hospitalized patients with acute COVID-19 (n=116), we observed a positive correlation of Spike protein with D-dimer, length of hospitalization, and peak WHO score while viral RNA correlated with a tissue injury marker, lactate dehydrogenase (LDH). When comparing patients with post-COVID symptoms (n=33) and patients without (n=14), we found that Spike protein and viral RNA were more likely to be present in patients with PASC and in some cases at higher levels compared to acute COVID-19 patients. We also observed that the percent positivity of circulating viral RNA increased in the PASC positive individuals compared to acute COVID-19 group while Spike protein positivity remained the same. Additionally, we report that part of the circulating Spike protein is linked to extracellular vesicles without any presence of viral RNA in these vesicles. In conclusion, our findings suggest that Spike protein and/or viral RNA fragments persist in the recovered COVID-19 patients with PASC, regardless of their presence or absence during the acute COVID-19 phase. These results may help in understanding the reason(s) for why patients experience PASC symptoms and may offer potential therapeutic targets.
Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a local growth advantage over BA.2.38, BA.2.76 and BA.5 in India. The underlying mechanism of BA.2.75’s enhanced infectivity, especially compared to BA.5, remains unclear. Here, we show that BA.2.75 exhibits substantially higher ACE2-binding affinity than BA.5. Also, BA.2.75 spike shows decreased thermostability and increased “up” RBD conformation in acidic conditions, suggesting enhanced low-pH-endosomal cell-entry pathway utilization. BA.2.75 is less humoral immune evasive than BA.4/BA.5 in BA.1/BA.2 breakthrough-infection convalescents; however, BA.2.75 shows heavier neutralization evasion in Delta breakthrough-infection convalescents. Importantly, plasma from BA.5 breakthrough infection exhibit significantly weaker neutralization against BA.2.75 than BA.5, mainly due to BA.2.75’s distinct RBD and NTD-targeting antibody escaping pattern from BA.4/BA.5. Additionally, Evusheld and Bebtelovimab remain effective against BA.2.75, and Sotrovimab recovered RBD-binding affinity. Together, our results suggest BA.2.75 may prevail after the global BA.4/BA.5 wave, and its increased receptor-binding capability could allow further incorporation of immune-evasive mutations.
Multiple BA.4 and BA.5 subvariants with R346 mutations on the spike glycoprotein have been identified in various countries, such as BA.4.6/BF.7 harboring R346T, BA.4.7 harboring R346S, and BA.5.9 harboring R346I. These subvariants, especially BA.4.6, exhibit substantial growth advantages compared to BA.4/BA.5. In this study, we showed that BA.4.6, BA.4.7, and BA.5.9 displayed higher humoral immunity evasion capability than BA.4/BA.5, causing 1.5 to 1.9-fold decrease in NT50 of the plasma from BA.1 and BA.2 breakthrough-infection convalescents compared to BA.4/BA.5. Importantly, plasma from BA.5 breakthrough-infection convalescents also exhibits significant neutralization activity decrease against BA.4.6, BA.4.7, and BA.5.9 than BA.4/BA.5, showing on average 2.4 to 2.6-fold decrease in NT50. For neutralizing antibody drugs, Bebtelovimab remains potent, while Evusheld is completely escaped by these subvariants. Together, our results rationalize the prevailing advantages of the R346 mutated BA.4/BA.5 subvariants and urge the close monitoring of these mutants, which could lead to the next wave of the pandemic.
To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting broadly neutralizing antibody responses to CoVs. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein with a two-shot protocol generated potent serum receptor binding domain cross-neutralizing antibody responses to both SARS-CoV-2 and SARS-CoV-1. Furthermore, responses were equally effective against most SARS-CoV-2 variants of concern (VOCs) and some were highly effective against Omicron. This result contrasts with human infection or many two-shot vaccination protocols where responses were typically more SARS-CoV-2 specific and where VOCs were less well neutralized. Structural studies showed that cloned macaque neutralizing antibodies, particularly using a given heavy chain germline gene, recognized a relatively conserved region proximal to the angiotensin converting enzyme 2 receptor binding site (RBS), whereas many frequently elicited human neutralizing antibodies targeted more variable epitopes overlapping the RBS. B cell repertoire differences between humans and macaques appeared to influence the vaccine response. The macaque neutralizing antibodies identified a pan-SARS–related virus epitope region less well targeted by human antibodies that could be exploited in rational vaccine design.
SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease called post-acute sequelae of COVID-19 (PASC) or Long COVID1–3. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions1–3; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Here, 215 individuals were included in an exploratory, cross-sectional study to perform multi-dimensional immune phenotyping in conjunction with machine learning methods to identify key immunological features distinguishing Long COVID. Marked differences were noted in specific circulating myeloid and lymphocyte populations relative to matched control groups, as well as evidence of elevated humoral responses directed against SARS-CoV-2 among participants with Long COVID. Further, unexpected increases were observed in antibody responses directed against non-SARS-CoV-2 viral pathogens, particularly Epstein-Barr virus. Analysis of circulating immune mediators and various hormones also revealed pronounced differences, with levels of cortisol being uniformly lower among participants with Long COVID relative to matched control groups. Integration of immune phenotyping data into unbiased machine learning models identified significant distinguishing features critical in accurate classification of Long COVID, with decreased levels of cortisol being the most significant individual predictor. These findings will help guide additional studies into the pathobiology of Long COVID and may aid in the future development of objective biomarkers for Long COVID.
The BA.2.75 variant is rising fast in the country, but hospitalization rates are low so far.
August 9, 2022
The COVID-19 pandemic is far from over. SARS-CoV-2 mutates relatively slowly (~1 × 10−6 per base per infection cycle); yet, the world continues to experience a series of viral surges fuelled by the evolving sub-lineages of the Omicron variant. Now, 32 months into the pandemic, more than 66% of the world’s population is estimated to have some form of immunity against SARS-CoV-2, either through infection (‘natural’), vaccination (‘artificial’) or both (‘hybrid’). Hybrid immunity emerged as a form of ‘super immunity’ in 2021, when convalescent people receiving vaccine doses were found to have neutralizing antibody titres on average 50-fold higher than unvaccinated convalescent individuals1. As breakthrough infections emerged in vaccinated people, hybrid immunity became an established arm of the anti-SARS-CoV-2 immune landscape. What do we now know about hybrid immunity and its ‘super immunity’ abilities?
While making virus-specific immune responses to SARS-CoV-2, residual B and T cell diversity are key to making responses to concurrent co-infections and/or cancers. We applied an antigen receptor–sequencing technology and provide a comprehensive description of the global immune repertoire in hospitalized and nonhospitalized individuals infected with SARS-CoV-2. Although B cell diversity predictably narrowed, significant narrowing of αβ and γδ T cell diversity was unexpectedly observed only in those aged over 50, which is a major inflexion point for COVID-19–associated mortality. Such a discrepancy in how older persons mount T cell responses to a new virus may be considered a risk factor for the elderly, particularly vis-à-vis new virus variants against which T cell immunity may be particularly important.
Spike-specific neutralizing antibodies (NAbs) are generally considered key correlates of vaccine protection against SARS-CoV-2 infection. Recently, robust vaccine prevention of severe disease with SARS-CoV-2 variants that largely escape NAb responses has been reported, suggesting a role for other immune parameters for viro-logic control. However, direct data demonstrating a role of CD8+ T cells in vaccine protection has not yet been reported. In this study, we show that vaccine-elicited CD8+ T cells contribute substantially to virologic control following SARS-CoV-2 challenge in rhesus macaques. We vaccinated 30 macaques with a single immunization of the adenovirus vector-based vaccine Ad26.COV2.S or sham and then challenged them with 5x105 TCID50 SARS- CoV-2 B.1.617.2 (Delta) by the intranasal and intratracheal routes. All vaccinated animals were infected by this high-dose challenge but sho wed rapid virologic control in nasal sw abs and br onchoalveolar lavage by day 4 following challenge. However, administration of an anti-CD8α or anti-CD8β depleting monoclonal antibody in vaccinated animals prior to SARS-CoV-2 challenge resulted in higher levels of peak and day 4 virus in both the upper and lower respiratory tracts. These data demonstrate that CD8+ T cells contribute substantially to vaccine protection against SARS-CoV-2 replication in macaques.
Two omicron subvariants have come to dominate infections worldwide. Elisabeth Mahase summarises what we know about them so far
In the absence of a solid evidence base, some physicians worry about potential harm from long-COVID treatments. Shinichiro Morioka, deputy director of the Disease Control and Prevention Center at the National Center for Global Health and Medicine in Tokyo, says that some doctors are using epipharyngeal abrasive therapy, in which the throat is scraped with cotton swabs soaked in zinc chloride. The aim is to decrease inflammation at a key site of coronavirus infection, he says. Some physicians say they have achieved promising results in small trials with no control group5. “But I do not think this is evidence-based, and it is invasive for patients,” says Morioka. “We need to run randomized controlled trials.” At the moment, he does not know of any randomized controlled trials for this or any other long-COVID treatment in Japan.
August 8, 2022
First-generation vaccines and drugs have helped reduce disease severity and blunt the spread of SARS-CoV-2. However, ongoing virus transmission and evolution and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease (Mpro/3CLpro) of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional inhibitor in clinical development, ensitrelvir, shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that nirmatrelvir-resisting variants have pre-existed the introduction of this drug into the human population and are capable of spreading. A similarly strong argument can be made for ensitrelvir. These results caution against broad administration of protease inhibitors as stand-alone therapies and encourage the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles.
Nirmatrelvir, an oral antiviral targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful in reducing hospitalization or death due to COVID-191,2. However, as SARS-CoV-2 has evolved to become resistant to other therapeutic modalities3–9, there is a concern that the same could occur for nirmatrelvir. Here, we have examined this possibility by in vitro passaging of SARS-CoV-2 in increasing concentrations of nirmatrelvir using two independent approaches, including one on a large scale in 480 wells. Indeed, highly resistant viruses emerged from both, and their sequences revealed a multitude of 3CL protease mutations. In the experiment done at scale, 53 independent viral lineages were selected with mutations observed at 23 different residues of the enzyme. Yet, several common mutational pathways to nirmatrelvir resistance were preferred, with a majority of the viruses descending from T21I, P252L, or T304I as precursor mutations. Construction and analysis of 13 recombinant SARS-CoV-2 clones, each containing a unique mutation or a combination of mutations showed that the above precursor mutations only mediated low-level resistance, whereas greater resistance required accumulation of additional mutations. E166V mutation conferred the strongest resistance (∼300-fold), but this mutation resulted in a loss of viral replicative fitness that was restored by compensatory changes such as L50F and T21I. Structural explanations are discussed for some of the mutations that are proximal to the drug-binding site, as well as cross-resistance or lack thereof to ensitrelvir, another clinically important 3CL protease inhibitor. Our findings indicate that SARS-CoV-2 resistance to nirmatrelvir does readily arise via multiple pathways in vitro, and the specific mutations observed herein form a strong foundation from which to study the mechanism of resistance in detail and to shed light on the design of next generation protease inhibitors.
SARS-CoV-2 Omicron BA.2.75 emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically different from BA.5, the currently predominant BA.2 descendant. Here, we showed that the effective reproduction number of BA.2.75 is greater than that of BA.5. While the sensitivity of BA.2.75 to vaccination- and BA.1/2 breakthrough infection-induced humoral immunity was comparable to that of BA.2, the immunogenicity of BA.2.75 was different from that of BA.2 and BA.5. Three clinically-available antiviral drugs were effective against BA.2.75. BA.2.75 spike exhibited a profound higher affinity to human ACE2 than BA.2 and BA.5 spikes. The fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were comparable to those of BA.5 but were greater than those of BA.2. Our multiscale investigations suggest that BA.2.75 acquired virological properties independently of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.
August 5, 2022
Compared with patients aged 0–17 years without previous COVID-19, those with previous COVID-19 had higher rates of acute pulmonary embolism (adjusted hazard ratio = 2.01), myocarditis and cardiomyopathy (1.99), venous thromboembolic event (1.87), acute and unspecified renal failure (1.32), and type 1 diabetes (1.23), all of which were rare or uncommon in this study population. COVID-19 prevention strategies, including vaccination for all eligible persons aged ≥6 months, are critical to preventing SARS-CoV-2 infection and subsequent illness, and reducing the public health impact of post-COVID symptoms and conditions among persons aged 0–17 years.
On July 19, 2022, the Advisory Committee on Immunization Practices made an interim recommendation for use of the Novavax vaccine in persons aged ≥18 years as a primary 2-dose series vaccination for the prevention of COVID-19. The adjuvanted, protein subunit–based Novavax COVID-19 vaccine provides an additional option for unvaccinated adults, increasing flexibility for the public and for vaccine providers. Vaccination is important for protection against COVID-19.
During the first 2 years of the U.S. COVID-19 pandemic, pediatric centers anecdotally reported increased rates of intracranial bacterial infections, many of which were diagnosed during or immediately after an infection with SARS-CoV-2, the virus that causes COVID-19 (1,2). Although intracranial bacterial infections occur as a rare complication of partially treated or untreated bacterial rhinosinusitis in adolescents as well as mastoiditis in children of all ages (3), a 236% increase in cases among children was observed at a Michigan children’s hospital (Aldrich A and Ogrin S, Helen DeVos Children’s Hospital of Spectrum Health, unpublished data, 2022). Most of these cases were in infants and children aged <12 years and associated with a diversity of identified pathogens, including a range of Streptococcus species with more severe disease requiring extended intensive care unit admission and multiple surgical interventions; many of the cases had recent or concurrent SARS-CoV-2 infection.
COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. However, the underlying cellular and molecular mechanisms driving this condition are unclear. Evidence supports the concept that CAC involves complex interactions between the innate immune response, the coagulation and fibrinolytic pathways, and the vascular endothelium, resulting in a procoagulant condition. Understanding of the pathogenesis of this condition at the genomic, molecular and cellular levels is needed in order to mitigate thrombosis formation in at-risk patients. In this Perspective, we categorize our current understanding of CAC into three main pathological mechanisms: first, vascular endothelial cell dysfunction; second, a hyper-inflammatory immune response; and last, hypercoagulability. Furthermore, we pose key questions and identify research gaps that need to be addressed to better understand CAC, facilitate improved diagnostics and aid in therapeutic development. Finally, we consider the suitability of different animal models to study CAC.
In this cohort study of 140 000 class meetings at a large US university, there were over 850 cases of SARS-CoV-2 infection identified through weekly surveillance testing of all students and faculty on campus during the fall 2021 semester. There were 9 instances of potential in-class transmission identified as identical lineages confirmed by SARS-CoV-2 genome sequencing, and none of these instances were confirmed to be in-class transmission.
Screening of more than 50 000 youths in diverse populations of Colorado and Bavaria found no association of SARS-CoV-2 infection with autoimmunity related to development of type 1 diabetes. Study limitations include the low prevalence of autoantibodies, limiting the power to detect an increase in risk associated with SARS-CoV-2 infection. Moreover, the cross-sectional design did not allow determination of whether autoantibodies developed before or after SARS-CoV-2 infection. Long-term follow-up of persons with preexisting autoimmunity is necessary to determine whether SARS-CoV-2 accelerates progression to clinical diabetes.
n 1939 prominent Soviet microbiologist Abram Lvovich Berlin was working on a plague vaccine as deputy director of the Workers’ and Peasants’ Red Army Biotechnology Institute, then located in Vlasikha, on the outskirts of Moscow. He immunized laboratory animals with a candidate live-attenuated plague vaccine and challenged them with Yersinia pestis (then called Pasteurella pestis) aerosol, and he was infected in the process. He was called to Moscow to present interim results of his vaccine development efforts to superiors; shared a train compartment with numerous fellow travelers; came into close contact with National Hotel receptionists, its barber, and other visitors and residents; then was evaluated by a physician for emerging cough and malaise before presenting his research results to high-ranking officials.
August 4, 2022
The worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the repeated emergence of variants of concern. For the Omicron variant, sub-lineages BA.1 and BA.2 respectively contain 33 and 29 nonsynonymous and indel spike protein mutations. These amino acid substitutions and indels are implicated in increased transmissibility and enhanced immune evasion. By reverting individual Spike mutations of BA.1 or BA.2, we characterize the molecular effects of the Omicron spike mutations on expression, ACE2 receptor affinity, and neutralizing antibody recognition. We identified key mutations enabling escape from neutralizing antibodies at a variety of epitopes. Stabilizing mutations in the N-terminal and S2 domains of the spike protein can compensate for destabilizing mutations in the receptor binding domain, enabling the record number of mutations in Omicron. Our results provide a comprehensive account of the mutational effects in the Omicron spike protein and illuminate previously uncharacterized mechanisms of host evasion.
In this cohort study, 88.2% of patients reporting a COVID-19–related smell or taste dysfunction completely recovered within 2 years. A late recovery was observed in 10.9% of patients. Although these results must be interpreted with caution owing to study limitations (eg, data were self-reported based on a cross-sectional survey; outcomes not specifically validated for olfactory loss were used; a psychophysical evaluation of the chemosensory function was not performed; the sample was relatively small and geographically limited, with patients with more severe symptoms not included; data regarding potential treatments used for chemosensory impairment were lacking), contrary to what is often reported, patients should be reassured that recovery from smell or taste impairment may continue for many months after the onset. These results apply to patients infected in the pre-Omicron period. COVID-19 driven by the SARS-CoV-2 Omicron variant has been indeed observed to less frequently and less severely affect chemosensory function.
August 3, 2022
In April 2020, when hundreds of thousands of people worldwide had already succumbed to COVID-19, one infected individual—4-year-old Nadia—made global headlines. A Malayan tiger residing in New York’s Bronx Zoo, Nadia was among the first animals known to have contracted the virus from a human, likely a caretaker.
The COVID-19 pandemic is the most significant medical and public health challenge the US has encountered in the last 100 years. As of July 26, 2022, an estimated 90 million cases of COVID-19 have been reported in the US, with an estimated 1 million COVID-19–related deaths. The current number of SARS-CoV-2 infections is difficult to estimate accurately, considering that many individuals with positive self-test results do not seek care or report their infection. At the same time, new coronavirus variants continue to emerge, with Omicron subvariants such as BA.5 and BA.4 now identified as the dominant circulating strains.
In this cross-sectional study of 2031 US adults with children aged 6 months through 4 years, half indicated they intended to get their child a COVID-19 vaccine at some point, but only one-fifth intended to do so within 3 months of the child’s eligibility. The top concerns about and facilitators to COVID-19 vaccination for this age group related to COVID-19 vaccination safety and efficacy.
In this cohort study of individuals newly diagnosed with COVID-19, 75% continued to have positive RAT results, while 35% had culturable virus on day 6. Everyone with a negative day-6 RAT result had a negative viral culture. However, only 50% of those with a positive RAT result had culturable virus. Acknowledging the caveats of a small cohort of mostly young, vaccinated, nonhospitalized individuals with a presumed Omicron variant and potential variation in self-sampling techniques and lab-based culture methods, these data suggest that a negative RAT result in individuals with residual symptoms could provide reassurance about ending isolation. However, a universal requirement of a negative RAT result may unduly extend isolation for those who are no longer infectious. Meanwhile, a recommendation to end isolation based solely on the presence of improving symptoms risks releasing culture-positive, potentially infectious individuals prematurely, underscoring the importance of proper mask wearing and avoidance of high-risk transmission venues through day 10.
In this population-based cohort study, a substantial proportion of persons experienced SARS-CoV-2 reinfection during the first 74 days of the Omicron wave in Iceland, with rates as high 15.1% among those aged 18 to 29 years. Longer time from initial infection was associated with a higher probability of reinfection, although the difference was smaller than expected. Surprisingly, 2 or more doses of vaccine were associated with a slightly higher probability of reinfection compared with 1 dose or less. This finding should be interpreted with caution because of limitations of our study, which include the inability to adjust for the complex relationships among prior infection, vaccine eligibility, and underlying conditions. Importantly, by December 1, 2021, all persons aged 12 years and older were eligible for 2 or more vaccine doses free of charge, and 71.1% of the Icelandic population had been vaccinated,5 compared with only 25.5% of our cohort of previously infected persons. Our results suggest that reinfection is more common than previously thought. Now the key question is whether infection with the Omicron variant will produce better protection against Omicron reinfection, compared with other variants.
The findings of this case-control study suggest that 2 doses of BNT162b2 were associated with preventing ED and UC encounters for ARI caused by either the Delta or Omicron variants of SARS-CoV-2 in the first few months after vaccination. However, this effectiveness waned over time, although waning was more pronounced for the Omicron variant. A third dose of BNT162b2 was associated with improved protection beyond that seen initially after 2 doses. These findings underscore the important role of booster doses to enhance protection against COVID-19 for adolescents aged 12 to 17 years.
The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.
August 2, 2022
The investigators analyzed National Center for Health Statistics data from people who died within 42 days after pregnancy. In 2018, 2019, and the first quarter of 2020, the maternal death rate was 18.8 per 100 000 live births. During April to December 2022, the rate increased to 25.1 per 100 000 live births, a relative increase of 33.3%. The maternal death rate increased 74.2% among Hispanic individuals, 40.2% among non-Hispanic Black individuals, and 17.2% among non-Hispanic White individuals during the study period.
Sickle cell trait (SCT) should be considered an adverse prognostic factor for COVID-19, a genetic association study suggests.
In this cohort study including 10 920 patients, the use of neoadjuvant-intent chemotherapy and hormonal treatment increased during the COVID-19 era, but there was substantial regional variability. Bridging hormonal therapy was a more common adaptation to cancer treatment in the COVID-19 era than neoadjuvant chemotherapy; neoadjuvant-intent systemic treatment was not associated with short-term outcomes in the COVID-19 era.
This cross-sectional study found a substantial increase in adult and pediatric mechanical ventilators reported by acute care hospitals in 2020 compared with 2019. Study limitations include possible response bias. The AHA Annual Survey did not differentiate between ventilator functionality, changes in numbers of anesthesia ventilators, or transport, backup, or rental ventilators, nor did it account for temporary ventilator allocation coordinated through state public health departments or the Dynamic Ventilator Reserve.5 The increase in ventilators that were deployed in hospitals was not correlated with the state’s COVID-19 ICU burden, but this finding may not account for more dynamic shifts in ventilator stock across hospitals during waves of the pandemic. For both the current COVID-19 pandemic as well as future pandemic preparedness, these findings may help guide policy makers in deploying ventilators to states with the most urgent need of ventilators.
In the spring of 2020, US regions impacted early by COVID-19, such as northern New Jersey and New York City, exceeded the usual mechanical ventilation capability at numerous hospitals. As COVID-19 spread to other communities with limited immunity, similar challenges to provide surge mechanical ventilation were reported. Hospitals, health care systems, and jurisdictional authorities sought to purchase more mechanical ventilators and quickly realized that the supply chain could not accommodate the perceived need. Numerous creative engineering ideas were proposed to augment the supply of resuscitators or mechanical ventilators. Tremendous public and governmental effort focused on preventing shortages of these potentially life-saving devices and on strategies to ration them should demand exceed supply.
Findings: In both the primary and secondary analyses, 12% of participants had viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47 years, P=0.04). Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound to ≥5.0 log10 RNA copies/mL and symptom rebound after initial improvement was observed in 1-2% of participants. Interpretation: Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare.
In this multicenter cohort study of 29 611 health care workers in Israel, the breakthrough infection rate among those who received 4 doses was 6.9% compared with 19.8% in those who received 3 doses. These findings suggest that a fourth vaccine dose was effective in preventing breakthrough COVID-19 infections in health care workers, helping to maintain the function of the health care system during the pandemic.
Some studies suggest that the risk of cardiovascular problems, such as a heart attack or stroke, remains high even many months after a SARS-CoV-2 infection clears up. Researchers are starting to pin down the frequency of these issues and what is causing the damage.
Recently, we reported that BNT162b2-vaccinated individuals after Omicron BA.1 breakthrough infection have strong serum neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 variants of concern (VOCs), yet less against the highly contagious Omicron sublineages BA.4 and BA.5 that have displaced previous variants. As the latter sublineages are derived from Omicron BA.2, we characterized serum neutralizing activity of COVID-19 mRNA vaccine triple-immunized individuals who experienced BA.2 breakthrough infection. We demonstrate that sera of these individuals have broadly neutralizing activity against previous VOCs as well as all tested Omicron sublineages, including BA.2 derived variants BA.2.12.1, BA.4/BA.5. Furthermore, applying antibody depletion we showed that neutralization of BA.2 and BA.4/BA.5 sublineages by BA.2 convalescent sera is driven to a significant extent by antibodies targeting the N-terminal domain (NTD) of the spike glycoprotein, whereas their neutralization by Omicron BA.1 convalescent sera depends exclusively on antibodies targeting the receptor binding domain (RBD). These findings suggest that exposure to Omicron BA.2, in contrast to BA.1 spike glycoprotein, triggers significant NTD specific recall responses in vaccinated individuals and thereby enhances the neutralization of BA.4/BA.5 sublineages. Given the current epidemiology with a predominance of BA.2 derived sublineages like BA.4/BA.5 and rapidly ongoing evolution, these findings are of high relevance for the development of Omicron adapted vaccines.
August 1, 2022
The SARS-CoV-2 Omicron subvariant BA.2.75 emerged recently and appears to be spreading rapidly. It has nine mutations in its spike compared to BA.2, raising concerns it may further evade vaccine-elicited and therapeutic antibodies. Here, we found BA.2.75 to be moderately more neutralization resistant to sera from vaccinated/boosted individuals than BA.2 (1.8-fold), similar to BA.2.12.1 (1.1-fold), but more neutralization sensitive than BA.4/5 (0.6-fold). Relative to BA.2, BA.2.75 showed heightened resistance to class 1 and class 3 monoclonal antibodies to the receptor-binding domain, while gaining sensitivity to class 2 antibodies. The resistance was largely conferred by the G446S and R460K mutations. Of note, BA.2.75 was slightly resistant (3.7-fold) to bebtelovimab, the only therapeutic antibody with potent activity against all Omicron subvariants. BA.2.75 also exhibited higher receptor binding affinity than other Omicron subvariants. BA.2.75 provides yet another example of the ongoing evolution of SARS-CoV-2 as it gains transmissibility while incrementally evading antibody neutralization.
Findings: From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods – 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43·06 (95% CI: 40·18;45·94), and the mean EQ-5D health index was 0·66 (95% CI: 0·64;0·68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0·01; 95% CI: -0·02;0·04; p =0·45) or the change in PCC-related symptom score (with a mean difference of -1·18; 95% CI: -3·54;1·17; p =0·32). Interpretation: We conclude that CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo.
In children aged 5-11 years, two doses of BNT162b2 provide moderate protection against symptomatic Omicron infection and high protection against severe outcomes. Protection wanes more rapidly for infection than severe outcomes. Longer dosing intervals may confer higher protection against symptomatic infection in the short-term, but further evaluation of the duration of the observed protection is needed.
Aerosol inhalation is increasingly well recognized as a major if not primary mode of transmission of SARS-CoV-21,2. Over the course of the COVID-19 pandemic, three highly transmissible lineages evolved and became globally dominant3. One hypothesis to explain increased transmissibility is that natural selection favours variants with higher rates of viral aerosol shedding. However, the extent of aerosol shedding of successive SARS-CoV-2 variants is unknown. Here, we demonstrate that viral shedding (measured as RNA copies) into exhaled breath aerosol was significantly greater during infections with Alpha, Delta, and Omicron than with ancestral strains and variants not associated with increased transmissibility. The three highly transmissible variants independently evolved a high viral aerosol shedding phenotype, demonstrating convergent evolution. We did not observe statistically significant differences in rates of shedding between Alpha, Delta, and Omicron infections. The highest shedder in our study, however, had an Omicron infection and shed three orders of magnitude more viral RNA copies than the maximum observed for Delta and Alpha4. Our results also show that fully vaccinated and boosted individuals, when infected, can shed infectious SARS-CoV-2 via exhaled breath aerosols. These findings provide additional evidence that inhalation of infectious aerosols is the dominant mode of transmission and emphasize the importance of ventilation, filtration, and air disinfection to mitigate the pandemic and protect vulnerable populations. We anticipate that monitoring aerosol shedding from new SARS-CoV-2 variants and emerging pathogens will be an important component of future threat assessments and will help guide interventions to prevent transmission via inhalation exposure.
July 31, 2022
Facemasks have become a symbol of disease prevention in the context of COVID-19; yet, there still exists a paucity of collected scientific evidence surrounding their epidemiological efficacy in the prevention of SARS-CoV-2 transmission. This systematic review sought to analyze the efficacy of facemasks, regardless of type, on the prevention of SARS-CoV-2 transmission in both healthcare and community settings. The initial review yielded 1732 studies, which were reviewed by three study team members. Sixty-one full text studies were found to meet entry criteria, and 13 studies yielded data that was used in the final analysis. In all, 243 subjects were infected with COVID-19, of whom 97 had been wearing masks and 146 had not. The probability of getting COVID-19 for mask wearers was 7% (97/1463, p=0.002), for non-mask wearers, probability was 52% (158/303, p=0.94). The Relative Risk of getting COVID-19 for mask wearers was 0.13 (95% CI: 0.10-0.16). Based on these results, we determined that across healthcare and community settings, those who wore masks were less likely to contact COVID-19. Future investigations are warranted as more information becomes available.
July 30, 2022
Booster vaccination with mRNA-1273 COVID-19 vaccine was more effective than BNT162b2 in preventing SARS-CoV-2 infection and COVID-19 hospitalisation during the first 12 weeks after vaccination, during a period of Delta followed by Omicron variant dominance.
July 29, 2022
Among persons aged ≥50 years who reported homologous mRNA COVID-19 vaccination, injection site and systemic reactions were less frequent after a second booster dose than after the first booster dose. Ninety-five percent of 8,515 events reported to the Vaccine Adverse Event Reporting System were nonserious.
July 27, 2022
The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste. A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid.
Epidemiologic data consistently show strong protection for young children against severe COVID-19 illness. Several mechanisms have been proposed to explain this phenomenon, including cross-reactive immunity—in which prior exposure to non-SARS-CoV-2 coronaviruses that commonly infect children confers some resistance to severe COVID-19 illness. We identified 3,126,427 adults (24% [N = 743,814] with children ≤18, and 8.8% [N = 274,316] with youngest child 0–5 years) to assess whether parents of young children—who have high exposure to non-SARS-CoV-2 coronaviruses—may also benefit from potential cross-immunity. In a large, real-world population, exposure to young children was strongly associated with less severe COVID-19 illness, after balancing known COVID-19 risk factors. This epidemiologic signal suggests endemic coronavirus cross-immunity may play a role in protection against severe COVID-19 outcomes.
Because variants of SARS-CoV-2 continue to arise and reduce the protection afforded by vaccination or prior infection, it is becoming increasingly important that vaccines be developed that target more conserved regions of the SARS-CoV-2 spike protein. Here, Ng et al. tested whether antibodies targeting the more conserved S2 subunit of the spike protein could confer protection against infection with distinct coronaviruses. The authors observed that S2-targeted vaccination produced antibodies in mice that could neutralize diverse alphacoronaviruses and betacoronaviruses. These antibodies had increased breadth relative to antibodies elicited by full-length spike protein vaccination, suggesting less repertoire focusing. Thus, S2-targeted vaccination may be a strategy to achieve pan-SARS-CoV-2 immunity.
In this cohort study of more than 95 000 Rhode Island residents from March 2020 to December 2021, including residents and employees of long-term congregate care (LTCC) facilities, completion of the primary vaccination series after recovery from COVID-19 was associated with 49% protection from reinfection among LTCC residents, 47% protection among LTCC employees, and 62% protection in the general population during periods when wild type, Alpha, and Delta strains of SARS-CoV-2 were predominant. These findings suggest that among people who have recovered from COVID-19, subsequent completion of the primary vaccination series reduced the risk of reinfection by approximately half.
July 26, 2022
When the US Centers for Disease Control and Prevention (CDC) halved its recommended isolation time for people with COVID-19 to five days back in December, it said that the change was motivated by science. Specifically, the CDC said that most SARS-CoV-2 transmission occurs early in the course of the illness, in the one to two days before the onset of symptoms and for two to three days after. Many scientists disputed that decision then and they continue to do so. Such dissent is bolstered by a series of studies confirming that many people with COVID-19 remain infectious well into the second week after they first experience symptoms. Reductions in the length of the recommended isolation period — now common around the world — are driven by politics, they say, rather than any reassuring new data.
This is the eighth update alert for a living rapid review (1) on the use of masks for the prevention of respiratory virus infections, including SARS-CoV-2, in health care and community settings. The first 3 updates (2–4) were monthly, after which the interval was switched to bimonthly (5, 6). Beginning in June 2021, the interval was extended to biannually. For this update, searches were done from 3 December 2021 to 2 June 2022 using the same search methods as the original review. Inclusion was restricted to randomized trials and observational studies that controlled for confounders. Non–peer-reviewed studies were excluded unless they were based on data collected after February 2021 to capture evidence on mask use in the B.1.617.2 (Delta) and B.1.1.529 (Omicron) variant predominant periods. The update searches identified 1592 citations. No new randomized controlled trials (RCTs) and 5 new observational studies on the association of mask use and SARS-CoV-2 infection met inclusion criteria (Supplement Table 1). Three studies were done in community settings (7–9), and 2 studies (10, 11) were done in health care settings. One preprint study (9) of mask use in community settings collected data during Delta and Omicron predominant periods; the other studies were done before the emergence of these variants. All studies had methodological limitations, including unclear or low participation rate, potential recall bias, and failure to report attrition or missing data (Supplement Table 2).
Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings, have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Here we aimed to deeply profile the vaccine-induced humoral immune response in 6 to 11 year old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children that experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100 μg dose, but more variable immunity at a 50 μg dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain-binding, but robustly preserved omicron spike protein-binding. Fc-receptor binding capabilities were also preserved in a dose dependent manner. These data indicate that both the 50 μg and 100 μg doses of mRNA vaccination in children elicits robust cross-VOC antibody responses and that 100 μg doses in children results in highly preserved omicron-specific functional humoral immunity.
Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 is critical to preventing zoonotic outbreaks before they become the next pandemic. The Huanan Seafood Wholesale Market in Wuhan, China, was identified as a likely source of cases in early reports but later this conclusion became controversial. We show the earliest known COVID-19 cases from December 2019, including those without reported direct links, were geographically centered on this market. We report that live SARS-CoV-2 susceptible mammals were sold at the market in late 2019 and, within the market, SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals. While there is insufficient evidence to define upstream events, and exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred via the live wildlife trade in China, and show that the Huanan market was the epicenter of the COVID-19 pandemic.
Understanding the circumstances that lead to pandemics is important for their prevention. Here, we analyze the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted A and B. Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October–8 December), while the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.
Communities most at risk of severe COVID-19 outcomes have half the rate of prescriptions compared with less vulnerable communities, according to a CDC report.
Tixagevimab plus cilgavimab, a SARS-CoV-2–neutralizing monoclonal antibody combination marketed as Evusheld, protected nonhospitalized individuals with mild to moderate COVID-19 symptoms from progressing to severe COVID-19 or death in a clinical trial. The study, published in The Lancet Respiratory Medicine, is the first to evaluate the intramuscular injection for outpatient treatment; other anti–SARS-CoV-2 monoclonal antibodies must be administered intravenously or subcutaneously.
July 25, 2022
Background In a context of multiple Omicron lineages circulation, it is relevant to clarify the effect of vaccination and previous infections on the risk of infection and severe post-infection outcomes. Methods Using electronic health records and SARS-CoV-2 laboratory surveillance data, we conducted a case-case and a cohort study covering the period of Omicron BA.2/BA.5 lineage replacement in Portugal, to compare vaccine effectiveness of complete primary and booster dose against infection, COVID-19 hospitalization, and mortality. Variant classification was performed through whole-genome sequencing (WGS) or Spike Gene Target Failure (SGTF). Findings Between April 25 and June 10, 2022, within a total of 27702 collected samples, 55.5% were classified as BA.2 and the remaining as BA.5. We observed no evidence of reduced vaccine effectiveness for the primary complete vaccination (OR=1.07, CI95%:0.93-1.23) or booster dose vaccination (OR=0.96, CI95%:0.84-1.09) against BA.5 infection compared with BA.2. The protection against reinfection was inferior in BA.5 cases when compared with BA.2 (OR=1.44; CI95%:1.30-1.60). Among those infected with BA.5, booster vaccination was associated with 77% and 88% of reduction in risk of COVID-19 hospitalization and death, respectively, while higher risk reduction was found for BA.2 cases, with 93% and 94%, respectively. Interpretation This study shows that the SARS-CoV-2 Omicron BA.5 lineage is associated with higher odds of reinfection compared with Omicron BA.2, regardless of the vaccination status. Although less effective compared with BA.2, COVID-19 booster vaccination still offers substantial protection against severe outcomes following BA.5 infection.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.
A robust antiviral innate immune response is indispensable for combating infections. However, an exacerbated response can result in pathological inflammation and tissue damage. mRNA translational control mechanisms play a crucial role in maintaining the appropriate magnitude and duration of the immune response. We show that the GIGYF2/4EHP translational repressor complex represses translation of Ifnb1 mRNA, which encodes type I interferon β (IFN-β). We also demonstrate that the NSP2 protein encoded by SARS-CoV-2 virus further impedes translation of Ifnb1 mRNA through coopting the GIGYF2/4EHP complex, leading to evasion of a cellular innate immune response. The knowledge of the mechanism of action of NSP2-mediated IFN-β suppression provides valuable information for development of treatments for infections of SARS-CoV-2 and other coronaviruses.
Tixagevimab-cilgavimab is a combination medication to help prevent COVID-19 infection. Tixagevimab-cilgavimab (Evusheld) consists of 2 long-acting monoclonal antibodies that bind to the spike protein of the virus that causes COVID-19 to prevent it from infecting human cells.
July 22, 2022
In this cohort study of 1884 SARS-CoV-2–positive children with 90-day follow-up, 5.8% of patients, including 9.8% of hospitalized children and 4.6% of discharged children, reported PCCs. Characteristics associated with PCCs included being hospitalized 48 hours or more, having 4 or more symptoms reported at the index ED visit, and being 14 years of age or older. In this cohort study, SARS-CoV-2 infection was associated with reporting PCCs at 90 days in children. Guidance and follow-up are particularly necessary for hospitalized children who have numerous acute symptoms and are older.
Children between the ages of 6 months and 5 years of age finally became eligible for COVID-19 vaccination in the U.S. on June 18, after the Director of the Centers for Disease Control and Prevention (CDC) recommended their use for this population, following emergency use authorization granted by the Food and Drug Administration. We recently wrote about some of the issues to consider in vaccinating young children, ranging from fewer access points and more reticence among their parents, compared to their 5-11 year-old counterparts. Here, we examine the status of vaccine uptake in this group, one month into their eligibility. Our analysis is based on data obtained from CDC’s Data Tracker on the number of first COVID-19 doses administered by age as of July 20, 2022 nationally and by jurisdiction (see methods below for more information). Overall, we find that vaccination has already peaked in the youngest age group, and is far below where 5-11 year-olds (who became eligible in November of last year) were at this point in their eligibility:
July 21, 2022
As the virus continues its accelerated ability to evade our immune response and increase its transmissibility, we urgently need to achieve population-wide respiratory mucosal immunity. The objective of breaking the chain of transmission at the individual and population level will put us in a far better position to achieve containment of the virus, no less reducing the toll of sickness and long COVID-19. The prospect of achieving this with nasal vaccines is high, but will only be possible with dedicated funding, priority, and breaking down of any regulatory hurdles. While we have waited far too long to take such initiative, a new operation at lightning speed could help us get ahead of the virus and build on the initial success of COVID-19 vaccines.
The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a shorter incubation period and a higher transmission rate than previous variants. Recently, the Centers for Disease Control and Prevention recommended shortening the strict isolation period for infected persons in non–health care settings from 10 days to 5 days after symptom onset or after the initial positive test, followed by 5 days of masking. However, the viral decay kinetics of the omicron variant and the duration of shedding of culturable virus have not been well characterized.
In the third year of the coronavirus disease 2019 (Covid-19) pandemic, the omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has swept the globe and yielded several subvariants. Currently, BA.2 is overtaking BA.1 in frequency. In addition, BA.2.12.1 infection is increasing quickly and already accounts for more than 50% of new infections in the United States. Therefore, the protection of current vaccines and the need to develop future vaccination strategies are of great concern.
July 20, 2022
As of June 2022, the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been divided into five distinct sublineages: BA.1, BA.2, BA.3, BA.4, and BA.5. Most circulating omicron variants belong to sublineage BA.2; however, the prevalence of BA.2.12.1 (a subvariant of BA.2), BA.4, and BA.5 is increasing rapidly in several regions of the world.2 Previous studies have shown that the BA.2 subvariants have sensitivities to some monoclonal and polyclonal antibodies that are lower than those of the ancestral strains and other SARS-CoV-2 variants.
Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection represent a major issue in long coronavirus disease. How SARS-CoV-2 gains access to the brain and how infection leads to neurological symptoms are not clear because the principal means of viral entry by endocytosis, the angiotensin-converting enzyme 2 receptor, are barely detectable in the brain. We report that human neuronal cells, nonpermissive to infection through the endocytic pathway, can be infected when cocultured with permissive infected epithelial cells. SARS-CoV-2 induces the formation of tunneling nanotubes (TNTs) and exploits this route to spread to uninfected cells. In cellulo correlative fluorescence and cryo–electron tomography reveal that SARS-CoV-2 is associated with TNTs between permissive cells. Furthermore, multiple vesicular structures such as double-membrane vesicles, sites of viral replication, are observed inside TNTs between permissive and nonpermissive cells. Our data highlight a previously unknown mechanism of SARS-CoV-2 spreading, likely used as a route to invade nonpermissive cells and potentiate infection in permissive cells.
A total of 255,936 children were included in the analysis. Among unvaccinated children, the crude incidence rates of all reported SARS-CoV-2 infections, PCR-confirmed SARS-CoV-2 infections, and Covid-19–related hospitalizations were 3303.5, 473.8, and 30.0 per 1 million person-days, respectively. Among partially vaccinated children, vaccine effectiveness was 13.6% (95% confidence interval [CI], 11.7 to 15.5) against all SARS-CoV-2 infections, 24.3% (95% CI, 19.5 to 28.9) against PCR-confirmed SARS-CoV-2 infection, and 42.3% (95% CI, 24.9 to 55.7) against Covid-19–related hospitalization; in fully vaccinated children, vaccine effectiveness was 36.8% (95% CI, 35.3 to 38.2), 65.3% (95% CI, 62.0 to 68.3), and 82.7% (95% CI, 74.8 to 88.2), respectively.
The course of the current pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will be determined in part by the quality and durability of protective immunity induced by previous infection, vaccination, or both, as well as by the severity of illness in persons with some level of immunity.1,2 From March 2020 through October 2021 in the Household Influenza Cohort Study (HICS) study, we followed 2353 participants, ranging in age from newborn infants to elderly persons up to 94 years of age, in 437 households in Nicaragua for the presence of SARS-CoV-2 infection (Figure 1A).
July 20, 2022
One emerging sublineage, BA.2.75, is increasing in frequency in India and has been detected in at least 15 countries as of 19 July 2022. Relative to BA.2, BA.2.75 carries nine additional mutations in spike. Here we report the sensitivity of the BA.2.75 spike to neutralization by a panel of clinically-relevant and pre-clinical monoclonal antibodies, as well as by serum from blood donated in Stockholm, Sweden, before and after the BA.1/BA.2 infection wave. BA.2.75 does not show greater immune evasion than the currently-dominating BA.5 in our set of serum samples, and exhibits moderate susceptibility to tixagevimab and cilgavimab that form a widely used monoclonal antibody cocktail (Evusheld).
July 19, 2022
The SARS-CoV-2 Omicron variant of concern comprises several sublineages with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1, and BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations lead to enhanced ACE2 binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, and BA.4/5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.
In this study, we found that CVD was increased early after COVID-19 mainly from pulmonary embolism, atrial arrhythmias, and venous thromboses. DM incidence remained elevated for at least 12 weeks following COVID-19 before declining. People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.
The US Food and Drug Administration (FDA) has revised the Emergency Use Authorization (EUA) for nirmatrelvir/ritonavir, commonly known as Paxlovid, to allow state-licensed pharmacists to prescribe the medication to eligible patients with COVID-19 who are at high risk of progressing to severe disease, with certain limitations. The action is expected to widen access to the drug during the brief period after the onset of symptoms when it is effective.
SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19 vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2) and Omicron BA.1.1 in the BAL compared to COVID-19 convalescents, despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses, not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during re-infection, but offer limited protection against breakthrough infection, especially by Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by Omicron sublineage and future VOCs.
Immune memory to Common Cold Coronaviruses (CCCs) influences SARS-CoV-2 infection outcome, and understanding its effect is crucial for pan-coronavirus vaccine development. We performed a longitudinal analysis of pre-COVID19-pandemic samples from 2016-2019 in young adults and assessed CCC-specific CD4+ T cell and antibody responses. Notably, CCC responses were commonly detected with comparable frequencies as other common antigens and were sustained over time. CCC-specific CD4+ T cell responses were associated with low HLA-DR+CD38+ signals and their magnitude did not correlate with yearly CCC infection prevalence. Similarly, CCC-specific spike RBD-specific IgG responses were stable in time. Finally, high CCC-specific CD4+ T cell reactivity, but not antibody titers, was associated with pre-existing SARS-CoV-2 immunity. These results provide a valuable reference for understanding immune response to endemic coronaviruses and suggest that steady and sustained CCC responses are likely from a stable pool of memory CD4+ T cells, due to repeated earlier exposures and possibly occasional reinfections.
July 18, 2022
Despite bebtelovimab's crucial interest related to COVID-19 treatment strategy, as a single intravenous dose administered in 30 s with no drug–drug interactions, it has not been submitted to regulatory authorities anywhere outside the USA, either for clinical care or for research purposes. However, Eli Lilly has just decided to supply an additional 150 000 doses of bebtelovimab solely to the US Government.
The most dire consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may not manifest during the initial infection but appear later and are disproportionately associated with compromised neural function. Central nervous system (CNS) complications often appear after the acute phase but persist and become prominent later and last for weeks to months (i.e., long COVID).
SARS-CoV-2 surveillance by wastewater-based epidemiology is poised to provide a complementary approach to sequencing individual cases. However, robust quantification of variants and de novo detection of emerging variants remains challenging for existing strategies. We deep sequenced 3,413 wastewater samples representing 94 municipal catchments, covering >59% of the population of Austria, from December 2020 to February 2022. Our system of variant quantification in sewage pipeline designed for robustness (termed VaQuERo) enabled us to deduce the spatiotemporal abundance of predefined variants from complex wastewater samples. These results were validated against epidemiological records of >311,000 individual cases. Furthermore, we describe elevated viral genetic diversity during the Delta variant period, provide a framework to predict emerging variants and measure the reproductive advantage of variants of concern by calculating variant-specific reproduction numbers from wastewater. Together, this study demonstrates the power of national-scale WBE to support public health and promises particular value for countries without extensive individual monitoring.
Above all, the government must stop gaslighting the public and be honest about the threat the pandemic still poses to them and the NHS. Being honest with the public will have two positive results, it will encourage the public to modify behaviour and, we hope, provoke urgent reflection about how the NHS is in such a mess so soon after the nation was applauding it on their doorsteps.
We found a high protection against BA.5 from prior omicron infection in triple-vaccinated individuals, and similar vaccine effectiveness for BA.5 infection as currently for BA.2. In an analysis adjusted for covariates, BA.5 infection was associated with an increased risk of hospitalisation which needs confirmation and continued surveillance as hospitalisations were low and stable during the study period.
July 17, 2022
SARS-CoV-2 Omicron rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission and immune evasion are thought to be driven by numerous mutations in the Omicron Spike protein. Here, we systematically introduced BA.1 and/or BA.2 Omicron Spike mutations into the ancestral Spike protein and examined impacts on Spike function, processing and susceptibility to neutralization. Individual mutations of S371F/L, S375F and T376A in the ACE2 receptor-binding domain as well as Q954H and N969K in the hinge region 1 impaired infectivity, while changes of G339D, D614G, N764K and L981F moderately enhanced it. Most mutations in the N-terminal region and the receptor binding domain reduced sensitivity of the Spike protein to neutralization by sera from individuals vaccinated with the BNT162b2 vaccine and by therapeutic antibodies. Our results represent a systematic functional analysis of Omicron Spike adaptations that have allowed this SARS-CoV-2 variant to dominate the current pandemic.
The SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern (VOC) and its sub-lineages (including BA.2, BA.4/5, BA.2.12.1) contain spike mutations that confer high level resistance to neutralizing antibodies. The NVX-CoV2373 vaccine, a protein nanoparticle vaccine, has value in countries with constrained cold-chain requirements. Here we report neutralizing titers following two or three doses of NVX-CoV2373. We show that after two doses, Omicron sub-lineages BA.1 and BA.4 were resistant to neutralization by 72% (21/29) and 59% (17/29) of samples. However, after a third dose of NVX-CoV2373, we observed high titers against Omicron BA.1 (GMT: 1,197) and BA.4 (GMT: 582), with responses similar in magnitude to those triggered by three doses of an mRNA vaccine. These data are of particular relevance as BA.4 is emerging to become the dominant strain in many locations, and highlight the potential utility of the NVX-CoV2373 vaccine as a booster in resource-limited environments.
July 15, 2022
Among presumed immunocompromised persons aged ≥12 years, local and systemic reactions were less frequently reported to v-safe after mRNA booster (dose 4) than after primary series dose 3. Only 17 serious adverse events were reported to VAERS. Serious adverse events after mRNA booster (dose 4) are rare. Immunocompromised persons aged ≥12 years should receive a first booster ≥3 months after a 3-dose primary COVID-19 vaccination series and a second booster ≥4 months after the first booster.
In this cohort study of self-reported data from 981 099 persons aged 12 years or older, simultaneous administration of a COVID-19 mRNA booster dose and an influenza vaccine was associated with 8% to 11% increases, respectively, in systemic reaction compared with COVID-19 mRNA booster alone. These differences were statistically significant.
Early in 2021, many people began sharing that they experienced unexpected menstrual bleeding after SARS-CoV-2 inoculation. We investigated this emerging phenomenon of changed menstrual bleeding patterns among a convenience sample of currently and formerly menstruating people using a web-based survey. In this sample, 42% of people with regular menstrual cycles bled more heavily than usual, while 44% reported no change after being vaccinated. Among respondents who typically do not menstruate, 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of postmenopausal people reported breakthrough bleeding. We found that increased/breakthrough bleeding was significantly associated with age, systemic vaccine side effects (fever and/or fatigue), history of pregnancy or birth, and ethnicity. Generally, changes to menstrual bleeding are not uncommon or dangerous, yet attention to these experiences is necessary to build trust in medicine.
July 14, 2022
SARS-CoV-2 variants may threaten the effectiveness of vaccines and antivirals to mitigate serious COVID-19 disease. This is of most concern in clinically vulnerable groups such as older adults. We analysed 72 sera samples from 37 individuals, aged 70–89 years, vaccinated with two doses of BNT162b2 (Pfizer–BioNTech) 3 weeks apart, for neutralizing antibody responses to wildtype SARS-CoV-2. Between 3 and 20 weeks after the second vaccine dose, neutralizing antibody titres fell 4.9-fold to a median titre of 21.3 (neutralization dose 80%), with 21.6% of individuals having no detectable neutralizing antibodies at the later time point. Next, we examined neutralization of 21 distinct SARS-CoV-2 variant spike proteins with these sera, and confirmed substantial antigenic escape, especially for the Omicron (B.1.1.529, BA.1/BA.2), Beta (B.1.351), Delta (B.1.617.2), Theta (P.3), C.1.2 and B.1.638 spike variants. By combining pseudotype neutralization with specific receptor-binding domain (RBD) enzyme-linked immunosorbent assays, we showed that changes to position 484 in the spike RBD were mainly responsible for SARS-CoV-2 neutralizing antibody escape. Nineteen sera from the same individuals boosted with a third dose of BNT162b2 contained higher neutralizing antibody titres, providing cross-protection against Omicron BA.1 and BA.2. Despite SARS-CoV-2 immunity waning over time in older adults, booster vaccines can elicit broad neutralizing antibodies against a large number of SARS-CoV-2 variants in this clinically vulnerable cohort.
A respiratory virus emitted in an aerosol particle will experience a tough journey with many obstacles before finding a new host where it can cause an infection (Fig. 1). By every second, its chances to replicate decrease due to removal by building ventilation, deposition on surfaces, or loss in infectivity. Thus, the transport of infectious viruses from the exhaled breath of one person to the inhaled air of another typically occurs within a few minutes. During this short time, the aerosol will undergo several transformations because of changing environmental conditions. Nevertheless, due to methodological challenges, we still have a remarkably limited understanding of the relationships between environmental factors and survival of pathogens in aerosols on short timescales. In a study in PNAS, Oswin et al. (1) show that the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can decrease abruptly when aerosol particles move between environments.
Infection with a pre-Omicron SARS-CoV-2 variant protects against reinfection with a second, although the effect fades almost completely after three years.
The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.
July 13, 2022
As compared with a third dose, a fourth dose of an mRNA COVID-19 vaccine, administered during the Omicron era, was associated with reduced risk of death from all causes in residents of LTCFs and in the oldest old during the first two months, after which the protection became slightly lower. These findings suggest that a fourth dose may prevent premature mortality in the oldest and frailest even after the emergence of the Omicron variant, although the timing of vaccination seems to be important with respect to the slight waning observed after two months.
We studied the prevalent cytotoxic CD8 T-cell response mounted against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein269-277 epitope (sequence YLQPRTFLL) via the most frequent Human Leukocyte Antigen (HLA) class I worldwide, HLA A∗02. The Spike P272L mutation that has arisen in at least 112 different SARS-CoV-2 lineages to date, including in lineages classified as ‘variants of concern’, was not recognised by the large CD8 T-cell response seen across cohorts of HLA A∗02+ convalescent patients and individuals vaccinated against SARS-CoV-2, despite these responses comprising of over 175 different individual T-cell receptors. Viral escape at prevalent T-cell epitopes restricted by high frequency HLAs may be particularly problematic when vaccine immunity is focussed on a single protein such as SARS-CoV-2 Spike providing a strong argument for inclusion of multiple viral proteins in next generation vaccines and highlighting the need for monitoring T-cell escape in new SARS-CoV-2 variants.
These findings indicate that adolescent and young adult men are at the highest risk of myocarditis after mRNA vaccination. Use of a Pfizer vaccine over a Moderna vaccine and waiting for more than 30 days between doses might be preferred for this population. Incidence of myocarditis in children aged 5-11 years is very rare but certainty was low. Data for clinical risk factors were very limited. A clinical course of mRNA related myocarditis appeared to be benign, although longer term follow-up data were limited. Prospective studies with appropriate testing (eg, biopsy and tissue morphology) will enhance understanding of mechanism.
In this series involving 44 young children with acute hepatitis of uncertain cause, human adenovirus was isolated in most of the children, but its role in the pathogenesis of this illness has not been established.
Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children’s of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain.
July 12, 2022
The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We use an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.
The coronavirus spike (S) glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus S proteins. This class of mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and beta-coronaviruses, including animal coronavirus WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope, which is hidden in prefusion stabilized S, and becomes exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.
This study estimates the effectiveness of previous infection with SARSCoV2 in preventing reinfection with Omicron BA.4/BA.5 subvariants using a test negative, case control study design. Cases (SARSCoV2 positive test results) and controls (SARSCoV2 negative test results) were matched according to sex, 10 year age group, nationality, comorbid condition count, calendar week of testing, method of testing, and reason for testing. Effectiveness was estimated using the S gene target failure (SGTF) infections between May 7, 2022 and July 4, 2022. SGTF status provides a proxy for BA.4/BA.5 infections, considering the negligible incidence of other SGTF variants during the study. Effectiveness was also estimated using all diagnosed infections between June 8, 2022 and July 4, 2022, when BA.4/BA.5 dominated incidence. Effectiveness of a previous pre-Omicron infection against symptomatic BA.4/BA.5 reinfection was 15.1% (95% CI: -47.1 to 50.9%), and against any BA.4/BA.5 reinfection irrespective of symptoms was 28.3% (95% CI: 11.4 to 41.9%). Effectiveness of a previous Omicron infection against symptomatic BA.4/BA.5 reinfection was 76.1% (95% CI: 54.9 to 87.3%), and against any BA.4/BA.5 reinfection was 79.7% (95% CI: 74.3 to 83.9%). Results using all diagnosed infections when BA.4/BA.5 dominated incidence confirmed the same findings. Sensitivity analyses adjusting for vaccination status confirmed study results. Protection of a previous infection against BA.4/BA.5 reinfection was modest when the previous infection involved a preOmicron variant, but strong when the previous infection involved the Omicron BA.1 or BA.2 subvariants. Protection of a previous infection against BA.4/BA.5 was lower than that against BA.1/BA.2, consistent with BA.4/BA.5 greater capacity for immune system evasion than that of BA.1/BA.2.
SARS-CoV-2 adaptation to its human host is evidenced by the emergence of new viral lineages with distinct genotypic and phenotypic characteristics, termed variants of concern (VOCs). Particular VOCs have become sequentially dominant globally (Alpha, Delta, Omicron) with each evolving independently from the ancestral Wuhan strain. Omicron is notable for its large number of Spike mutations found to promote immune escape and re-infection. Most recently, Omicron BA.4 and BA.5 subvariants have emerged with increasing levels of adaptive immune escape threatening vaccine effectiveness and increasing hospitalisations. Here, we demonstrate that the most recent Omicron variants have enhanced capacity to antagonise or evade human innate immune defenses. We find Omicron BA.4 and BA.5 replication is associated with reduced activation of epithelial innate immune responses versus earlier BA.1 and BA.2 subvariants. We also find enhanced expression of innate immune antagonist proteins Orf6 and N, similar to Alpha, suggesting common pathways of human adaptation and linking VOC dominance to improved innate immune evasion. We conclude that Omicron BA.4 and BA.5 have combined evolution of antibody escape with enhanced antagonism of human innate immunity to improve transmission and possibly reduce immune protection from severe disease.
Canada and the United States are wealthy federal democracies that share ties of history, culture, language, and the world’s longest undefended border. However, the countries are not identical, and this truth has been underlined during the recent pandemic. As Galvani et al. (1) note in PNAS, Canada’s response to the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been far more successful at preserving life and health than the US response, with per-capita SARS-CoV-2 attributed mortality around 3 times higher in the United States than in Canada. The authors suggest that is due, in part, to an important difference between Canada and the United States: Canada has universal, single-payer health insurance; the US health insurance system is a patchwork, with millions of individuals uninsured, or underinsured.
Neurological and neuropsychiatric symptoms occur in as many as one-third of patients with or recovering from COVID-19. To address severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neural tropism, we evaluated the vulnerability of primary developing and adult cortical tissue and stem-cell-derived cortical organoids to SARS-CoV-2 infection. We observe robust infection and viral replication in human cortical astrocytes; they become reactive, have increased growth factor signaling, and activate cellular stress. Despite infection in astroglial cells, there is minimal infection of other neural cell types, including neurons. Surprisingly, we discover that astrocyte infection is unlikely to be mediated by the predominant coronavirus receptor, ACE2, and instead observe alternative glycoproteins, CD147 and DPP4, expressed on astrocytes; they are necessary and sufficient for SARS-CoV-2 infection.
July 11, 2022
Pfizer’s coronavirus protease inhibitor Paxlovid (nirmatrelvir and ritonavir) is being widely used now, and it’s been clear since the beginning that resistant strains of the virus could appear against it. After all, that’s what viruses do. With their vast numbers, fast generation time, and number of mutations, resistance to a given small molecule is generally just a matter of “when”, not “if”. The usual way around this problem is to try to use a drug cocktail, hitting the pathogen simultaneously with compounds that target more than one mechanism. That’s the idea behind the two most successful small-molecule viral therapies we have, against HIV and Hepatitis C.
Currently, many restrictions and protective measures are relaxed because Omicron is highly transmissible but usually causes mild to moderate acute disease. This raises hope that SARS-CoV-2 may evolve towards reduced pathogenicity and become similar to circulating coronaviruses causing mild respiratory infections. More work needs to be done to clarify whether the current Omicron and future variants of SARS-CoV-2 may also cause lasting brain abnormalities and whether these can be prevented by vaccination or therapy. However, the finding by Douaud and colleagues1 that SARS-CoV-2 causes structural changes in the brain that may be permanent and could relate to neurological decline is of concern and illustrates that the pathogenesis of this virus is markedly different from that of circulating human coronaviruses. Further studies, to elucidate the mechanisms underlying COVID-19-associated neurological abnormalities and how to prevent or reverse them are urgently needed.
July 10, 2022
The infectivity of virus in primary swabs and expanded isolates revealed whilst BA.1 and BA.2 are attenuated through ACE2/TMPRSS2, BA.5 infectivity is equivalent to that of an early 2020 circulating clade and has greater sensitivity to the TMPRSS2 inhibitor Nafamostat. As with BA.1, we observed BA.5 to significantly reduce neutralisation titres across all donors. Concentrated pooled human IgG from convalescent and vaccinated donors had greater breadth of neutralisation, although the potency was still reduced 7-fold with BA.5. Of all therapeutic antibodies tested, we observed a 14.3-fold reduction using Evusheld and 16.8 reduction using Sotrovimab when neutralising a Clade A versus BA.5 isolate. These results have implications for ongoing tracking and management of Omicron waves globally.
July 9, 2022
The present analysis included 223 individuals recovered from mainly mild to moderate SARS-CoV-2 infections (100 female/123 male, age [years], mean +- SD, 55.54 +- 7.07) and 223 matched healthy controls (93 female/130 male, 55.74 +- 6.60). Among all 11 MR imaging markers tested, significant differences between groups were found in global measures of mean diffusivity and extracellular free-water which were both elevated in the white matter of post-SARS-CoV-2 individuals comparing to matched controls (free-water: 0.148 +- 0.018 vs. 0.142 +- 0.017, P<.001; mean diffusivity [10-3 mm2/s]: 0.747 +- 0.021 vs. 0.740 +- 0.020, P<.001). Classification accuracy for detecting post-SARS-CoV-2 individuals based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups. Conclusions and Relevance: Our findings suggest that subtle changes in white matter extracellular water content may last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed.
July 8, 2022
Immunocompromised patients accounted for 12.2% of all adult COVID-19 hospitalizations among 10 states and had increased odds of ICU admission and in-hospital death compared with nonimmunocompromised patients, irrespective of vaccination status. Known multilayered prevention measures, including nonpharmaceutical interventions, up-to-date COVID-19 vaccination, and therapeutics, can prevent hospitalization and subsequent severe COVID-19 outcomes among immunocompromised persons.
The acute effects of various respiratory viral infections have been well studied, with extensive characterization of the clinical presentation as well as viral pathogenesis and host responses. However, over the course of the recent COVID-19 pandemic, the incidence and prevalence of chronic sequelae after acute viral infections have become increasingly appreciated as a serious health concern. Post-acute sequelae of COVID-19, alternatively described as “long COVID-19,” are characterized by symptoms that persist for longer than 28 days after recovery from acute illness. Although there exists substantial heterogeneity in the nature of the observed sequelae, this phenomenon has also been observed in the context of other respiratory viral infections including influenza virus, respiratory syncytial virus, rhinovirus, severe acute respiratory syndrome coronavirus, and Middle Eastern respiratory syndrome coronavirus. In this Review, we discuss the various sequelae observed following important human respiratory viral pathogens and our current understanding of the immunological mechanisms underlying the failure of restoration of homeostasis in the lung.
Researchers in California have flushed a wealth of data out of toilet waste. For the first time, scientists have been able to detect specific variants of SARS-CoV-2 in sewage weeks before they were showing up in testing clinics.
July 7, 2022
As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing/sequencing capacity, which can also introduce biases1–3. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing4,5. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here, we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We develop and deploy improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detect emerging variants of concern up to 14 days earlier in wastewater samples, and identify multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.
A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.
July 6, 2022
SARS-CoV-2 spreads via droplets, aerosols, and smear infection. From the beginning of the COVID-19 pandemic, using a facemask in different locations was recommended to slow down the spread of the virus. To evaluate facemasks' performance, masks' filtration efficiency is tested for a range of particle sizes. Although such tests quantify the blockage of the mask for a range of particle sizes, the test does not quantify the cumulative amount of virus-laden particles inhaled or exhaled by its wearer. In this study, we quantify the accumulated viruses that the healthy person inhales as a function of time, activity level, type of mask, and room condition using a physics-based model. We considered different types of masks, such as surgical masks and filtering facepieces (FFPs), and different characteristics of public places such as office rooms, buses, trains, and airplanes. To do such quantification, we implemented a physics-based model of the mask. Our results confirm the importance of both people wearing a mask compared to when only one wears the mask. The protection time before the healthy wearer has an infection risk of 50% reduces by 80% if only one wears the facemask instead of both people. The protection time is further reduced if the infected person starts to cough or increases the activity level by 85% and 99%, respectively. Results show the leakage of the mask can considerably affect the performance of the mask. For the surgical mask, the apparent filtration efficiency reduces by 75% with such a leakage, which cannot provide sufficient protection despite the high filtration efficiency of the mask. The facemask model presented provides key input in order to evaluate the protection of masks for different conditions in public places. The physics-based model of the facemask is provided as an online application.
SARS-CoV-2 neutralizing antibodies play a critical role in COVID-19 prevention and treatment but are challenged by viral evolution and the emergence of novel escape variants. Importantly, the recently identified Omicron sublineages BA.2.12.1 and BA.4/5 are rapidly becoming predominant in various countries. By determining polyclonal serum activity of 50 convalescent or vaccinated individuals against BA.1, BA.1.1, BA.2, BA.2.12.1, and BA.4/5, we reveal a further reduction of BA.4/5 susceptibility to vaccinee sera. Most notably, delineation of sensitivity to an extended 163-antibody panel demonstrates pronounced antigenic differences with distinct escape patterns among Omicron sublineages. Antigenic distance and/or higher resistance may therefore favor immune escape-mediated BA.4/5 expansion after the first Omicron wave. Finally, while most clinical-stage monoclonal antibodies are inactive against Omicron sublineages, we identify promising antibodies with high pan-SARS-CoV-2 neutralizing potency. Our study provides a detailed understanding of Omicron sublineage antibody escape that can inform on effective strategies against COVID-19.
We identified a total of 43 studies from 17 different countries. Our meta-analyses show that protection from recent infection and any symptomatic disease was high for ancestral, Alpha, Beta, and Delta variants but was substantially lower for the Omicron variant. Pooled effectiveness against reinfection by the Omicron variant was 38.8% (95% uncertainty interval [UI] 31.5–46.3) and 43.7% (18.4–74.4) against Omicron symptomatic disease. Mean pooled effectiveness was greater than 85% against severe disease (hospitalisation and death) for all variants, including Omicron. Protection from reinfection from ancestral, Alpha, and Delta variants declined over time but remained at 78.2% (38.9–95.1) at 40 weeks. Protection against reinfection by the Omicron variant declined more rapidly and was estimated at 29.0% (10.4–64.4) at 40 weeks. There were not enough data to estimate protection against symptomatic disease and severe disease considering time since infection.
July 5, 2022
To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded, rather than variable, immunodominant, and exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicrons and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.
Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it's still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune mediated mechanisms. Here, we assess neuropathology alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia / respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in specific brainstem nuclei of 5 COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2, the role of SARS-CoV-2 neurotropism in COVID-19 and its long-term sequelae require further investigation.
Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.
From March 2020 to October 2021, COVID-19 accounted for 1 in 8 deaths in the US and was a top 5 cause of death in every age group aged 15 years and older. Cancer and heart disease deaths exceeded COVID-19 deaths overall and in most age groups, whereas accidents were the leading cause of death among those aged 1 to 44 years. Compared with the 2020 time period, deaths from COVID-19 in the 2021 time period decreased in ranking among those aged 85 years or older but increased in ranking among those aged 15 to 54 years, and became the leading cause of death among those aged 45 to 54 years. The increased ranking of COVID-19 as a leading cause of death in some age groups is consistent with a downward age shift in the distribution of COVID-19 deaths in the US in 2021 compared with 2020, perhaps driven by higher COVID-19 vaccination rates in 2021 in the oldest age groups.
SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively1,2. These novel subvariants carrying additional mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.
July 4, 2022
Protease inhibitors are among the most powerful antiviral drugs. A first protease inhibitor against the SARS-CoV-2 protease 3CLpro, Paxlovid (nirmatrelvir / ritonavir), has recently been authorized by the U.S. FDA for emergency use (EUA 105 Pfizer Paxlovid). To find resistant mutants against the protease-inhibitor-component of Paxlovid, nirmatrelvir, we engineered a chimeric Vesicular Stomatitis Virus (VSV). By replacing an intergenic region, which is essential for separate gene transcription, with 3CLpro, this chimeric VSV became dependent on the protease to process two of its genes. We then applied selective pressure with nirmatrelvir to induce mutations. The effect of those mutants was confirmed by re-introduction in the 3CLpro and testing with a recently developed cellular assay. Furthermore, we found that mutations predicted by our method already exist in SARS-CoV-2 sequence depositions in NCBI and GISAID data bases. These may represent emerging resistant virus variants or a natural heterogeneity in the susceptibility to nirmatrelvir.
The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals’ lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.
July 1, 2022
By April 25, 2022, most U.S. counties had a pharmacy or public health clinic offering COVID-19 vaccines to children aged 5–11 years; fewer counties had a pediatric clinic, family medicine clinic, or federally qualified health center. The availability of each provider type was associated with higher county-level vaccination coverage among children aged 5–11 years.
A 2020 U.S. Public Health Service recommendation to test transplant candidates for HIV, HBV, and HCV during the transplant hospital admission could result in potentially harmful blood loss in pediatric transplant candidates. Children aged <13 years are among those at lowest risk for new HIV infections, and incidence of acute HBV and HCV infection in U.S. residents aged <20 years is extremely low.
In this longitudinal observational study conducted among health care workers with SARS-CoV-2 infections not requiring hospitalization, 2 or 3 doses of vaccine, compared with no vaccination, were associated with lower long COVID prevalence. Study limitations include that symptoms and duration were self-reported, and causality cannot be inferred.
Association of BNT162b2 Vaccine Third Dose Receipt With Incidence of SARS-CoV-2 Infection, COVID-19–Related Hospitalization, and Death Among Residents of Long-term Care Facilities, August to October 2021
In this cohort study of 18 611 residents at 640 long-term care facilities, the risk of SARS-CoV-2 infection, COVID-19–related hospitalizations, and COVID-19–related deaths was 89% to 96% lower among residents who received the third dose of BNT162b2 vaccine compared with vaccinees who received 2 doses at least 5 months earlier during the Delta variant surge in Israel.
In this pilot cohort study of 153 health care workers and hospital employees from a single health system, the group-coaching program was feasible and acceptable, as demonstrated by high demand, retention, and satisfaction. Measured according to validated scales, self-reported resilience, stress, anxiety, and burnout improved among participants.
The results of this cross-sectional study expand on recent single-center studies1,2 showing that hospitalizations for COVID-19–related croup increased after the onset of the Omicron variant. A more recent national investigation3 found that the percentage of children diagnosed with SARS-CoV-2 hospitalized with upper-airway infections increased significantly from pre-Omicron (1.4%) compared with Omicron (4.1%) periods. The hospitalization rate was higher in our study, which may be associated with use of ICD-10 codes rather than positive SARS-CoV-2 test results for COVID-19 data. Findings for association with COVID-19–related croup severity were mixed in our study. We noted a significant increase in the proportion of children requiring RE during Alpha or other variant and Omicron periods compared with the period of Delta predominance. However, we also observed no difference in the median number of RE doses, which was comparable to an estimate prior to COVID-19.5 The overall ICU admission rate in our sample was lower than a rate described prior to COVID-19,5 which may be associated with constraints on ICU capacity or, alternatively, less severe illness.
We hypothesise that the recently reported cases of severe acute hepatitis in children could be a consequence of adenovirus infection with intestinal trophism in children previously infected by SARS-CoV-2 and carrying viral reservoirs (appendix). In mice, adenovirus infection sensitises to subsequent Staphylococcal-enterotoxin-B-mediated toxic shock, leading to liver failure and death.9 This outcome was explained by adenovirus-induced type-1 immune skewing, which, upon subsequent Staphylococcal enterotoxin B administration, led to excessive IFN-γ production and IFN-γ-mediated apoptosis of hepatocytes.9 Translated to the current situation, we suggest that children with acute hepatitis be investigated for SARS-CoV-2 persistence in stool, T-cell receptor skewing, and IFN-γ upregulation, because this could provide evidence of a SARS-CoV-2 superantigen mechanism in an adenovirus-41F-sensitised host. If evidence of superantigen-mediated immune activation is found, immunomodulatory therapies should be considered in children with severe acute hepatitis.
June 30, 2022
Using BMI categories, there is evidence of protection against severe COVID-19 in people with overweight or obesity who have been vaccinated, which was of a similar magnitude to that of people of healthy weight. Vaccine effectiveness was slightly lower in people with underweight, in whom vaccine uptake was also the lowest for all ages. In the vaccinated cohort, there were increased risks of severe COVID-19 outcomes for people with underweight or obesity compared with the vaccinated population with a healthy weight. These results suggest the need for targeted efforts to increase uptake in people with low BMI (<18·5 kg/m2), in whom uptake is lower and vaccine effectiveness seems to be reduced. Strategies to achieve and maintain a healthy weight should be prioritised at the population level, which could help reduce the burden of COVID-19 disease.
Effective vaccines protect individuals by not only reducing the susceptibility to infection, but also reducing the infectiousness of breakthrough infections in vaccinated cases. To disentangle the vaccine effectiveness against susceptibility to infection (VES) and vaccine effectiveness against infectiousness (VEI), we took advantage of Danish national data comprising 24,693 households with a primary case of SARS-CoV-2 infection (Delta Variant of Concern, 2021) including 53,584 household contacts. In this setting, we estimated VES as 61% (95%-CI: 59-63), when the primary case was unvaccinated, and VEI as 31% (95%-CI: 26-36), when the household contact was unvaccinated. Furthermore, unvaccinated secondary cases with an infection exhibited a three-fold higher viral load compared to fully vaccinated secondary cases with a breakthrough infection. Our results demonstrate that vaccinations reduce susceptibility to infection as well as infectiousness, which should be considered by policy makers when seeking to understand the public health impact of vaccination against transmission of SARS-CoV-2.
The response to the COVID-19 pandemic prompted abrupt and potentially lasting changes to human behavior, including the types of direct contact that enable transmission of common pathogens. Although the handshake and other types of physical contact are gradually returning, they have been on an extended hiatus. Such changes have already altered the epidemiology of a broad range of infectious diseases, including influenza, measles, and norovirus, and will likely continue to affect their age distribution, severity, and typical seasonal patterns. Changes to contact patterns may also nudge the evolutionary trajectory of pathogens, as they adapt to new norms of less human contact. Initiatives to measure social contact patterns through time and track their effects on the epidemiology of endemic pathogens are essential to both manage
June 29, 2022
Scientists in Thailand have established that a tabby passed SARS-CoV-2 to a veterinary surgeon — although such cases of cat-to-human transmission are probably rare.
Lab studies identify resistance mutations in SARS-CoV-2’s protease, and some circulating variants have them.
This rapid systematic review found evidence suggesting that long distance airborne transmission of SARS-CoV-2 might occur in indoor settings such as restaurants, workplaces, and venues for choirs, and identified factors such as insufficient air replacement that probably contributed to transmission. These results strengthen the need for mitigation measures in indoor settings, particularly the use of adequate ventilation.
The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a shorter incubation period and a higher transmission rate than previous variants.1,2 Recently, the Centers for Disease Control and Prevention recommended shortening the strict isolation period for infected persons in non–health care settings from 10 days to 5 days after symptom onset or after the initial positive test, followed by 5 days of masking.3 However, the viral decay kinetics of the omicron variant and the duration of shedding of culturable virus have not been well characterized.
Among 136,127 eligible children who had been vaccinated during the study period, 94,728 were matched with unvaccinated controls. The estimated vaccine effectiveness against documented infection was 17% (95% confidence interval [CI], 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. The absolute risk difference between the study groups at days 7 to 21 after the second dose was 1905 events per 100,000 persons (95% CI, 1294 to 2440) for documented infection and 599 events per 100,000 persons (95% CI, 296 to 897) for symptomatic Covid-19. The estimated vaccine effectiveness against symptomatic Covid-19 was 18% (95% CI, −2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. We observed a trend toward higher vaccine effectiveness in the youngest age group (5 or 6 years of age) than in the oldest age group (10 or 11 years of age).
The value of variant-adapted vaccines that are capable of inducing a higher and broader immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at booster vaccination is currently being evaluated.1-4 We conducted a multicenter, randomized, single-blind trial to assess the immunogenicity and safety of two adjuvanted recombinant vaccines and the messenger RNA (mRNA) vaccine BNT162b2 (Pfizer–BioNTech) administered as a booster.
Since the beginning of the COVID-19 pandemic, many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have emerged that are resistant to varying extents to neutralizing antibody responses induced by current vaccines and natural infection, especially the recent Omicron variants. Neutralizing potency and breadth for an antibody are often somewhat mutually exclusive. Here, we delineate the molecular interaction between a therapeutic antibody (ADG20) and SARS-CoV-2 receptor-binding domain (RBD) by X-ray crystallography and characterize its binding epitope. We show that this site is targeted by a few rare antibodies that have both potency and breadth. These findings provide insights into the design of more universal vaccines and broad therapeutic antibodies, which are pressingly needed.
June 28, 2022
The SARS-CoV-2 main protease (Mpro) is a cysteine protease and a validated antiviral drug target. Paxlovid is an FDA-approved oral COVID-19 antiviral that contains the Mpro inhibitor nirmatrelvir and the metabolic booster ritonavir. The emergence of SARS-CoV-2 variants mutations in the Mpro raised the alarm of potential drug resistance. In this study, we aim to discover Mpro drug resistant mutants from naturally observed polymorphisms. Through analyzing the SARS-CoV-2 sequences deposited in Global initiative on Sharing Avian influenza Data (GISAID) database, we identified 66 prevalent Mpro mutations located at the nirmatrelvir binding site. The Mpro mutant proteins were expressed and characterized for enzymatic activity and nirmatrelvir inhibition. While the majority of the Mpro mutants had reduced enzymatic activity (kcat/Km >10-fold decrease), 11 mutants including S144M/F/A/G/Y, M165T, E166Q, H172Q/F, and Q192T/S/V showed comparable enzymatic activity as the wild-type (kcat/Km <10-fold change) and resistance to nirmatrelvir (Ki > 10-fold increase). We further demonstrate that the enzymatic activity and inhibitor resistance of these single mutations can be enhanced by additional substitutions in a double mutant. X-ray crystal structures were determined for six of the single mutants with and/or without GC-376/nirmatrelvir. The structures illustrate how mutations can reduce ligand binding by impacting the conformational stability of the active site. Overall, our study identified several drug resistant hot spots that warrant close monitoring for possible clinical evidence of Paxlovid resistance.
The SARS-CoV-2 omicron (B.1.1.529) variant is highly resistant against antibody-mediated neutralisation due to many mutations in the spike (S) protein. Several omicron subvariants have been detected, with BA.2.12.1 (first detected in the USA) and BA.4 and BA.5 (first detected in South Africa) currently outcompeting the previously circulating BA.1 and BA.2 subvariants in several countries. The S proteins of BA.4 and BA.5, which are identical on the protein level, and BA.2.12.1 harbour unique mutations (appendix pp 1–2), but it is largely unknown whether they differ from BA.1 and BA.2 regarding neutralisation sensitivity.
The aerosol microenvironment is dynamic, exposing pathogens, such as severe acute respiratory syndrome coronavirus 2 virus, when exhaled in respiratory aerosol to extreme conditions of solute concentration, pH, and evaporative cooling. Yet surviving this environment is a key step in the transmission of such pathogens. Understanding the impact that airborne transport has on pathogens and the influence of environmental conditions on pathogen survival can inform the implementation of strategies to mitigate the spread of diseases such as coronavirus disease 2019. We report changes in the infectivity of the airborne virus over timescales from 5 s to 20 min and demonstrate the role of two microphysical processes in this infectivity loss, namely, particle crystallization and aerosol droplet pH change.
The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterize the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals and evaluate transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses reveal lower vaccine-induced functions and Fc receptor-binding after Ad26.COV2.S compared to mRNA vaccination and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccines have higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination results in enhanced maternal antibody-dependent NK-cell activation, cellular and neutrophil phagocytosis, and complement deposition relative to second trimester. Higher transplacental transfer ratios following first and second trimester vaccination may reflect placental compensation for waning maternal titers. These results provide novel insight into the impact of platform and trimester of vaccination on maternal humoral immune response and transplacental antibody transfer.
On June 18, 2022, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for the use of the Moderna COVID-19 vaccine for children aged 6 months–5 years and for the Pfizer-BioNTech COVID-19 vaccine for children aged 6 months–4 years in the United States for prevention of COVID-19. ACIP determined that the benefits of vaccination outweigh risks for this population.
In the US, maternal deaths increased substantially (33.3%) after March 2020, corresponding to COVID-19 onset, a figure higher than the 22% overall excess death estimate associated with the pandemic.4 Increases were highest for Hispanic and non-Hispanic Black women. Change in maternal deaths during the pandemic may involve conditions directly related to COVID-19 (respiratory or viral infection) or conditions exacerbated by COVID-19 or other health care disruptions (diabetes or cardiovascular disease)5 but could not be discerned from the data.
June 27, 2022
Two and a half years into the COVID-19 pandemic, we have gained many insights into the human antibody response to the causative SARS-CoV-2 virus. In this Review, we summarize key observations of humoral immune responses in people with COVID-19, discuss key features of infection- and vaccine-induced neutralizing antibodies, and consider vaccine designs for inducing antibodies that are broadly protective against different variants of the SARS-CoV-2 virus.
Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial
Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events.
June 25, 2022
Science denialism during the COVID-19 pandemic has been “a really serious problem”, Oreskes says. “I think we are noticing it because it is so present and so immediate—many of these other things have been on a kind of slow burn. There are people who died who didn’t have to die. And who, if they had been willing to follow scientific advice or if they had been encouraged to follow scientific advice, could be alive today…Trust in science has actually become a matter of life and death.” Yet she notes, “Overall trust in science as an activity…remains quite high…But that said, we have definite subsectors of the population who have rejected science in important areas with big consequences for public health.” She highlights how “The basic framework is the phenomenon of deliberate fomenting of distrust for political, ideological, and economic reasons. This is hugely important for scientists to understand. If we don’t actually understand, analyse, and work with these social factors, we won’t achieve the results that we want.”
June 24, 2022
This study found that individuals with mild COVID-19 infected during the Gamma and Omicron waves had lower odds of reporting olfactory dysfunction than individuals infected during the period of the original lineages. These results suggest that the type of SARS-CoV-2 variant might be a risk factor for olfactory dysfunction, along with host genetic susceptibility.2 The association with Omicron also was observed after controlling for vaccination status, supporting its independence of host immunologic factors.
The findings of this population-based cohort study of Ontario adolescents and adults with myocarditis or pericarditis following mRNA COVID-19 vaccination suggest that vaccine products and interdose intervals, in addition to age and sex, may be associated with the risk of myocarditis or pericarditis after receipt of these vaccines. Vaccination program strategies, such as age-based product considerations and longer interdose intervals, may reduce the risk of myocarditis or pericarditis following receipt of mRNA vaccines.
During October 1, 2021–June 15, 2022, a total of 296 U.S. pediatric patients received a diagnosis of hepatitis of unknown etiology, with adenovirus detected among 45%. Preliminary analyses have not identified common exposures (e.g., travel or toxicants).
June 23, 2022
The emergence and rapid spread of SARS-CoV-2 variants may impact vaccine efficacy significantly. The Omicron variant termed BA.2, which differs substantially from BA.1 based on genetic sequence, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed. Here, we used antigenic cartography to quantify and visualize antigenic differences between early SARS-CoV-2 variants (614G, Alpha, Beta, Gamma, Zeta, Delta and Mu) using hamster antisera obtained after primary infection. We first verified that the choice of the cell line for the neutralization assay did not affect the topology of the map substantially. Antigenic maps generated using pseudotyped SARS-CoV-2 on the widely used VeroE6 cell line and the human airway cell line Calu-3 generated similar maps. Maps made using authentic SARS-CoV-2 on Calu-3 cells also closely resembled those generated with pseudotyped viruses. The antigenic maps revealed a central cluster of SARS-CoV-2 variants, which grouped based on mutual spike mutations. Whereas these early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape vaccine-induced antibody responses as a result of different antigenic characteristics. Thus, antigenic cartography could be used to assess antigenic properties of future SARS-CoV-2 variants of concern that emerge and to decide on the composition of novel spike-based (booster) vaccines.
The in vivo pathogenicity, transmissibility, and fitness of the SARS-CoV-2 Omicron (B.1.1.529) variant are unclear. We compared these virological attributes of this new variant of concern with those of the Delta (B.1.617.2) variant in a Syrian hamster model of COVID-19. Omicron-infected hamsters lost significantly less body weight and exhibited reduced clinical scores, respiratory tract viral burdens, cytokine/chemokine dysregulation, and lung damage than Delta-infected hamsters. Both variants were highly transmissible via contact transmission. In non-contact transmission studies, Omicron demonstrated similar or higher transmissibility than Delta. Delta outcompeted Omicron without selection pressure. This scenario drastically changed once immune selection pressure with neutralizing antibodies active against Delta but poorly active against Omicron was introduced. Next-generation vaccines and antivirals effective against this new VOC are urgently needed.
The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity.
Based on official reported COVID-19 deaths, we estimated that vaccinations prevented 14·4 million (95% credible interval [Crl] 13·7–15·9) deaths from COVID-19 in 185 countries and territories between Dec 8, 2020, and Dec 8, 2021. This estimate rose to 19·8 million (95% Crl 19·1–20·4) deaths from COVID-19 averted when we used excess deaths as an estimate of the true extent of the pandemic, representing a global reduction of 63% in total deaths (19·8 million of 31·4 million) during the first year of COVID-19 vaccination. In COVAX Advance Market Commitment countries, we estimated that 41% of excess mortality (7·4 million [95% Crl 6·8–7·7] of 17·9 million deaths) was averted. In low-income countries, we estimated that an additional 45% (95% CrI 42–49) of deaths could have been averted had the 20% vaccination coverage target set by COVAX been met by each country, and that an additional 111% (105–118) of deaths could have been averted had the 40% target set by WHO been met by each country by the end of 2021.
SARS-CoV-2 spike protein, which forms the basis for high pathogenicity and transmissibility of the virus, is a prime target for the development of both diagnostics and vaccines for the debilitating disease caused by the virus. We present a full model of spike methodically crafted and used to study its atomic-level dynamics by multiple microsecond simulations. The results shed light on the impact of posttranslational modifications on the pathogenicity of the virus. We show how glycan–glycan and glycan–lipid interactions broaden the protein’s dynamical range and thereby, its effective interaction with the surface receptors on the host cell. Palmitoylation of the spike membrane domain, however, results in a unique deformation pattern that might prime the membrane for fusion.
June 22, 2022
Among 2 117 443 children included in the study, 253 children developed MIS-C, corresponding to an incidence rate of 6·8 (95% CI: 6·0-7·6) per 100 000 person-years. Male sex (HR 1·65, 95% CI: 1·28-2·14), age 5-11 years (adjusted HR 1·44, 95% CI: 1·06-1·95 using children 0-4 years as reference), foreign-born parents (HR 2·53, 95% CI: 1·93-3·34), asthma (aHR 1·49, 95% CI: 1·00-2·20), obesity (aHR 2·15, 95% CI: 1·09-4·25) and life-limiting conditions (aHR 3·10, 95% CI: 1·80-5·33) were associated with MIS-C. Children 16-18 years had a reduced risk for MIS-C (aHR 0·45, 95% CI: 0·24-0·85).
In this analysis of data from a mass COVID-19 vaccination site, the proportion of Black and Hispanic patients receiving the COVID-19 vaccine was substantially higher with CBO outreach than when self-scheduled through the patient portal. Restriction to local zip codes for self-scheduling was also associated with a higher proportion of racial and ethnic minority patients receiving the COVID-19 vaccine. These findings suggest that direct outreach from trusted community resources can address challenges navigating self-scheduling technology6 and may mitigate distrust of COVID-19 vaccination in Hispanic and Black communities.
Pregnant individuals who received a booster dose of the BNT162b2 (Pfizer-BioNTech) COVID-19 mRNA vaccine during their second trimester developed higher antibody levels than those who received the second shot in their primary vaccine series during the same trimester, researchers in Israel recently reported in Obstetrics & Gynecology. Infants in the booster group also had higher antibody levels at birth than those in the 2-dose group. The study’s authors say the findings support a COVID-19 maternal booster following full COVID-19 vaccination to protect both pregnant people and their infants.
A total of 537 case infants (181 of whom had been admitted to a hospital during the delta period and 356 during the omicron period; median age, 2 months) and 512 control infants were enrolled and included in the analyses; 16% of the case infants and 29% of the control infants had been born to mothers who had been fully vaccinated against Covid-19 during pregnancy. Among the case infants, 113 (21%) received intensive care (64 [12%] received mechanical ventilation or vasoactive infusions). Two case infants died from Covid-19; neither infant’s mother had been vaccinated during pregnancy. The effectiveness of maternal vaccination against hospitalization for Covid-19 among infants was 52% (95% confidence interval [CI], 33 to 65) overall, 80% (95% CI, 60 to 90) during the delta period, and 38% (95% CI, 8 to 58) during the omicron period. Effectiveness was 69% (95% CI, 50 to 80) when maternal vaccination occurred after 20 weeks of pregnancy and 38% (95% CI, 3 to 60) during the first 20 weeks of pregnancy.
The benefits of maternal vaccination to the infant through maternal antibody transfer across the placenta have long been recognized. In the 1870s, babies born to mothers who had received smallpox vaccination were unlikely to have smallpox early in life.1 Tetanus toxoid vaccination during pregnancy, along with improved hygiene during delivery, has resulted in substantially reduced rates of neonatal tetanus in some developing countries.1 Decreased risks of influenza and pertussis have been reported during the first few months of life among infants whose mothers had received the inactivated influenza vaccine and the combined tetanus–diphtheria–acellular pertussis (Tdap) vaccine, respectively. Both vaccines are routinely recommended during pregnancy in the United States; the influenza vaccine is recommended anytime during pregnancy, whereas the Tdap vaccine is recommended preferentially during the early part of gestational weeks 27 to 36 in order to maximize maternal antibody production, placental transfer, and antibody levels in the newborn.2 Studies to evaluate whether maternal vaccination could prevent illness from other infections (e.g., respiratory syncytial virus infection or group B streptococcus infection) among infants are underway.
Pregnant women with symptomatic coronavirus disease 2019 (Covid-19) have a higher risk of adverse outcomes than do women who are not pregnant.1,2 In part because of these findings, Covid-19 vaccination has been recommended for pregnant women. However, uptake has been lower in pregnant women than among women who are not pregnant.3,4 The concern of many women regarding safety remains a barrier to maternal vaccination.
In recent months, multiple lineages of the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged,1 with subvariants BA.1 and BA.2 showing substantial escape from neutralizing antibodies.2-5 Subvariant BA.2.12.1 is now the dominant strain in the United States, and BA.4 and BA.5 are dominant in South Africa (Figure 1A). Subvariants BA.4 and BA.5 have identical sequences of the spike protein.
Compared with controls, children aged 0–14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial.
June 21, 2022
During December 23, 2021–May 21, 2022, 1,076,762 oral antiviral prescriptions were dispensed in the United States. The overall number of antivirals dispensed increased; however, by the end of the study period, dispensing rates were lowest in high vulnerability zip codes, despite these zip codes having the largest number of dispensing sites.
COVID-19–related hospital admissions and emergency department (ED) encounters occurring 5–15 days after Paxlovid treatment were described using data from a large integrated health care system. Reports of such hospitalizations or ED encounters occurred infrequently, representing <1% of Paxlovid-treated patients over the study period.
Baricitinib (Olumiant) recently became the first immunomodulatory treatment for COVID-19 to receive FDA approval. The agency approved it for treating COVID-19 among hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Baricitinib, discovered by Incyte and licensed to Eli Lilly, still remains under Emergency Use Authorization (EUA) status for hospitalized patients aged 2 years through 17 years who require breathing help.
A booster shot of mRNA vaccine after 2 doses of inactivated virus vaccine significantly increases immune response to the SARS-CoV-2 virus, and may offer better protection against severe COVID-19 than 3 doses of inactivated vaccine, suggests a preliminary study published in Nature Communications.
Investigation of the use of a sensor bracelet for the presymptomatic detection of changes in physiological parameters related to COVID-19: an interim analysis of a prospective cohort study (COVI-GAPP)
A total of 1.5 million hours of physiological data were recorded from 1163 participants (mean age 44±5.5 years). COVID-19 was confirmed in 127 participants of which, 66 (52%) had worn their device from baseline to symptom onset (SO) and were included in this analysis. Multi-level modelling revealed significant changes in five (RR, HR, HRV, HRV ratio and WST) device-measured physiological parameters during the incubation, presymptomatic, symptomatic and recovery periods of COVID-19 compared with baseline. The training set represented an 8-day long instance extracted from day 10 to day 2 before SO. The training set consisted of 40 days measurements from 66 participants. Based on a random split, the test set included 30% of participants and 70% were selected for the training set. The developed long short-term memory (LSTM) based recurrent neural network (RNN) algorithm had a recall (sensitivity) of 0.73 in the training set and 0.68 in the testing set when detecting COVID-19 up to 2 days prior to SO.
Respiratory droplets are widely recognized as the primary vehicle in viral respiratory disease transmission. Accurate information on their number and size distributions is important for appropriate mitigation strategies, for quantitative modeling of airborne disease transmission, and for evaluating the relative importance of droplets originating from saliva versus airway lining fluid. A straightforward experimental setup using inexpensive, readily available components is developed for simultaneous characterization of larger particles by video analysis of laser light scattering and monitoring of smaller sizes by an optical particle counter. Measurements indicate that in a healthy volunteer, the airborne mass of speech aerosol far exceeds that generated by breathing, even when accounting for faster sedimentation of the larger particles.
The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.
Although substantial federal funding has been available to improve indoor ventilation and filtration in schools to slow the spread of SARS-CoV-2, most US public schools have made no major investments in such strategies since the emergence of the COVID-19 pandemic, according to a study from the Centers for Disease Control and Prevention (CDC).
An experimental device that meets US Food and Drug Administration (FDA) performance requirements for emergency use ventilators can be constructed for about $1700—far less than the $10 000 for the lowest-cost commercial models, according to an article in PLoS One.
June 20, 2022
In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient’s body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.
Here we developed three recombinant Newcastle disease virus (rNDV) vectored vaccines and assessed their immunogenicity, safety, and protective efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice and hamsters. Intranasal administration of rNDV-based vaccine candidates elicited high levels of neutralizing antibodies. Importantly, the nasally administrated vaccine prevented lung damage, and significantly reduced viral load in the respiratory tract of vaccinated animal which was compounded by profound humoral immune responses. Taken together, the presented NDV-based vaccine candidates fully protected animals against SARS-CoV-2 challenge and warrants evaluation in a Phase I human clinical trial as a promising tool in the fight against COVID-19.
June 19, 2022
The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2.
June 18, 2022
Overall, we found a reduction in odds of long COVID with the omicron variant versus the delta variant of 0·24–0·50 depending on age and time since vaccination. However, the absolute number of people experiencing long COVID at a given time depends on the shape and amplitude of the pandemic curve. For example, given the high numbers of people infected with omicron in the UK from December, 2021, to February, 2022, our data are consistent with the UK Office for National Statistics, who estimated that the numbers of people experiencing long COVID actually increased from 1·3 million in January, 2022, to 1·7 million in March, 2022. Considering the UK omicron peak of more than 350 000 new symptomatic COVID-19 cases per day estimated on March 26, 2022, by the ZOE app model and 4% of cases being long COVID, future numbers with long COVID will inevitably rise.
June 17, 2022
A comprehensive understanding of host dependency factors for SARS-CoV-2 remains elusive. Here, we map alterations in host lipids following SARS-CoV-2 infection using nontargeted lipidomics. We find that SARS-CoV-2 rewires host lipid metabolism, significantly altering hundreds of lipid species to effectively establish infection. We correlate these changes with viral protein activity by transfecting human cells with each viral protein and performing lipidomics. We find that lipid droplet plasticity is a key feature of infection and that viral propagation can be blocked by small-molecule glycerolipid biosynthesis inhibitors. We find that this inhibition was effective against the main variants of concern (alpha, beta, gamma, and delta), indicating that glycerolipid biosynthesis is a conserved host dependency factor that supports this evolving virus.
SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.21. The new variants’ receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab4 and Cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.
COVID-19–associated hospitalization rates among disability-eligible Medicare beneficiaries (3,148 per 100,000) were approximately 50% higher than rates among age-eligible (i.e., ≥65 years) beneficiaries (2,129 per 100,000), and hospitalization rates increased by age in both groups. Among persons with disabilities, American Indian or Alaska Native persons experienced the highest rate of COVID-19–associated hospitalization (4,962 per 100,000).
U.S. adults aged ≥65 years are at increased risk for severe illness and death from COVID-19 (1). The communal nature of long-term care facilities (LTCFs), and the vulnerability of the LTCF population (typically aged ≥65 years, and often having underlying chronic conditions, cognitive and physical impairments, immunocomprised status, or other disabilities) further increases risk for COVID-19 infection, hospitalization, and death in this group (2). Although multiple studies highlight these risks (3), there is limited information comparing the risk among LTCF residents with that in an age-comparable population living in the community. This report estimates the risk for death among LTCF residents by comparing COVID-19–associated mortality rates among LTCF residents aged ≥65 years and persons aged ≥65 years who are not LTCF residents (community-dwelling adults) in Illinois. Illinois infectious disease registry data and population data from state regulatory sources and the U.S. Census Bureau were used to calculate COVID-19 death rates among persons aged ≥65 years living within and outside of LTCFs during a prevaccination baseline month (December 2020) and a comparison month 1 year after COVID-19 vaccination began (January 2022).
This randomized clinical trial among 8287 Black and Latino adults aged 65 years and older found that both standard and culturally tailored electronic secure messages and mailings from individuals’ own PCPs led to significantly higher COVID-19 vaccination rates at 8 weeks than usual care. There was no difference in vaccination rates between standard and culturally tailored PCP outreach.
In this qualitative study consisting of interviews with 25 Latinx individuals who were unvaccinated and hospitalized with COVID-19, participants described the impact of hospitalization on their vaccine deliberation. After hospitalization, Latinx individuals who remained undecided and those who ultimately accepted the COVID-19 vaccine described COVID-19 vaccine concerns, and those who were vaccinated after hospitalization were motivated to engage in advocacy to encourage vaccination and suggested additional patient-centered opportunities to increase vaccine uptake.
In this cohort study of 3922 children with KD, cases of KD across the United States fell by 28% and remained low during periods of COVID-19–related masking and school closure. In the San Diego region, there was a disproportionate decline in KD cases in children aged 1 to 5 years, male children, and Asian children, and clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were rare.
First infection with SARS-CoV-2 is associated with increased risk of acute and post-acute death and sequelae in the pulmonary and extrapulmonary organ systems. However, whether reinfection adds to the risk incurred after the first infection is not clear. Here we use the national health care databases of the US Department of Veterans Affairs to build a cohort of people with first infection (n = 257,427), reinfection (2 or more infections, n = 38,926), and a non-infected control group (n = 5,396,855) to estimate risks and 6-month burdens of all-cause mortality, hospitalization, and a set of pre-specified incident outcomes. We show that compared to people with first infection, reinfection contributes additional risks of all-cause mortality, hospitalization, and adverse health outcomes in the pulmonary and several extrapulmonary organ systems (cardiovascular disorders, coagulation and hematologic disorders, diabetes, fatigue, gastrointestinal disorders, kidney disorders, mental health disorders, musculoskeletal disorders, and neurologic disorders); the risks were evident in those who were unvaccinated, had 1 shot, or 2 or more shots prior to the second infection; the risks were most pronounced in the acute phase, but persisted in the post-acute phase of reinfection, and most were still evident at 6 months after reinfection. Compared to non-infected controls, assessment of the cumulative risks of repeated infection showed that the risk and burden increased in a graded fashion according to the number of infections. The constellation of findings show that reinfection adds non-trivial risks of all-cause mortality, hospitalization, and adverse health outcomes in the acute and post-acute phase of the reinfection. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.
June 16, 2022
The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC.
Timely evaluation of the protective effects of Coronavirus Disease 2019 (COVID-19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is urgently needed to inform pandemic control planning. Based on 78 vaccine efficacy or effectiveness (VE) data from 49 studies and 1,984,241 SARS-CoV-2 sequences collected from 31 regions, we analyzed the relationship between genetic distance (GD) of circulating viruses against the vaccine strain and VE against symptomatic infection. We found that the GD of the receptor-binding domain of the SARS-CoV-2 spike protein is highly predictive of vaccine protection and accounted for 86.3% (P = 0.038) of the VE change in a vaccine platform-based mixed-effects model and 87.9% (P = 0.006) in a manufacturer-based model. We applied the VE-GD model to predict protection mediated by existing vaccines against new genetic variants and validated the results by published real-world and clinical trial data, finding high concordance of predicted VE with observed VE. We estimated the VE against the Delta variant to be 82.8% (95% prediction interval: 68.7–96.0) using the mRNA vaccine platform, closely matching the reported VE of 83.0% from an observational study. Among the four sublineages of Omicron, the predicted VE varied between 11.9% and 33.3%, with the highest VE predicted against BA.1 and the lowest against BA.2, using the mRNA vaccine platform. The VE-GD framework enables predictions of vaccine protection in real time and offers a rapid evaluation method against novel variants that may inform vaccine deployment and public health responses.
They span three continents, but a trio of researchers who’ve never met share a singular focus made vital by the still-raging pandemic: deciphering the causes of Long Covid and figuring out how to treat it.
In this cluster randomized trial of 33 SARS-CoV-2 testing sites, the community health promoters intervention was associated with 3.84 times more Latinx individuals tested per event than control sites, and the intervention was associated with testing a greater proportion of the Latinx populace per event.
Participants had statistically significant increases in weight during the preshutdown year (mean change, 0.18 [95% CI, 0.15 to 0.22] kg) and postshutdown year (mean change, 0.22 [95% CI, 0.19 to 0.26] kg), but the difference between the preshutdown and postshutdown changes was not significant (difference, 0.04 [95% CI, −0.01 to 0.10] kg; P = .11) (Table). The sensitivity analysis including only patients with all 4 measures assessed in-person found significantly less weight gain in the postshutdown interval vs preshutdown interval (Table). The percentage of individuals who remained weight-stable decreased by 2% from the preshutdown to postshutdown periods, whereas the percentage who either gained or lost 5% increased by approximately 0.7% (Figure). Changes in weight from preshutdown to postshutdown periods did not differ among subgroups. Results for BMI were similar (Table).
BBV152 was well tolerated in children aged 2–18 years, and induced higher neutralising antibody responses than those observed in adults, in whom the efficacy (ie, the prevention or decrease in the severity of COVID-19 infection) has been demonstrated.
June 15, 2022
Tracking SARS-CoV-2 evolution during persistent cases provides insight into the origins of Omicron and other global variants. What can scientists do with this knowledge?
In this survey study of more than 1.4 million respondents in the US Behavioral Risk Factor Surveillance System survey, responses to a screening question calibrated to a 4-item Patient Health Questionnaire score of 6 or greater suggested that aggregate prevalence of clinically significant anxiety and depression increased only modestly overall among US adults in 2020 compared with 2017 to 2019.
There were 295 771 patients admitted for 1 825 610 hospital-days (mean, 6.2 days per admission); 13 392 admissions included a diagnosis of SARS-CoV-2 infection (53.3% men; mean age, 61.3 years) and 434 cases (3.2%) were diagnosed on hospital day 5 or later. Of these, 178/3820 (4.7%) were diagnosed during the 2021-2022 Omicron winter surge and 111/3218 (3.4%) during the 2020-2021 winter surge (Table). The incidence of hospital-onset infections was significantly higher during the winter 2021-2022 Omicron surge vs the prior winter surge: 0.87 vs 0.56 cases per 1000 patient-days for diagnoses on hospital day 5 or later (relative risk [RR], 1.54; 95% CI, 1.22-1.95), 0.57 vs 0.35 for diagnoses on hospital day 8 or later (RR, 1.62; 95% CI, 1.21-2.18), and 0.37 vs 0.16 for diagnoses on hospital day 15 or later (RR, 2.31; 95% CI, 1.53-3.49). The increase in hospital-onset infections during the Omicron wave vs the prior winter wave mirrored similar increases in community and health care worker case numbers during these same periods (Figure).
As the US reckons with the consequences of the COVID-19 pandemic, there has been growing discussion of the ways in which unmet social needs can be met within health care systems. Adding to this conversation, organizational leaders and clinicians in health care systems are uniquely positioned to contribute to changes in broader social systems outside their walls. Specifically, safety net programs and other social policies serve as powerful population-level interventions that can affect long-standing health disparities. For example, the largest US poverty alleviation program—the Earned Income Tax Credit—is associated with improved birth outcomes, and more so for Black women who have the highest rates of preterm birth due in part to toxic exposures to structural racism. Academic and nonacademic health care systems have an important role in generating the science, case examples, and momentum toward strengthening social safety net programs to the end of narrowing health gaps.
June 14, 2022
Following identification of pediatric hepatitis cases of unknown etiology in the United States and the United Kingdom, CDC issued a request in April 2022 for U.S. providers to report additional cases. Many reported cases had test results positive for adenovirus, which is not known to cause hepatitis in immunocompetent children.
Among immunocompetent patients, VE against Omicron COVID-19 hospitalization for a primary series plus one booster of any vaccine product dose was 77% (95% CI: 71-82%), and for a primary series alone was 44% (95% CI: 31-54%) (p<0.001). VE was higher for a boosted regimen than a primary series alone for both mRNA vaccines used in the US (BNT162b2: primary series plus booster VE 80% (95% CI: 73-85%), primary series alone VE 46% (95% CI: 30-58%) [p<0.001]; mRNA-1273: primary series plus booster VE 77% (95% CI: 67-83%), primary series alone VE 47% (95% CI: 30-60%) [p<0.001]). Among immunocompromised patients, VE for a primary series of any vaccine product against Omicron COVID-19 hospitalization was 60% (95% CI: 41-73%). Insufficient sample size has accumulated to calculate effectiveness of boosted regimens for immunocompromised patients. Conclusions: Among immunocompetent people, a booster dose of COVID-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing COVID-19 hospitalization due to the Omicron variant.
The Omicron, or Pango lineage B.1.1.529, variant of SARS-CoV-2 carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection from severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple mRNA vaccinated healthcare workers (HCW) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple vaccinated individuals, but magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCW who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants, but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529.
June 13, 2022
Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations.
The fragmented and inefficient healthcare system in the United States leads to many preventable deaths and unnecessary costs every year. Universal healthcare could have alleviated the mortality caused by a confluence of negative COVID-related factors. Incorporating the demography of the uninsured with age-specific COVID-19 and nonpandemic mortality, we estimated that a single-payer universal healthcare system would have saved 212,000 lives in 2020 alone. We also calculated that US$105.6 billion of medical expenses associated with COVID-19 hospitalization could have been averted by a Medicare for All system.
Fewer people are eligible for the massive studies needed to test treatments for severe COVID-19.
In this randomized clinical trial comprising 16 045 participants, text messaging did not result in a higher response rate than outbound telephone calls. Behaviorally informed messaging did not result in a significantly higher response than usual content.
June 12, 2022
COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
June 11, 2022
A total of 411 myocarditis or pericarditis, or both, events were observed among 15 148 369 people aged 18–64 years who received 16 912 716 doses of BNT162b2 and 10 631 554 doses of mRNA-1273. Among men aged 18–25 years, the pooled incidence rate was highest after the second dose, at 1·71 (95% CI 1·31 to 2·23) per 100 000 person-days for BNT162b2 and 2·17 (1·55 to 3·04) per 100 000 person-days for mRNA-1273. The pooled IRR in the head-to-head comparison of the two mRNA vaccines was 1·43 (95% CI 0·88 to 2·34), with an excess risk of 27·80 per million doses (–21·88 to 77·48) in mRNA-1273 recipients compared with BNT162b2.
June 10, 2022
Asian and non-Hispanic White adults had the highest COVID-19 vaccination coverage by the end of April 2021. By the end of November 2021, disparities in vaccination coverage for some racial and ethnic groups narrowed, and coverage was similar for non-Hispanic Black (78.2%), Hispanic (81.3%), Native Hawaiian and other Pacific Islander (75.7%), and non-Hispanic White (78.7%) adults.
A recent outbreak of acute non-A-E hepatitis with serum transaminases greater than 500 IU/L identified in children aged under 16 years reported in United Kingdom (UK) has become a serious cause for concern for public health authorities and paediatric liver and critical care services. From 1 January to 16 May 2022, UK public health authorities have reported 197 cases with median age 3 years, male (50%), from all regions of UK with 11 children requiring liver transplantation (LT).
June 9, 2022
Despite the ability of current vaccines to significantly prevent severe disease due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), vaccinated individuals are still susceptible to infection and contribute to the spread of the virus. The present study demonstrates that a live, replication-deficient recombinant virus vaccine induces greater immunity and a greater level of protection in the respiratory tract of susceptible transgenic mice when inoculated intranasally compared with intramuscularly. Second-generation vaccines administered via the upper respiratory tract have the potential to limit the spread of SARS-CoV-2 more effectively than current vaccines.
A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group.
The number of cases of SARS-CoV-2 infection per 100,000 person-days at risk (adjusted rate) increased with the time that had elapsed since vaccination with BNT162b2 or since previous infection. Among unvaccinated persons who had recovered from infection, this rate increased from 10.5 among those who had been infected 4 to less than 6 months previously to 30.2 among those who had been infected 1 year or more previously. Among persons who had received a single dose of vaccine after previous infection, the adjusted rate was low (3.7) among those who had been vaccinated less than 2 months previously but increased to 11.6 among those who had been vaccinated at least 6 months previously. Among previously uninfected persons who had received two doses of vaccine, the adjusted rate increased from 21.1 among those who had been vaccinated less than 2 months previously to 88.9 among those who had been vaccinated at least 6 months previously.
Continued evolution of the spike protein is the biggest threat to all monoclonal antibody–based interventions against SARS-CoV-2, and it can be stymied only by decreasing the total global burden of viral replication in human hosts. Although the shifting antigenic landscape of the spike protein may mean that monoclonal antibodies will require periodic updates, the ability to passively immunize persons who have an increased risk of an ineffective immune response is an important leap forward in the ongoing fight against viral evolution.
After two doses, both vaccines were equally effective against severe disease caused by the omicron variant. These estimates of vaccine effectiveness were calculated in a South African population with a high background prevalence of SARS-CoV-2 exposure during the Covid-19 pandemic.5 These data provide reassurance about the continued value of the national Covid-19 vaccine program during a surge in the omicron variant.
There were no differences in spike-specific T-cell responses between participants 7 weeks after omicron breakthrough infection and participants without omicron infection, regardless of previous SARS-CoV-2 infection status (figure B,D). A significant increase in specific T-cells against nucleocapsid and membrane proteins was observed in omicron-infected individuals without past SARS-CoV-2 infection, showing that omicron breakthrough infection can prime specific T-cells (appendix p 11). Higher serological responses against both BA.1 and BA.2, but similar T-cell responses, were observed in BA.1-infected compared with BA.2-infected individuals (appendix p 12).
Safety and immunogenicity of the FINLAY-FR-1A vaccine in COVID-19 convalescent participants: an open-label phase 2a and double-blind, randomised, placebo-controlled, phase 2b, seamless, clinical trial
From April 9, 2021, to April 17, 2021, 663 COVID-19 convalescent participants were enrolled in the study; 213 participants did not meet the selection criteria and 450 volunteers were recruited. 20 participants aged 60–78 years were included in the open, single-group, phase 2a study and 430 participants were randomly assigned to the experimental (n=344) or control groups (n=86) in the phase 2b study of participants aged 19–78 years. 19 (95%) of 20 phase 2a volunteers achieved a successful immune response after vaccination. No vaccine-associated serious adverse events were reported in the whole study population. Minor adverse events were found, the most common being pain at the injection site (105 [29%] of 364 in the intervention group; 13 [15%] of 86 in the placebo group). A successful immune response was found in 289 (81%) of 358 participants 28 days after vaccination. The vaccine elicited a greater than 31-times increase in anti-RBD-IgG antibodies compared with prevaccination rates, and the seroconversion rate was 302 (84%) of 358 on day 28 after vaccination; the geometric mean titres of live-virus neutralisation test increased from 15·4 (95% CI 10·3–23·2) to 400·3 (272·4–588·1) and high response was found against alpha, beta, and delta variants of concern.
June 8, 2022
Our results underscore the potential importance of selective pressures such as the use of monoclonal antibodies — in combination with the lack of an effective endogenous immune response — in promoting the emergence of SARS-CoV-2 escape mutations. These findings highlight the need to better understand the ramifications of different therapies in immunocompromised patients. Our results also corroborate the findings of previous studies in which patients with B-cell deficiencies were found to elicit effector T cells,5 an outcome that may signal an important role for T cells in controlling infection.
The implication is that the phenomenon of enhanced vaccine response would be less effective if the infection involved a heterologous spike protein from a variant of concern than if the infection involved a spike protein that was homologous with the spike protein expressed by the vaccine. Arguably, there might even be a hierarchy of immune responses, depending on the heterologous infection subtype. Insights to be gained from research about the relation between protective efficacy and variant subtype in a previous infection may also inform the formulation of future vaccines.
Ho dismisses Pfizer’s contention that rebound is uncommon. He and his coauthors noted that 5 of the 10 relapses described in their report occurred within 2 families—2 in his family and 3 in another—suggesting it isn’t rare. That’s concerning, Ho said, because it appears that people who experience a relapse can infect others. Among the 10 cases in the report he coauthored, viral load during the relapse was comparable to levels during the initial infection. During their relapse, 1 symptomatic and 1 presymptomatic patient transmitted SARS-CoV-2 to family members, Ho and his coauthors wrote.
Epidemiologic surveillance has revealed decoupling of COVID-19 hospitalizations and deaths from case counts following emergence of the Omicron (B.1.1.529) SARS-CoV-2 variant globally. However, assessment of the relative severity of Omicron variant infections presents challenges because of differential acquired immune protection against Omicron and prior variants, and because longer-term changes have occurred in testing and healthcare practices. Here we show that Omicron variant infections were associated with substantially reduced risk of progression to severe clinical outcomes relative to time-matched Delta (B.1.617.2) variant infections within a large, integrated healthcare system in southern California. Adjusted hazard ratios (aHRs) for any hospital admission, symptomatic hospital admission, intensive care unit admission, mechanical ventilation, and death comparing cases with Omicron versus Delta variant infection were 0.59 (95% confidence interval: 0.51-0.69), 0.59 (0.51-0.68), 0.50 (0.29-0.87), 0.36 (0.18-0.72), and 0.21 (0.10-0.44) respectively. This reduced severity could not be explained by differential history of prior infection among cases with Omicron or Delta variant infection, and was starkest among cases not previously vaccinated against COVID-19 (aHR=0.40 [0.33-0.49] for any hospital admission and 0.14 [0.07-0.28] for death). Infections with the Omicron BA.2 subvariant were not associated with differential risk of severe outcomes in comparison to BA.1/BA.1.1 subvariant infections. Lower risk of severe clinical outcomes among cases with Omicron variant infection should inform public health response amid establishment of the Omicron variant as the dominant SARS-CoV-2 lineage globally.
Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1.
During the current pandemic, SARS-CoV-2 has considerably diversified. The omicron variant (B.1.1.529) was identified at the end of November, 2021, and rapidly spread worldwide. As of May, 2022, the omicron BA.2 subvariant is the most dominant variant in the world. Other omicron subvariants have since emerged and some of them have begun to outcompete BA.2 in multiple countries. For instance, omicron BA.2.11 subvariant is spreading in France, and the BA.2.12.1 and BA.4/5 subvariants are becoming dominant in the USA and South Africa, respectively.
Mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that confer escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection. Such viral evasion is hypothesized to contribute to the emergence of global variants of concern. In the absence of effective immune responses, selective pressures such as those from monoclonal antibody treatment may lead to the emergence of immunologically important mutations.
Although some mutations in a gene alter the amino-acid sequence of the protein that the gene encodes, others — known as synonymous mutations — have no effect on protein sequence. Does it follow, then, that synonymous mutations are unimportant? Writing in Nature, Shen et al.1 present evidence that synonymous mutations are frequently just as harmful as the non-synonymous mutations that alter proteins, upending a common assumption about molecular evolution.
In this cohort study, SARS-CoV-2 genome sequences in air samples collected at a nurses station were identified in all particle sizes and were identical to human samples from a nosocomial outbreak. Detection of aerosol-borne SARS-CoV-2 was statistically less frequent on units under surveillance (7 of 210 samples) than without surveillance (24 of 300 samples).
The Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa’s Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.
June 7, 2022
Participants receiving molnupiravir showed faster normalization of CRP and Spo2, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19–related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants.
Among a nationally representative sample of U.S. K–12 public schools, higher-cost and resource-intensive ventilation improvement strategies, such as using portable high-efficiency particular air (HEPA) filtration systems in classrooms were less frequently reported. Overall, rural and mid-poverty schools were the least likely to report implementing several resource-intensive ventilation strategies.
The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID. To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance. These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.
Improving air quality has the potential to reduce not only infections with SARS-CoV-2 but also infections with other respiratory viruses and bacteria, reactive airway disease (eg, asthma) triggered by antigens,9 pulmonary and cardiovascular injury from inhalation of harmful respiratory particulates (eg, wildfires, smog), and toxicity from inhalation of volatile organic compounds. A once-in-decades opportunity now exists to make sustained improvements to public and private indoor air quality, reduce COVID-19 risk, and improve school, workplace, and consumer health and safety.
The oral protease inhibitor nirmatrelvir is expected to play a pivotal role for prevention of severe cases of coronavirus disease 2019 (COVID-19). To facilitate monitoring of potentially emerging resistance, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir. Resistant variants selected in cell culture harbored different combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetic studies in a homologous infectious cell culture system revealed up to 80-fold resistance conferred by the combination of substitutions L50F and E166V. Resistant variants had high fitness increasing the likelihood of occurrence and spread of resistance. Molecular dynamics simulations revealed that E166V and L50F+E166V weakened nirmatrelvir-Mpro binding. The SARS-CoV-2 polymerase inhibitor remdesivir retained activity against nirmatrelvir resistant variants and combination of remdesivir and nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatment programs with high efficacy against SARS-CoV-2 and potentially emerging coronaviruses.
A single intramuscular tixagevimab–cilgavimab dose provided statistically and clinically significant protection against progression to severe COVID-19 or death versus placebo in unvaccinated individuals and safety was favourable. Treating mild to moderate COVID-19 earlier in the disease course with tixagevimab–cilgavimab might lead to more favourable outcomes.
The World Health Organization has defined long COVID-19 (LC) as a condition where patients exhibit persistent symptoms over time after its acute phase, which cannot be explained by alternative diagnosis. Since we have previously reported residual viral antigens in tissues of convalescent patients, we now aim to assess the presence of such antigens in post-convalescent tissues. Here, we established the presence of residual virus within the appendix and breast tissue of 2 patients who exhibited LC symptoms, 175 to 462 days upon positive diagnosis, using immunohistological techniques. We observed positive staining for viral nucleocapsid protein (NP) in the appendix, and tumour-adjacent region of the breast, but not within the tumour via multiplex immunohistochemistry. Notably, with RNAscope, both positive-sense and negative-sense (replicative intermediate) viral RNA were detected. As a single-stranded virus, SARS-CoV-2, have to produce a replicative intermediate as a template to synthesize new genomic RNAs. Thus, the detection of negative-sense viral RNA suggests ongoing viral replication. While viral RNA and antigen from gastrointestinal and stool samples of convalescent patients has been extensively reported, we believe this is the first study to detect viable virus. Furthermore, our positive finding in the breast tissue also corroborated with recent reports that immunocompromised patients had also experienced LC symptoms and persistent viral replication. Overall, our findings, along with emerging LC studies, raises the possibility of the gastrointestinal tract functioning as a reservoir.
Partisan differences in attitudes toward the COVID-19 pandemic and toward the appropriateness of local policies requiring masks, social distancing, and vaccines are apparent in the United States. Previous research suggests that areas with a higher Republican vote share may experience more COVID-19 mortality, potentially as a consequence of these differences. In this observational study that captured data from a majority of US counties, we compared the number of COVID-19 deaths through October 31, 2021, among counties with differing levels of Republican vote share, using 2020 presidential election returns to characterize county political affiliation. Our analyses controlled for demographic characteristics and social determinants likely to influence COVID-19 transmission and outcomes using state fixed effects. We found a positive dose-response relationship between county-level Republican vote share and county-level COVID-19 mortality. Majority Republican counties experienced 72.9 additional deaths per 100,000 people relative to majority Democratic counties during the study period, and COVID-19 vaccine uptake explains approximately 10 percent of the difference. Our findings suggest that county-level voting behavior may act as a proxy for compliance with and support of public health measures that would protect residents from COVID-19.
June 3, 2022
The immune system is highly time-of-day dependent. Pioneering studies in the 1960s were the first to identify immune responses to be under a circadian control. Only in the last decade, however, have the molecular factors governing circadian immune rhythms been identified. These studies have revealed a highly complex picture of the interconnectivity of rhythmicity within immune cells with that of their environment. Here, we provide a global overview of the circadian immune system, focusing on recent advances in the rapidly expanding field of circadian immunology.
June 2, 2022
Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.
We evaluate the impact of government-mandated proof of vaccination requirements for access to public venues and non-essential businesses on COVID-19 vaccine uptake. We find that the announcement of a mandate is associated with a rapid and significant surge in new vaccinations (a more than 60% increase in weekly first doses), using the variation in the timing of these measures across Canadian provinces in a difference-in-differences approach. Time-series analysis for each province and for France, Italy and Germany corroborates this finding. Counterfactual simulations using our estimates suggest the following cumulative gains in the vaccination rate among the eligible population (age 12 and over) as of 31 October 2021: up to 5 percentage points (p.p.) (90% confidence interval, 3.9–5.8) for Canadian provinces, adding up to 979,000 (425,000–1,266,000) first doses in total for Canada (5 to 13 weeks after the provincial mandate announcements); 8 p.p. (4.3–11) for France (16 weeks post-announcement); 12 p.p. (5–15) for Italy (14 weeks post-announcement) and 4.7 p.p. (4.1–5.1) for Germany (11 weeks post-announcement).
Booster mRNA vaccine-doses were moderately effective in preventing infection with the omicron variant of SARS-CoV-2 for over a month after administration, which indicates their suitability as a strategy to limit the health effects of COVID-19 in periods of omicron variant domination. Estimated effectiveness was higher for mRNA-1273 compared with BNT162b2 and increased with time between completed primary vaccination and booster.
June 1, 2022
Communicating doctors’ consensus persistently increases COVID-19 vaccinations
The reluctance of people to get vaccinated represents a fundamental challenge to containing the spread of deadly infectious diseases, including COVID-19. Identifying misperceptions that can fuel vaccine hesitancy and creating effective communication strategies to overcome them are a global public health priority. Medical doctors are a trusted source of advice about vaccinations, but media reports may create an inaccurate impression that vaccine controversy is prevalent among doctors, even when a broad consensus exists. Here we show that public misperceptions about the views of doctors on the COVID-19 vaccines are widespread, and correcting them increases vaccine uptake. We implement a survey among 9,650 doctors in the Czech Republic and find that 90% of doctors trust the vaccines. Next, we show that 90% of respondents in a nationally representative sample (n = 2,101) underestimate doctors’ trust; the most common belief is that only 50% of doctors trust the vaccines. Finally, we integrate randomized provision of information about the true views held by doctors into a longitudinal data collection that regularly monitors vaccination status over 9 months. The treatment recalibrates beliefs and leads to a persistent increase in vaccine uptake. The approach demonstrated in this paper shows how the engagement of professional medical associations, with their unparalleled capacity to elicit individual views of doctors on a large scale, can help to create a cheap, scalable intervention that has lasting positive impacts on health behaviour.
DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?
Seasonal influenza vaccines are updated every year, depending on what strains are circulating globally, leaving many people—especially those who still contracted COVID-19 after 2 booster shots—wondering why vaccines against SARS-CoV-2 haven’t changed as variants have come and gone.
May 31, 2022
We directly analyze the effect of mask wearing on SARS-CoV-2 transmission, drawing on several datasets covering 92 regions on six continents, including the largest survey of wearing behavior (n= 20 million) [F. Kreuter et al., https://gisumd.github.io/COVID-19-API-Documentation (2020)]. Using a Bayesian hierarchical model, we estimate the effect of mask wearing on transmission, by linking reported wearing levels to reported cases in each region, while adjusting for mobility and nonpharmaceutical interventions (NPIs), such as bans on large gatherings. Our estimates imply that the mean observed level of mask wearing corresponds to a 19% decrease in the reproduction number R. We also assess the robustness of our results in 60 tests spanning 20 sensitivity analyses. In light of these results, policy makers can effectively reduce transmission by intervening to increase mask wearing.
Superspreading events and overdispersion are hallmarks of the COVID-19 pandemic. However, the specific roles and influence of established viral and physical factors related to the mechanisms of transmission, on overdispersion, remain unresolved. We, therefore, conducted mechanistic modeling of SARS-CoV-2 point-source transmission by infectious aerosols using real-world occupancy data from more than 100 000 social contact settings in ten US metropolises. We found that 80% of secondary infections are predicted to arise from approximately 4% of index cases, which show up as a stretched tail in the probability density function of secondary infections per infectious case. Individual-level variability in viral load emerges as the dominant driver of overdispersion, followed by occupancy. We then derived an analytical function, which replicates the simulated overdispersion, and with which we demonstrate the effectiveness of potential mitigation strategies. Our analysis, connecting the mechanistic understanding of SARS-CoV-2 transmission by aerosols with observed large-scale epidemiological characteristics of COVID-19 outbreaks, adds an important dimension to the mounting body of evidence with regard to airborne transmission of SARS-CoV-2 and thereby emerges as a powerful tool toward assessing the probability of outbreaks and the potential impact of mitigation strategies on large scale disease dynamics.
An mRNA booster is recommended to supplement any primary vaccine course. Heterologous and homologous three dose regimens work comparably well in preventing covid-19 infections, even against different variants. The effectiveness of three dose vaccine regimens against covid-19 related death remains uncertain.
In this retrospective cohort study of 7126 patients with COVID-19, an analysis of 1216 patients with oxygen saturation levels that were concurrently measured by pulse oximetry and arterial blood gas demonstrated that pulse oximetry overestimated arterial oxygen saturation among Asian, Black, and Hispanic patients compared with White patients. Separately, among 6673 patients with pulse oximetry measurements and available covariate data, predicted overestimation of arterial oxygen saturation levels by pulse oximetry among 1903 patients was associated with a systematic failure to identify Black and Hispanic patients who were qualified to receive COVID-19 therapy and a statistically significant delay in recognizing the guideline-recommended threshold for initiation of therapy.
May 30, 2022
The evolving virus and the uncertainty of predicting the trajectory of the pandemic call for strengthened surveillance and continued monitoring of SARS-CoV-2. The TAG-VE will continue to critically appraise state-of-the-art methodologies for predicting further evolution of SARS-CoV-2 and will continue to rapidly determine the threat levels posed by new variants. The pandemic is not over, and SARS-CoV-2 is spreading at a high level globally. Now is the time to enhance global sequencing capacities, focusing on widening coverage to include previous geographical and population blind spots, and to build a global consensus toward continued concerted multidisciplinary efforts, under the leadership of the WHO R&D Blueprint for action to prevent epidemics, to track and assess the threat posed by future SARS-CoV-2 variants.
The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here, we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues via skeletal muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signaling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin releasing hormone (CRH) neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, thus calibrating the immune system’s capacity to respond to physical threats.
May 29, 2022
Main Outcomes: Composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and all-cause mortality. We used cox proportional hazards modelling to estimate the hazard ratios (HR) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes. Results: Most (69%) tixagevimab/cilgavimab recipients were ≥65 years old, 92% were identified as immunocompromised in electronic data, and 73% had ≥3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, 0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR 0.36; 95%CI, 0.18-0.73). Limitations: Confounding by indication and immortal time bias. Conclusions: Using national real-world data from predominantly vaccinated, immunocompromised Veterans, administration of tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.
It remains undetermined whether burden of diabetes newly detected during acute COVID-19 persist in post-acute COVID phase. This meta-analysis was conducted to summarize the available literature and provide a pooled estimate of the risk of developing incident diabetes following hospital discharge or at least 28 days after the COVID-19 diagnosis compared to matched controls or severity matched influenza/ non-COVID-19 acute upper respiratory tract infections (AURI). Pooled analysis of 5787,027 subjects from four observational studies showed 59 % higher risk of developing incident diabetes in post-acute COVID-19 phase versus healthy controls (HR:1.59; 95 % CI:1.40–1.81, p < 0.001, I2=94 %, random-effects model). The high degree of heterogeneity in pooled estimate can be attributed to difference in demographic characteristics, hospitalization rates or disease severity between study subjects. Pooling data from three studies, higher risk of incident diabetes was also observed following COVID-19 versus severity matched non-COVID-19 respiratory tract infections (moderate-severe/hospitalized cases, HR 1.52; 95 % CI: 1.36–1.70, p < 0.01, I2=0 %, fixed-effects model; mild cases, HR 1.22; 95 % CI: 1.14–1.31, p < 0.001; I2=0 %, fixed-effects model). Majority of studies had median follow-up period of around 4 months. In view of several limitations due to retrospective design of these studies, prospective studies with long term follow-up are warranted.
May 27, 2022
Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5–11, 12–21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.
If COVID-19 moves toward endemicity, then it should not disrupt everyday life. However, with ongoing transmission and with an estimated 10% to 30% of individuals experiencing long COVID symptoms after infection, this issue will require careful attention to further define the syndrome and possible intervention (such as the RECOVER cohort study at the National Institutes of Health). Data suggest that vaccination can decrease the risk of long COVID and thus continuing to focus on improving vaccination rates must remain the cornerstone of COVID-19 prevention and mitigation not only locally, but globally.
May 26, 2022
The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and show that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. Introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the 8th human-infecting coronavirus.
Multiple COVID-19 vaccines, representing diverse vaccine platforms, successfully protect against symptomatic COVID-19 cases and deaths. Head-to-head comparisons of T cell, B cell, and antibody responses to diverse vaccines in humans are likely to be informative for understanding protective immunity against COVID-19, with particular interest in immune memory. Here, SARS-CoV-2-spike-specific immune responses to Moderna mRNA-1273, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Novavax NVX-CoV2373 were examined longitudinally for 6 months. 100% of individuals made memory CD4+ T cells, with cTfh and CD4-CTL highly represented after mRNA or NVX-CoV2373 vaccination. mRNA vaccines and Ad26.COV2.S induced comparable CD8+ T cell frequencies, though only detectable in 60-67% of subjects at 6 months. A differentiating feature of Ad26.COV2.S immunization was a high frequency of CXCR3+ memory B cells. mRNA vaccinees had substantial declines in antibodies, while memory T and B cells were comparatively stable. These results may also be relevant for insights against other pathogens.
Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.
We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD). The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.
Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir against mortality, hospitalization, and in-hospital outcomes among community-dwelling, ambulatory COVID-19 patients during the BA.2.2 wave in Hong Kong: an observational study
Findings from case-control analysis broadly confirmed those of primary analysis. Interpretation Amid the Omicron BA.2.2 wave, early initiation of oral antivirals among non-institutionalised COVID-19 patients was associated with reduced risks of mortality and in-hospital outcomes. Nirmatrelvir/ritonavir use was associated with greater and more consistent protection than molnupiravir.
May 25, 2022
The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.
SARS-CoV-2 has proven to be a rapidly evolving RNA virus with steadily emerging new viral variants. Several of them show enhanced infectivity and/or escape from neutralization by monoclonal antibodies (mAbs), and some were termed variants of concern (VoC).
For persons who received a single dose of the Ad26.COV2S vaccine (Johnson & Johnson–Janssen) against coronavirus disease 2019 (Covid-19), a booster dose of a messenger RNA (mRNA) vaccine at least 2 months after the primary dose is recommended. Recipients of Ad26.COV2.S for both the primary and booster doses may receive a second booster dose of an mRNA Covid-19 vaccine at least 4 months after the first Ad26.COV2.S booster dose. Immunogenicity data from a phase 1–2 clinical trial conducted before B.1.1.529 and the BA sublineages of omicron emerged showed that increases in the titers of binding and neutralizing antibodies with heterologous boosting were similar to or greater than the increases with homologous boosting.
Over the course of the pandemic variants have arisen at a steady rate. The most recent variants to emerge, BA.4 and BA.5, form part of the Omicron lineage and were first found in Southern Africa where they are driving the current wave of infection. In this report, we perform an in-depth characterisation of the antigenicity of the BA.4/BA.5 Spike protein by comparing sera collected post-vaccination, post-BA.1 or BA.2 infection, or post breakthrough infection of vaccinated individuals with the Omicron variant. In addition, we assess sensitivity to neutralisation by commonly used therapeutic monoclonal antibodies. We find sera collected post-vaccination have a similar ability to neutralise BA.1, BA.2 and BA.4/BA.5. In contrast, in the absence of vaccination, prior infection with BA.2 or, in particular, BA.1 results in an antibody response that neutralises BA.4/BA.5 poorly. Breakthrough infection with Omicron in vaccinees leads to a broad neutralising response against the new variants. The sensitivity of BA.4/BA.5 to neutralisation by therapeutic monoclonal antibodies was similar to that of BA.2. These data suggest BA.4/BA.5 are antigenically distinct from BA.1 and, to a lesser extent, BA.2. The enhanced breadth of neutralisation observed following breakthrough infection with Omicron suggests that vaccination with heterologous or multivalent antigens may represent viable strategies for the development of cross-neutralising antibody responses.
Among persons who had been previously infected with SARS-CoV-2 (regardless of whether they had received any dose of vaccine or whether they had received one dose before or after infection), protection against reinfection decreased as the time increased since the last immunity-conferring event; however, this protection was higher than that conferred after the same time had elapsed since receipt of a second dose of vaccine among previously uninfected persons. A single dose of vaccine after infection reinforced protection against reinfection.
Individuals who contract Covid-19 often experience problems with memory, attention, andconcentration, even after recovering from the initial illness. In the current manuscript, we argue that these symptoms are likely to manifest as cognitive failures in the workplace. Downstream, cognitive failures were expected to be associated with decreased task performance and increased turnover intentions. We collected data from a sample of working adults who either had (n = 45) or had not (n = 49) contracted Covid-19 at least one month prior to the study. Both groups were matched on key demographic characteristics. As anticipated, individuals who had contracted Covid-19 reported significantly more cognitive failures at work, relative to individuals who did not. More so, having contracted Covid-19 had significant indirect effects on task performance and turnover intentions via cognitive failure. These results indicate that beyond physical harm, Covid-19 can also have a detrimental influence on an individual’s capacity to perform at work.
May 24, 2022
A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19.
COVID-19 survivors have twice the risk for developing pulmonary embolism or respiratory conditions; one in five COVID-19 survivors aged 18–64 years and one in four survivors aged ≥65 years experienced at least one incident condition that might be attributable to previous COVID-19.
The omicron (B.1.1.529) variant, first detected in the UK on Nov 27, 2021, rapidly became the dominant strain, due in part to reduced vaccine effectiveness. An increase in sequenced cases of the omicron sub-lineage BA.2 was observed in the week beginning on Jan 3, 2022. BA.2 has a growth advantage over BA.1 and has become the dominant strain in the UK at the time of writing. Neutralisation assays using monoclonal antibodies have suggested a small antigenic difference between BA.1 and BA.2, although sera from individuals with booster vaccinations neutralise both variants similarly.
Circulation of contagious SARS-CoV-2 variants and suboptimal vaccine protection create the conditions for simultaneous infections with multiple strains, which could generate inter-lineage SARS-CoV-2 recombinants with novel unpredictable features. Mixed infections have been reported since the first epidemic waves. Co-infection with omicron and delta have been found in immunocompetent and immunocompromised patients living in different geographical areas. Because these variants are characterised by different genomic sequences, their co-presence can be identified promptly. However, recombination between closely related variants is difficult to identify but can also occur. A total of 637 cases of the omicron BA.1 and BA.2 recombinant, known as XE, have been confirmed in the UK up to now, and the number is increasing. These data also suggest that intralineage recombination generates highly transmissible chimeric strains. It is necessary to detect all co-infections to minimise the risk of recombination.
Repeated emergence of SARS-CoV-2 variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR0, a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR0 to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many non-spike mutations within the nucleocapsid and nonstructural proteins. PyR0 forecasts growth of new lineages from their mutational profile, ranks the fitness of lineages as new sequences become available, and prioritizes mutations of biological and public health concern for functional characterization.
The COVID-19 pandemic emerged at a time when we had won our way to a hilltop where many diseases are treatable. Improved treatment means that our health systems need to care for an increasing number of survivors of all types, including cancer survivors, older adults living with multiple comorbid conditions, and survivors of severe critical illnesses struggling to reintegrate into society. Humbled and cast down as we were by the tragedy of the worst of the COVID-19 pandemic, there was reassurance in the fact that many patients with SARS-CoV-2 infection were asymptomatic or had mild acute illness. We were unprepared for the onslaught of survivors of acute SARS-CoV-2 infection with persistent symptoms long after acute illness. Many of these patients present requesting diagnoses, expecting treatment, and worrying about their future lives in the shadow of COVID-19. Too often, these patients suffer the injustices of not being believed, being misdiagnosed as having anxiety disorder, or having their symptoms misattributed to pandemic stress.
May 23, 2022
Infection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal-time Assessment of Community Transmission -1 (REACT-1) study has been monitoring the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell and taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and induced changes in daily activities will become increasingly important.
Airborne transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other pathogens is probably increased during indoor exercise, but data on the emission of aerosol particles by an exercising individual are lacking. Here, we report that aerosol particle emission increases on average 132-fold from 580 ± 489 particles/min at rest to 76,200 ± 48,000 particles/min during maximal exercise. Aerosol particle emission increases moderately up to an exercise intensity of ≈2 W/kg and exponentially at higher exercise intensities. These data not only explain SARS-CoV-2 transmissions during indoor group exercise but also can be used to design better targeted mitigation measures for physical activity indoors such as physical education in school, dance events during weddings, or high-intensity gym classes such as spinning.
The Omicron lineage of SARS-CoV-2, first described in November 2021, spread rapidly to become globally dominant and has split into a number of sub-lineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sub-lineages, BA.4 and BA.5 which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences and, although closely related to BA.2, contain further mutations in the receptor binding domain of spike. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by serum from triple AstraZeneca or Pfizer vaccinated individuals compared to BA.1 and BA.2. Furthermore, using serum from BA.1 vaccine breakthrough infections there are likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.
Overall, we found that the COVID-19 illness trajectory includes persistent cardio-renal inflammation, hemostatic pathway activation and lung involvement. Our results demonstrate a link between the post-COVID-19 syndrome and multisystem disease, which partly explains the lingering impairments in patient-reported health-related quality of life, physical function and psychological well-being after COVID-19. The implication of multisystem injury pathways as mediators of post-COVID-19 syndrome should help to inform clinical guideline updates4, and the findings support the prioritization of targeted preventive therapy development for post-COVID-19 syndromes in hospitalized patients.
Compared to controls (n = 29), at 28–60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.
We describe relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir (NM/R) in 10 non-immunocompromised patients aged 31 to 71-years-old. Most patients improved rapidly after treatment with NM/R and had negative antigen or PCR tests prior to relapse on Days 9-12 of their illness. Relapse symptoms were described most frequently as cold symptoms, though some patients experiencing a recurrence of fatigue and headache. All relapses resolved without additional antiviral treatment. Viral load during relapse was comparable to levels during initial infection. Sequencing in three patients indicated that relapse was not due to a treatment-emergent mutation or infection with a different viral strain. One symptomatic and one presymptomatic patient transmitted SARS-CoV-2 to family members during relapse. The presence of high viral load and the occurrence of two transmission events suggest that patients with relapse should isolate until antigen testing is negative.
May 20, 2022
Updated growth modelling suggests BA.4 and BA.5 are likely to have a growth advantage overBA.2, including within the UK. This is based on small numbers of cases and there is a high degree of uncertainty. However, together with the laboratory data suggesting some degree of immune escape, BA.4 and BA.5 have been designated Variants of Concern, as this classification is intended to provide an early warning of potential risk of increased community transmission. There is no data to determine the impact of these variants on the hospital admissions in the UK.
May 19, 2022
Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1 and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site, however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focussed in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains and many show broad reactivity with variants of concern.\
Multiple lineages of the SARS-CoV-2 Omicron variant (B.1.1.529) have emerged, and BA.1 and BA.2 have demonstrated substantial escape from neutralizing antibodies (NAbs). BA.2.12.1 has now become dominant in the United States, and BA.4 and BA.5 have become dominant in South Africa. Our data show that BA.2.12.1 and BA.4/BA.5 substantially escape NAbs induced by both vaccination and infection. Moreover, BA.4/BA.5 NAb titers, and to lesser extent BA.2.12.1 NAb titers, were lower than BA.1 and BA.2 NAb titers, suggesting that the SARS-CoV-2 Omicron variant has continued to evolve with increasing neutralization escape. These findings have important public health implications and provide immunologic context for the current surges with BA.2.12.1 and BA.4/BA.5 in populations with high rates of vaccination and BA.1/BA.2 infection.
May 18, 2022
The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.
Benefits are possible, but we need more evidence and a mechanism of action
May 15, 2022
In this randomized clinical trial that included 400 adults with acute hypoxemic respiratory failure from COVID-19, awake prone positioning compared with usual care resulted in endotracheal intubation at 30 days in 34.1% vs 40.5% of participants, respectively. Although the hazard ratio was 0.81, the result was not statistically significant.
May 13, 2022
In a test-negative, case-control study conducted from December 2021 to February 2022 during Omicron variant predominance that included 121 952 tests from sites across the US, estimated vaccine effectiveness against symptomatic infection for children 5 to 11 years of age was 60.1% 2 to 4 weeks after dose 2 and 28.9% during month 2 after dose 2. Among adolescents 12 to 15 years of age, estimated vaccine effectiveness was 59.5% 2 to 4 weeks after dose 2 and 16.6% during month 2; estimated booster dose effectiveness in adolescents 2 to 6.5 weeks after the booster was 71.1%.
The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.
May 12, 2022
The messenger RNA (mRNA) boosters were highly effective against symptomatic delta infection, but they were less effective against symptomatic omicron infection. However, with both variants, mRNA boosters led to strong protection against Covid-19–related hospitalization and death.
May 11, 2022
Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults.
Regardless of initial disease severity, COVID-19 survivors had longitudinal improvements in physical and mental health, with most returning to their original work within 2 years; however, the burden of symptomatic sequelae remained fairly high. COVID-19 survivors had a remarkably lower health status than the general population at 2 years. The study findings indicate that there is an urgent need to explore the pathogenesis of long COVID and develop effective interventions to reduce the risk of long COVID.
May 10, 2022
Many aspects of SARS-CoV-2 have fully conformed with the principles established by decades of viral immunology research, ultimately leading to the crowning achievement of highly effective COVID-19 vaccines. Nonetheless, the pandemic has also exposed areas where our fundamental knowledge is thinner. Some key unknowns are the duration of humoral immunity post-primary infection or vaccination, and for how long booster shots confer protection. As a corollary, if protection does not last as long as desired, what are some ways it can be improved? Here, I discuss lessons from other infections and vaccines that point to several key features that influence durable antibody production and the perseverance of immunity. These include 1) the specific innate sensors that are initially triggered; 2) the kinetics of antigen delivery and persistence; 3) the starting B cell receptor (BCR) avidity and antigen valency; 4) the memory B cell subsets that are recalled by boosters. I further highlight the fundamental B cell-intrinsic and -extrinsic pathways which, if understood better, would provide a rational framework for vaccines to reliably provide durable immunity.
SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development.
Identifying antibodies that neutralize these variants of concern and determining their prevalence are important goals for understanding immune protection. To determine the Delta- and Omicron BA.1-variant specificity of B cell repertoires established by an initial Wuhan strain infection, we measured neutralization potencies of 73 antibodies from an unbiased survey of the early memory B cell response. Antibodies recognizing each of three, previously defined, epitopic regions on the spike receptor-binding domain (RBD) varied in neutralization potency and variant-escape resistance. The ACE2 binding surface (“RBD-2”) harbored the binding sites of the neutralizing antibodies with highest potency but with the greatest sensitivity to viral escape; two other epitopic regions on the RBD (“RBD-1 and “RBD-3”) bound antibodies of more modest potency but greater breadth. The structures of several Fab:spike complexes that neutralized all five variants of concern tested, including one Fab each from the RBD-1, -2 and -3 clusters, illustrated the determinants of broad neutralization and showed that B cell repertoires can have specificities that avoid immune escape driven by widely distributed (“public”) antibodies. The structure of the RBD-2-binding, broad neutralizer shows why it retains neutralizing activity for Omicron BA.1, unlike most others in the same public class. Our results correlate with real-world data on vaccine efficacy, which indicate mitigation of disease caused by Omicron BA.1.
Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months after acute SARS-CoV-2 infection. The etiologies are unknown but may include persistent inflammation, unresolved tissue damage, or delayed clearance of viral protein or RNA. Attempts to classify subsets of PASC by symptoms alone have been unsuccessful. To molecularly define PASC, we evaluated the serum proteome in longitudinal samples from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection and compared this to symptomatically recovered SARS-CoV-2 infected and uninfected individuals. We identified subsets of PASC with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), were the most differentially enriched pathways. These findings help to resolve the heterogeneity of PASC, identify patients with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance.
We find that the level of immunity induced by the March 2022 vaccination campaign would be insufficient to prevent an Omicron wave that would result in exceeding critical care capacity with a projected intensive care unit peak demand of 15.6-times the existing capacity and causing approximately 1.55 million deaths. However, we also estimate that protecting vulnerable individuals by ensuring accessibility to vaccines and antiviral therapies, and maintaining implementation of non-pharmaceutical interventions could be sufficient to prevent overwhelming the healthcare system, suggesting that these factors should be points of emphasis in future mitigation policies.
May 9, 2022
The emergency use authorizations (EUAs) of two mRNA-based severe acute respiratory syndrome coronavirus (SARS-CoV)-2 vaccines approximately 11 months after publication of the viral sequence highlights the transformative potential of this nucleic acid technology. Most clinical applications of mRNA to date have focused on vaccines for infectious disease and cancer for which low doses, low protein expression and local delivery can be effective because of the inherent immunostimulatory properties of some mRNA species and formulations. In addition, work on mRNA-encoded protein or cellular immunotherapies has also begun, for which minimal immune stimulation, high protein expression in target cells and tissues, and the need for repeated administration have led to additional manufacturing and formulation challenges for clinical translation. Building on this momentum, the past year has seen clinical progress with second-generation coronavirus disease 2019 (COVID-19) vaccines, Omicron-specific boosters and vaccines against seasonal influenza, Epstein–Barr virus, human immunodeficiency virus (HIV) and cancer. Here we review the clinical progress of mRNA therapy as well as provide an overview and future outlook of the transformative technology behind these mRNA-based drugs.
May 8, 2022
The SARS-CoV-2 Omicron variant has evolved into four sub-lineages, BA.1, BA.1.1, BA.2 and BA.3, with BA.2 becoming dominant worldwide. We and others have reported antibody evasion of BA.1 and BA.2, but side-by-side comparisons of Omicron sub-lineages to vaccine-elicited or monoclonal antibody (mAb)-mediated neutralization are necessary. Using VSV-based pseudovirus, we report that sera from individuals vaccinated by two doses of an inactivated whole-virion vaccine shows weak to no neutralization activity, while homologous or heterologous boosters markedly improve neutralization titers against all Omicron sub-lineages. We also present neutralization profiles against a 20-mAb panel, including 10 authorized or approved, against the Omicron sub-lineages, along with mAb mapping against single or combinatorial spike mutations. Most mAbs lost neutralizing activity, while some demonstrate distinct neutralization patterns among Omicron sub-lineages, reflecting antigenic differences. Collectively, our results suggest the Omicron sub-lineages threaten the neutralization efficacy of current vaccines and antibody therapeutics, highlighting the importance of vaccine boosters.
May 7, 2022
Our data suggest that COVID-19 vaccine is protective against post-acute sequelae of SARS-CoV-2 (PASC) symptoms, new onset of health conditions, and mortality.
May 6, 2022
Effectiveness of a COVID-19 Additional Primary or Booster Vaccine Dose in Preventing SARS-CoV-2 Infection Among Nursing Home Residents During Widespread Circulation of the Omicron Variant — United States, February 14–March 27, 2022
Analysis of COVID-19 surveillance and vaccination data from approximately 15,000 skilled nursing facilities found that, compared with primary series vaccination only, an additional or booster dose provided greater protection (relative VE = 46.9%) against SARS-CoV-2 infection during Omicron variant predominance.
In this cross-sectional study of 278 participants self-performing SARS-CoV-2 RADT in an intended-use setting, the accuracy of RADT interpretation was poor when the manufacturer’s instructions were used. A modified quick reference guide was associated with significantly better user performance.
In this cohort study of 1958 inpatients with serious mental illness in a statewide psychiatric hospital system, the use of second-generation antipsychotic medications was associated with a decreased risk of COVID-19 infection; the largest association was observed with the use of paliperidone. Valproic acid use was associated with an increased risk of infection.
May 5, 2022
Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19.
May 2, 2022
This Canadian surveillance study included 6012 completed pregnancies between March 2020 and October 2021. Among cases of infection during pregnancy compared with cases of infection among the general Canadian population of reproductive-age female individuals, there was a significantly increased risk of SARS-CoV-2–related hospitalization (relative risk, 2.65) and intensive care unit admission (relative risk, 5.46). Among cases of infection during pregnancy compared with pregnant individuals without SARS-CoV-2 infection, there was a significantly increased risk of preterm birth (relative risk, 1.63).
As the US emerges from the recent Omicron surge of the COVID-19 pandemic following close to a million deaths in the country attributable to COVID-19, many people are hoping that the worst is over.1 Widespread vaccine- and infection-induced immunity, combined with the availability of effective therapeutics, could blunt the effects of future outbreaks. Nonetheless, it is time to accept that the presence of SARS-CoV-2, the virus that causes COVID-19, is the new normal. It will likely circulate globally for the foreseeable future, taking its place alongside other common respiratory viruses such as influenza. And it likely will require similar annual consideration for vaccine composition updates in consultation with the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC). A recent meeting of the VRBPAC on April 6, 2022, resulted in a lively discussion and agreement on many considerations for planning for upcoming approaches to COVID-19 vaccine strain composition decision-making, development, and recommendations.
May 1, 2022
Absolute BA.4 and BA.5 neutralization levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants. The observed escape of BA.4 and BA.5 from BA.1 elicited immunity is more moderate than of BA.1 against previous immunity. However, the low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection. This may indicate that, based on neutralization escape, BA.4 and BA.5 have potential to result in a new infection wave.
Abstract. Despite the obvious knowledge that infectious particles can be shared through respiration, whether other constituents of the nasal/oral fluids can be passed between hosts has surprisingly never even been postulated, let alone investigated. The circumstances of the present pandemic facilitated a unique opportunity to fully examine this provocative idea. The data we show provides evidence for a new mechanism by which herd immunity may be manifested, the aerosol transfer of antibodies between immune and non- immune hosts.
Containing the COVID-19 pandemic requires rapidly identifying infected individuals. Subtle changes in physiological parameters (such as heart rate, respiratory rate, and skin temperature), discernible by wearable devices, could act as early digital biomarkers of infections. Our primary objective was to assess the performance of statistical and algorithmic models using data from wearable devices to detect deviations compatible with a SARS-CoV-2 infection. We searched MEDLINE, Embase, Web of Science, the Cochrane Central Register of Controlled Trials (known as CENTRAL), International Clinical Trials Registry Platform, and ClinicalTrials.gov on July 27, 2021 for publications, preprints, and study protocols describing the use of wearable devices to identify a SARS-CoV-2 infection. Of 3196 records identified and screened, 12 articles and 12 study protocols were analysed. Most included articles had a moderate risk of bias, as per the National Institute of Health Quality Assessment Tool for Observational and Cross-Sectional Studies. The accuracy of algorithmic models to detect SARS-CoV-2 infection varied greatly (area under the curve 0·52–0·92). An algorithm's ability to detect presymptomatic infection varied greatly (from 20% to 88% of cases), from 14 days to 1 day before symptom onset. Increased heart rate was most frequently associated with SARS-CoV-2 infection, along with increased skin temperature and respiratory rate. All 12 protocols described prospective studies that had yet to be completed or to publish their results, including two randomised controlled trials. The evidence surrounding wearable devices in the early detection of SARS-CoV-2 infection is still in an early stage, with a limited overall number of studies identified. However, these studies show promise for the early detection of SARS-CoV-2 infection. Large prospective, and preferably controlled, studies recruiting and retaining larger and more diverse populations are needed to provide further evidence.
April 29, 2022
South Africa’s fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath™ COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.07 - 0.09) and 0.12 (95% CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa.
The results of this cohort study of home antigen tests suggest that sensitivity for SARS-CoV-2 was moderate compared with RT-PCR and high compared with viral culture. The results also suggest that symptomatic individuals with an initial negative home antigen test result for SARS-CoV-2 infection should test again 1 to 2 days later because test sensitivity peaked several days after illness onset and improved with repeated testing.
Prior heterologous SARS-CoV-2 infection provided substantial and sustained protection against Omicron hospitalization, greatest among those also vaccinated. In the context of program goals to prevent severe outcomes and preserve healthcare system capacity, >2 doses of ancestral Wuhan-like vaccine may be of marginal incremental value to previously-infected individuals.
Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.
Today my clinic began with a young adult coming in for follow-up for depression and needing paperwork completed for mental health–related medical leave. This was followed by an older adult whose visit notes read “annual visit, last seen 2019.” Next was another patient scheduled for an annual examination, who left with a diagnosis of complicated grief following a family member’s recent death from COVID-19, someone they had begged to get vaccinated. Then I switched gears to a telemedicine video visit with a new patient establishing care. This patient had been undergoing a long, inconclusive workup for chronic dyspnea. Since then they had rarely left their home, aside from essential activities.
April 28, 2022
Significant person-to-person variation in infectious virus shedding suggests that individual-level heterogeneity in viral dynamics contributes to ‘superspreading’. Viral genome loads often peaked days earlier in saliva than in nasal swabs, indicating strong tissue compartmentalization and suggesting that saliva may serve as a superior sampling site for early detection of infection. Viral loads and clearance kinetics of Alpha (B.1.1.7) and previously circulating non-variant-of-concern viruses were mostly indistinguishable, indicating that the enhanced transmissibility of this variant cannot be explained simply by higher viral loads or delayed clearance. These results provide a high-resolution portrait of SARS-CoV-2 infection dynamics and implicate individual-level heterogeneity in infectiousness in superspreading.
We predict that species will aggregate in new combinations at high elevations, in biodiversity hotspots, and in areas of high human population density in Asia and Africa, driving the novel cross-species transmission of their viruses an estimated 4,000 times. Because of their unique dispersal capacity, bats account for the majority of novel viral sharing, and are likely to share viruses along evolutionary pathways that will facilitate future emergence in humans. Surprisingly, we find that this ecological transition may already be underway, and holding warming under 2 °C within the century will not reduce future viral sharing. Our findings highlight an urgent need to pair viral surveillance and discovery efforts with biodiversity surveys tracking species’ range shifts, especially in tropical regions that harbor the most zoonoses and are experiencing rapid warming.
A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19–related outcomes among persons who had received a third dose at least 4 months earlier.
April 27, 2022
Specifically, we predicted a dramatical decline in binding affinity of HLA-DRB1*03:01 and this peptide both because of the Omicron BA.1 mutations (N211 deletion, L212I substitution and EPE 212-214 insertion) and the Omicron BA.2 mutations (V213G substitution). The computational prediction was experimentally validated by ELISA with the use of corresponding thioredoxin-fused peptides and recombinant HLA-DR molecules. Another finding was the significant reduction in the number of tightly binding Spike peptides for HLA-B*07:02 HLA class I allele (both for Omicron and Delta variants). Overall, the majority of HLA alleles and haplotypes was not significantly affected by the mutations, suggesting the maintenance of effective T-cell immunity against the Omicron and Delta variants. Finally, we introduced the Omicron variant to T-CoV portal and added the functionality of haplotype-level analysis to it.
Had the COVID-19 pandemic not occurred, we estimate that there would be 6% fewer adolescents with high depressive symptoms. No effect of exposure to the pandemic on externalizing difficulties was found. Exploratory analyses to examine subgroup differences in impacts suggest that the negative impact of the COVID-19 pandemic on adolescent mental health may have been greater for females than males. Given the widespread concern over rising adolescent mental health difficulties prior to the pandemic, this paper quantifies the additional impacts of the pandemic. A properly resourced, multi-level, multi-sector public health approach for improving adolescent mental health is necessary.
SBQ-LC (version 1.0) is a comprehensive patient reported outcome instrument developed using modern psychometric methods. It measures symptoms of long covid important to people with lived experience of the condition and may be used to evaluate the impact of interventions and inform best practice in clinical management.
Janet Handal, who has taken immunosuppressive drugs since her 2010 kidney transplant, hasn’t exactly been impressed by public health messaging about COVID-19.
Within a population of hospitalized patients with severe/critical breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death, compared to fully vaccinated single-boosted individuals.
In total, 30 643 878 cases of covid-19 and 439 682 deaths associated with covid-19 occurred over 132 791 county weeks. A 10% improvement in vaccination coverage was associated with an 8% (95% confidence interval 8% to 9%) reduction in mortality rates and a 7% (6% to 8%) reduction in incidence. Higher vaccination coverage levels were associated with reduced mortality and incidence rates during the eras of alpha and delta variant predominance.
The findings of this study also make clear that many more lives could have been saved, and will be saved, by encouraging people to keep up to date with vaccination in the face of waning immunity and new SARS-CoV-2 variants and by achieving even higher population coverage. How many lives is a matter for others to explore. Meanwhile, this new study is another confidence booster for covid-19 vaccines.
Impact of the additional/booster dose of COVID-19 vaccine against severe disease during the epidemic phase characterized by the predominance of the Omicron variant in Italy, November 2021 - March 2022
Despite the stunning speed with which highly effective and safe vaccines have been developed, increasingly transmissible variants are emerging. Using surveillance data from Italy (November 2021-March 2022), during the epidemic phase characterized by the predominance of the Omicron variant, vaccination with additional/booster dose significantly reduces the risk at all ages for hospitalization (relative risk (RR): 0.16; 95% confidence interval (CI): 0.13-0.19), admission to ICU (RR: 0.08; 95% CI: 0.06-0.09) and death (RR: 0.13; 95% CI: 0.10-0.16). Results support the importance of receiving a third dose of mRNA COVID-19 vaccine.
Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.
April 26, 2022
As of February 2022, approximately 75% of children and adolescents had serologic evidence of previous infection with SARS-CoV-2, with approximately one third becoming newly seropositive since December 2021. The greatest increases in seroprevalence during September 2021–February 2022, occurred in the age groups with the lowest vaccination coverage; the proportion of the U.S. population fully vaccinated by April 2022 increased with age (5–11, 28%; 12–17, 59%; 18–49, 69%; 50–64, 80%; and ≥65 years, 90%).*** Lower seroprevalence among adults aged ≥65 years, who are at greater risk for severe illness from COVID-19, might also be related to the increased use of additional precautions with increasing age.
These findings illustrate a high infection rate for the Omicron variant, especially among children. Seropositivity for anti-N antibodies should not be interpreted as protection from future infection. Vaccination remains the safest strategy for preventing complications from SARS-CoV-2 infection, including hospitalization among children and adults (4,5). COVID-19 vaccination following infection provides additional protection against severe disease and hospitalization (6). Staying up to date††† with vaccination is recommended for all eligible persons, including those with previous SARS-CoV-2 infection.
In this cohort study of 40.7 million US commercially insured adults with acute clinical conditions, those with an initial telehealth encounter, compared with an in-person encounter, had higher odds for any follow-up encounter, an emergency department encounter, and in-patient admissions. For people with chronic conditions, the odds were lower for those with an initial telehealth encounter.
An estimated 936,911 excess deaths occurred during 2020 and 2021, of which 171,168 were not assigned to Covid-19 on death certificates. In the Far West, Great Lakes, Mideast, and New England, there was a substantial urban mortality disadvantage in 2020, which was reversed in 2021 to yield a rural mortality disadvantage. In the Southeast, Southwest, Rocky Mountain, and Plains regions, there was a rural mortality disadvantage in 2020, which was exacerbated in 2021. The proportion of excess deaths assigned to Covid-19 was lower in 2020 (76.3%) than in 2021 (87.0%), suggesting fewer Covid-19 deaths went unassigned later in the pandemic. However, in rural areas and in the Southeast and Southwest many excess deaths were still not assigned to Covid-19 during 2021.
Pregnant women with covid-19 are at greater risk of severe disease than their non-pregnant peers, and yet they are frequently denied investigations or treatments because of unfounded concerns about risk to the fetus. The basic principles of diagnosing and managing covid-19 are the same as for non-pregnant patients, and a multidisciplinary, expert team approach is essential to ensure optimal care. During pregnancy, treatment with corticosteroids should be modified to use non-fluorinated glucocorticoids. Il-6 inhibitors and monoclonal antibodies, together with specific antiviral therapies, may also be considered. Prophylaxis against venous thromboembolism is important. Women may require respiratory support with oxygen, non-invasive ventilation, ventilation in a prone position (either awake or during invasive ventilation), intubation and ventilation, and extracorporeal membrane oxygenation (ECMO). Pregnancy is not a contraindication for any of these supportive therapies, and the criteria for providing them are the same as in the general population. Decisions regarding timing, place, and mode of delivery should be taken with a multidisciplinary team including obstetricians, physicians, anesthetists, and intensivists experienced in the care of covid-19 in pregnancy. Ideally these decisions should take place in consultation with centers that have experience and expertise in all these specialties.
Initiation of NM/R treatment on Day 0 in a 71-year-old vaccinated and boosted male resulted in rapid resolution of COVID-19 symptoms followed one week later by the development of typical cold symptoms. SARS-CoV-2 viral load fluctuated in parallel with symptoms, with two distinct peaks on Day 1 and Day 9 of illness. No other respiratory pathogens were identified. Viral samples demonstrated sequence identity for the omicron subvariant BA.1 on Days 1, 7, and 11. Our findings suggest that viral replication and COVID-19 symptoms may recur after very early treatment with NM/R before natural immunity is sufficient to fully clear SARS-CoV-2.
Two vaccine doses were 31% effective against symptomatic or asymptomatic Omicron variant infection among children aged 5 to 11 years and 59% effective among adolescents aged 12 to 15 years. In contrast, 2 doses provided 87% protection against Delta variant infection among adolescents. Still, the authors recommended that all children and adolescents should receive COVID-19 vaccines as recommended, as they reduce the risk of infection even with the Omicron variant. The study also revealed differences in the variants’ effects among unvaccinated youth. About half of unvaccinated children and adolescents with Omicron infections were asymptomatic compared with 34% of those with Delta variant infections. Omicron symptoms lasted 3.4 fewer days and resulted in fewer missed school days than infections with the Delta variant. Vaccination reduced the time children infected with Omicron spent in bed by about a half-day.
Compared with White individuals, all other major racial and ethnic groups in the US experience more COVID-19 discrimination, according to a study coauthored by researchers from the National Institute on Minority Health and Health Disparities. Respondents who identified as Asian, irrespective of national origin, and American Indian or Alaska Native individuals were most likely to experience such discrimination. The findings also suggest that COVID-19 discrimination against Asian individuals has increased over the course of the pandemic.
April 25, 2022
Two new antiviral medications, ritonavir-boosted nirmatrelvir (Paxlovid, ie, nirmatrelvir-ritonavir) and molnupiravir (Lagevrio), are currently available in the US under emergency use authorization. These 2 drugs are authorized for treatment of patients with mild to moderate COVID-19 who are not currently hospitalized but are at high risk of developing severe disease. Nirmatrelvir-ritonavir and molnupiravir are approved for use only within 5 days of onset of COVID-19 symptoms.
Using simple mathematical modelling, we have shown that, although risk associated with avoiding vaccination during a virulent pandemic accrues chiefly to those who are unvaccinated, the choice of some individuals to refuse vaccination is likely to affect the health and safety of vaccinated people in a manner disproportionate to the fraction of unvaccinated people in the population. Risk among unvaccinated people cannot be considered self-regarding, and considerations around equity and justice for people who do choose to be vaccinated, as well as those who choose not to be, need to be considered in the formulation of vaccination policy. It is unlikely that SARS-CoV-2 will be eliminated, and our findings will likely be relevant to future seasonal SARS-CoV-2 epidemics or in the face of emerging variants.
This study demonstrates a substantial reduction in hospitalizations and deaths due to Covid-19 conferred by a second-booster in Israeli adults aged 60 years and over.
Two-dose vaccination induced robust anti-spike antibodies and neutralization titers (NTs) against the ancestral strain WK-521, whereas NTs against VOCs were significantly lower. Within 93–247 days of the second vaccine dose, NTs against Omicron were completely abolished in up to 80% of individuals in the vaccinee panel. Booster dose induced a robust increase in anti-spike antibodies and NTs against the WK-521, Delta, and Omicron variants. There were no significant differences in the neutralization ability of sera from boosted individuals among the Omicron subvariants BA.1, BA.1.1, and BA.2. Boosting increased the breadth of humoral immunity and
April 24, 2022
Recent reports of SARS-CoV-2 Omicron variant sub-lineages, BA.1, BA.1.1, and BA.2, have reignited concern over potential escape from vaccine- and infection-induced immunity. We examine the sensitivity of these sub-lineages and other major variants to neutralizing antibodies from mRNA-vaccinated and boosted individuals, as well as recovered COVID-19 patients, including those infected with Omicron. We find that all Omicron sub-lineages, especially BA.1 and BA.1.1, exhibit substantial immune escape that is largely overcome by mRNA vaccine booster doses. While Omicron BA.1.1 escapes almost completely from neutralization by early-pandemic COVID-19 patient sera and to a lesser extent from sera of Delta infected patients, BA.1.1 is sensitive to Omicron-infected patient sera. Critically, all Omicron sub-lineages, including BA.2, are comparably neutralized by Omicron patient sera. These results highlight the importance of booster vaccine doses for protection against all Omicron variants, and provide insight into the immunity from natural infection against Omicron sub-lineages.
April 23, 2022
Our results suggest that a homologous or heterologous booster dose for individuals with a complete primary vaccination schedule with CoronaVac provides a high level of protection against COVID-19, including severe disease and death. Heterologous boosters showed higher vaccine effectiveness than a homologous booster for all outcomes, providing additional support for a mix-and-match approach.
The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials.
April 22, 2022
Three doses of BNT162b2 conferred high protection against hospital and emergency department admission due to both the delta and omicron variants in the first 3 months after vaccination. However, 3 months after receipt of a third dose, waning was apparent against SARS-CoV-2 outcomes due to the omicron variant, including hospital admission. Additional doses of current, adapted, or novel COVD-19 vaccines might be needed to maintain high levels of protection against subsequent waves of SARS-CoV-2 caused by the omicron variant or future variants with similar escape potential.
The overall age-adjusted death rate increased by 0.7% in 2021 from 2020. Overall death rates were highest among non-Hispanic American Indian or Alaskan Native and non-Hispanic Black or African American populations. For a second year, COVID-19 was the third leading cause of death after heart disease and cancer.
From 2020 to 2021, disparities in AADR ratios from COVID-19 decreased significantly by 14.0%–40.2% for most racial and ethnic groups, including non-Hispanic White persons, who accounted for 59.6%–65.2% of all decedents; and increased nonsignificantly (7.2%) for non-Hispanic Native Hawaiian and other Pacific Islander persons (0.2%–0.3% of all decedents) compared with non-Hispanic multiracial persons.
The findings can inform strategies to increase booster dose vaccinations and effective messaging. COVID-19 vaccinations significantly lower the risk of serious illness from COVID-19 in pregnant individuals, and data indicate potential benefits to the developing fetus. Thus, continued focus to improve vaccinations with booster doses in this population, especially among those with lower vaccination coverage, such as individuals of Black or Hispanic race and ethnicity, is critical.
This cohort study of 49 993 participants in 11 longitudinal studies found that mental health has deteriorated from before the start of the COVID-19 pandemic, and this deterioration was sustained across the first year of the pandemic. Deterioration in mental health varied by sociodemographic factors, namely age, sex, and education, and did not recover when social restrictions were eased.
n this modeling study using data from the California Department of Public Health, COVID-19 vaccination was estimated to have prevented more than 1.5 million COVID-19 cases, 72 000 hospitalizations, and 19 000 deaths during the first 10 months of vaccination, through October 16, 2021.
In this cohort study of 25 million working-age adults in California, differences in the distribution of education and occupation across racial and ethnic groups were associated with racial and ethnic inequities in COVID-19 mortality, particularly for Latinx adults. If every working-age Californian had the COVID-19 mortality risk associated with the lowest-risk educational and occupational position, there would have been an estimated 8441 (43%) fewer deaths in this population.
In this decision analytical model study, for a month with transmission intensity similar to that of May 2021, a monoclonal antibody PEP program reaching 50% of exposed, unvaccinated household members aged 50 years and older was estimated to avert 528 hospitalizations and 84 deaths in a low-transmission scenario and 1404 hospitalizations and 223 deaths in a high-transmission scenario. The program was also estimated to be cost saving to payers in the high-transmission scenario as a result of averted hospitalizations.
In this cohort study among 61 individuals who had been vaccinated against COVID-19, cellular responses to the mutated regions of the Omicron spike protein were detected in 80% of participants. The mutations were associated with significantly reduced T-cell recognition compared with the vaccine strain, while reactivity to the whole spike protein was present in 100% of participants, and the proportion of remaining immunity to SARS-CoV-2 was estimated to be 87%.
To our knowledge, this is one of the first studies to evaluate the association of COVID-19 vaccination status with IVF-fresh embryo transfer cycles (including a high proportion of standard insemination cycles). We found no evidence to suggest that COVID-19 vaccination negatively affects cycle stimulation characteristics, embryological variables, or clinical outcomes in IVF. Current and emerging scientific evidence continues to support that COVID-19 vaccination is safe and effective and has no impact on fertility. The results of this study can be used to provide reassuring data to patients planning on pregnancy considering COVID-19 vaccination.
In an exploratory trial treating “long COVID” with the CCR5-binding antibody leronlimab, we observed significantly increased blood cell surface CCR5 in treated symptomatic responders but not in nonresponders or placebo-treated participants. These findings suggest an unexpected mechanism of abnormal immune downmodulation in some persons that is normalized by leronlimab.
These early national data suggest that omicron is associated with a two-thirds reduction in the risk of COVID-19 hospitalisation compared with delta. Although offering the greatest protection against delta, the booster dose of vaccination offers substantial additional protection against the risk of symptomatic COVID-19 for omicron compared with 25 weeks or more after the second vaccine dose.
We found a significantly lower risk of hospitalisation with omicron infection compared with delta infection among both vaccinated and unvaccinated individuals, suggesting an inherent reduced severity of omicron. Our results could guide modelling of the effect of the ongoing global omicron wave and thus health-care system preparedness.
April 21, 2022
Analysis of brain images taken before and after infection with SARS-CoV-2 suggests that even mild COVID-19 is associated with brain structure alterations and cognitive impairment. However, the clinical implications for individuals are unclear and further studies are needed to assess the generalizability of the findings and whether the effects are long-lasting.
Changes in mental health measures during the first 15 months of the COVID-19 pandemic were small. More stringent COVID-19 policies were associated with poorer mental health. Elimination strategies minimised transmission and deaths, while restricting mental health effects.
We find that the 3rd dose is accompanied by an increase in, and evolution of, anti-receptor binding domain-specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the 2nd dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared to antibodies obtained after the 2nd dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells that differed from the persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analyzed neutralizing antibodies in the memory compartment after a 3rd mRNA vaccine dose neutralized Omicron. Thus, individuals receiving 3 doses of an mRNA vaccine, have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help explain why a 3rd dose of a vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.
April 20, 2022
Among both age groups, VE against COVID-19-related hospitalization 14-30 days since vaccination with two or three doses was 94.8% or above for the Alpha and Delta variants, whereas among the youngest age group, VE estimates against the Omicron variant after two and three doses were 62.4% (95% CI: 46.3; 73.6) and 89.8% (95% CI: 87.9; 91.3), respectively. Conclusions Two vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha and Delta variants with protection waning over time. Two vaccine doses provided only limited protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Omicron variant. The third vaccine dose substantially increased the protection against Delta and Omicron.
Among 121 615 patients with more than 10 million days of follow-up, unvaccinated individuals with prior symptomatic COVID-19 had 85% lower risk of acquiring COVID-19 than unvaccinated individuals without prior COVID-19. Prior studies investigating protection against SARS-CoV-2 reinfection found similar results, with protection associated with natural immunity ranging from 80.5% to 100%. This level of protection is similar to that reported for mRNA vaccines. The findings that patients with prior COVID-19 had 88% protection against hospitalization for COVID-19 and 83% protection against COVID-19 not requiring hospitalization suggest that natural immunity was associated with similar protection against mild and severe disease. mRNA vaccines are associated with similar prolonged protection from severe COVID-19 as found in our study, although vaccine-associated protection from mild COVID-19 has been shown to wane at 6 months.
A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns.
Currently, SARS-CoV-2 has proven itself to be a dangerous new human respiratory pathogen with an unpredictable evolutionary capacity, leading to a risk of future variants too great not to ensure all regions of the world are screened by viral genome sequencing, protected through available and affordable vaccines, and have non-punitive strategies in place for detecting and responding to novel variants of concern.
April 19, 2022
During the period of Omicron predominance (December 19, 2021–February 28, 2022), COVID-19–associated hospitalization rates in children aged 5–11 years were approximately twice as high among unvaccinated as among vaccinated children. Non-Hispanic Black children represented the largest group of unvaccinated children. Thirty percent of hospitalized children had no underlying medical conditions, and 19% were admitted to an intensive care unit. Children with diabetes and obesity were more likely to experience severe COVID-19.
We found that in most individuals, resting heart rate (RHR) increased with respect to their individual baseline after vaccination, peaked on day 2, and returned to normal by day 6. This increase in RHR was greater than one standard deviation above individuals’ normal daily pattern in 47% of participants after their second vaccine dose. Consistent with other reports of subjective reactogenicity following vaccination, we measured a significantly stronger effect after the second dose relative to the first, except those who previously tested positive to COVID-19, and a more pronounced increase for individuals who received the Moderna vaccine. Females, after the first dose only, and those aged <40 years, also experienced a greater objective response after adjusting for possible confounding factors. These early findings show that it is possible to detect subtle, but important changes from an individual’s normal as objective evidence of reactogenicity, which, with further work, could prove useful as a surrogate for vaccine-induced immune response.
The DDIs identified in this systematic review involved 46 different drugs, with 575 DDIs for 58 drug pairs (305 associated with at least 1 adverse drug reaction) reported. Drug interaction checkers could have identified such events, including severe and life-threatening ones.
Consumer-grade wearables are needed to track disease, especially in the ongoing pandemic, as they can monitor patients in real time. We show that decomposing heart rate from low-cost wearable technologies into signals from different systems can give a multidimensional description of physiological changes due to COVID-19 infection. We find that the separate physiological features of basal heart rate, heart rate response to physical activity, circadian variation in heart rate, and autocorrelation of heart rate are significantly altered and can classify symptomatic versus healthy periods. Increased heart rate and autocorrelation begin at symptom onset, while the heart rate response to activity increases soon after symptom onset and increases more in individuals exhibiting cough. Symptom onset is associated with a blunting of circadian variation in heart rate, as measured by the uncertainty in the phase estimate. This work establishes an innovative data analytic approach to monitor disease progression remotely using consumer-grade wearables.
As debates over additional booster shots for COVID-19 intensify, many public health researchers are looking to the influenza model of vaccination as a guide for how to handle the lasting threat of SARS-CoV-2. That could mean annual shots, as is routine today with seasonal flu prophylaxis. But just as scientists have long sought a universal flu jab that can provide lasting protection against multiple subtypes of that respiratory virus, so too the field is on the hunt for pan-coronavirus vaccines that can ward off future variants of SARS-CoV-2 and preempt the next pandemic.
April 18, 2022
Previous exposure to SARS-CoV-2 decreased the risk and severity of subsequent COVID-19 infection, even against newly emerging variants. Protection is further enhanced by one or two doses of SCB-2019.
A 3rd vaccination significantly improved neutralization capacity per antibody. Conclusions and Relevance The primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation.
SARS-CoV-2 Omicron variants BA.1 and BA.2 seem to show reduced clinical severity. We classified 172 COVID-19 Omicron patient admissions. 66.2% of patients were admitted with primary or admission-contributing COVID-19. We therefore must be careful to base healthcare and public health decisions on the total number of hospitalized COVID-19 patients alone.
We found that AEs after the BNT162b2 mRNA vaccine booster dose were generally mild and usually did not require medical care. The proportion of self-reported AEs that occurred in our study was similar or lower than that after the administration of the second vaccine dose in several previous studies. A study by Menni et al found a similar proportion of systemic reactions among older individuals after the second vaccine dose as after the third dose in our study (16.4% vs 16.6%). The proportion of female respondents who reported systemic AEs was greater than the proportion of male respondents, with higher proportions among participants in the younger age group (60-69 years) than in the older age groups. Similar results were reported in previous studies after administration of the second vaccine dose.
April 16, 2022
In 1963, James Baldwin, one of the USA's greatest essayists, published The Fire Next Time. The book's title comes from a slave song—”God gave Noah the rainbow sign/No more water but the fire next time”. Baldwin's words sounded a warning that the USA needed to confront its racial hierarchy by embracing racial equality or doom its future. Sandro Galea's book, The Contagion Next Time, is titled in a homage to Baldwin and it also sounds a warning. Galea's central argument is that vulnerability to COVID-19 lies with a societal failure to recognise that the foundation of health rests on a healthy everyday life and not simply in the provision of health care. He ponders why this key lesson is not at the centre of pandemic discourse, which instead focuses on vaccination and treatment. In often lyrical prose, Galea roams across history, culture, literature, moral values, economics, politics, and personal pandemic experience. Although situated in a global context, the book's focus is the USA. Galea considers especially the enduring impacts of racism on health and the centrality of structural racism to understanding the USA.
Face masking in current COVID-19 pandemic seems to be a deceivingly simple decision-making problem due to its multifaceted nature. Questions arising from masking span biomedicine, epidemiology, physics, and human behaviors. While science has shown masks work generally, human behaviors (particularly under influences of politics) complicate the problem significantly given science generally assumes rationality and our minds are not always rational and/or honest. Minding minds, a legitimate concern, can also make masking legitimately confusing. To disentangle the potential confusions, particularly, the ramifications of irrationality and dishonesty, here we resort to evolutionary game theory.
April 15, 2022
In South Africa, a network of researchers are studying whether new lineages BA.4 and BA.5 escape immunity from COVID-19 vaccines and prior infections.
April 14, 2022
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns.
In this cohort study of 263 697 fully vaccinated US Department of Veterans Affairs patients, psychiatric disorder diagnoses were associated with increased incidence of SARS-CoV-2 breakthrough infection after vaccination.
Vaccine effectiveness against SARS-CoV-2 infection and severe outcomes among individuals with immune-mediated inflammatory diseases tested between March 1 and Nov 22, 2021, in Ontario, Canada: a population-based analysis
Two vaccine doses were found to be highly effective against both SARS-CoV-2 infection and severe COVID-19 outcomes in patients with rheumatoid arthritis, ankylosing spondylitis, psoriasis, and inflammatory bowel disease during the study period. Research is needed to determine the durability of effectiveness of three doses over time, particularly against emerging variants.
This cohort study of electronic health record data for 47 999 individuals receiving 3-dose mRNA COVID-19 vaccines found no significant increase in the reporting of severe adverse events (ie, anaphylaxis, cerebral venous sinus thrombosis, myocarditis, and pericarditis) after the third vaccine dose compared with before vaccination and after prior doses. Significantly increased reporting was found for low-severity adverse events (ie, fatigue, lymphadenopathy, nausea, and headache).
April 13, 2022
A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19–related outcomes among persons who had received a third dose at least 4 months earlier.
It is now incumbent on the CDC to determine who most benefits from booster dosing and to educate the public about the limits of mucosal vaccines. Otherwise, a zero-tolerance strategy for mild or asymptomatic infection, which can be implemented only with frequent booster doses, will continue to mislead the public about what Covid-19 vaccines can and cannot do.
The recently emerged Omicron variant is the most antigenically distinct SARS-CoV-2 variant of concern to date. As the heavily mutated spike protein enables escape from neutralizing antibodies, we studied the neutralizing activities of sera after Omicron BA.1 and BA.2 infections of naïve and vaccinated individuals. We show that primary BA.1 infections yielded reduced neutralizing antibody titers against wildtype (WT), Delta, and BA.2, while serum samples from individuals after BA.2 infection showed no cross-neutralization against the other variants. Fully vaccinated individuals were still able to neutralize both Omicron sub-lineages up to three months after vaccination, and Omicron-breakthrough infections showed equal cross-neutralizing activities against WT, Delta, BA.1, and BA.2. Our data demonstrate that Omicron variants are able to enhance cross-neutralizing antibodies in pre-immune individuals. Primary infections with one of the Omicron sub-lineages, however, induced variant-specific neutralizing antibodies. In particular, BA.2 infections generated a sub-lineage-specific response, emphasizing its antigenic distance.
April 12, 2022
Among persons with previous infection, COVID-19 mRNA vaccination provided protection against subsequent COVID-19–associated hospitalization. Estimated vaccine effectiveness against reinfection leading to hospitalization during the Omicron-predominant period was approximately 35% after dose 2, and 68% after a booster dose. To prevent COVID-19–associated hospitalization, all eligible persons should stay up to date with vaccination, including those with previous SARS-CoV-2 infection.
April 11, 2022
AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.
Coronavirus disease 2019 (COVID-19) resulted in a global pandemic and has overwhelmed health care systems worldwide. In this scientific statement, we describe the epidemiology, pathophysiology, clinical presentations, treatment, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multisystem inflammatory syndrome in children and young adults with a focus on cardiovascular manifestations and complications. We review current knowledge about the health consequences of this illness in children and young adults with congenital and acquired heart disease, the public health burden and health disparities of this infection in these populations, and vaccine-associated myocarditis.
The overall risk of myopericarditis after receiving a COVID-19 vaccine is low. However, younger males have an increased incidence of myopericarditis, particularly after receiving mRNA vaccines. Nevertheless, the risks of such rare adverse events should be balanced against the risks of COVID-19 infection (including myopericarditis).
Defining the most appropriate phenotypes in genome-wide association studies of COVID-19 is challenging, and two new publications demonstrate how case-control definitions critically determine outcomes and downstream clinical utility of findings.
In the region of olfactory bulb and olfactory tract, COVID-19 infection was associated with axon pathology and microvasculopathy, particularly in patients with smell alterations; the olfactory pathology did not result from direct viral injury and may be associated with local inflammation.
In the region of olfactory bulb and olfactory tract, COVID-19 infection was associated with axon pathology and microvasculopathy, particularly in patients with smell alterations; the olfactory pathology did not result from direct viral injury and may be associated with local inflammation.
April 8, 2022
Among persons aged ≥60 years in Hong Kong, 49% had received ≥2 doses of a COVID-19 vaccine, and vaccination coverage declined with age. During January–March 2022, reported COVID-19–associated deaths rose rapidly in Hong Kong. Among these deaths, 96% occurred in persons aged ≥60 years; within this age group, the risk for death was 20 times lower among those who were fully vaccinated compared with those who were unvaccinated.
Vaccination protects against infection with SARS-CoV-2 (the virus that causes COVID-19) and related hospitalizations, and surviving a previous infection protects against B.1.1.7 (Alpha) and B.1.617.2 (Delta) variant reinfections. Since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in the United States in late December 2021, reported reinfections have increased. Early reinfections (those occurring within 90 days of previous infection) are not well understood. Because some persons have prolonged detection of viral RNA after infection, repeat positive nucleic acid amplification test (NAAT) results within 90 days could reflect prolonged shedding from earlier infection, presenting technical challenges to documenting and characterizing early reinfections. This report describes 10 patients from four states, with whole genome sequencing (WGS)–confirmed Omicron variant infections within 90 days of a previous Delta infection. This activity was reviewed by CDC, approved by respective institutional review boards, and was conducted consistent with applicable federal law and CDC policy.
In this cohort study of a nationwide database of electronic health records of 636 465 vaccinated patients, the 45 253 vaccinated patients with cancer had significantly higher risk for breakthrough SARS-CoV-2 infections than propensity score–matched patients without cancer, with marked heterogeneity among 12 common cancers, including solid tumors and hematologic cancers, most common in patients with active cancer within the past year. Breakthrough infections in patients with cancer were associated with significant and substantial risks for hospitalizations and mortality.
In June 2020, preliminary results for the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial conducted in the UK indicated benefit from dexamethasone in severely ill hospitalized patients with COVID-19 but potential harm in those not requiring oxygen. In October 2020, the National Institutes of Health (NIH) issued COVID-19 treatment guidelines advising against systemic corticosteroid use in patients with mild to moderate COVID-19. Using 2 large US health care claims databases, we examined systemic corticosteroid use among nonhospitalized patients with COVID-19.
During the first year of the COVID-19 pandemic, 30% of outpatient visits for COVID-19 among Medicare beneficiaries were linked to an antibiotic prescription, 50.7% of which were for azithromycin. Randomized clinical trials demonstrated no benefit of azithromycin in treating COVID-19, and its use for the disease has been linked to antimicrobial resistance. The largest number of visits and highest rates of antibiotic prescribing were observed in the ED, perhaps reflecting acuity of care, and urgent care centers had the highest rate of azithromycin prescribing. Telehealth visits had the second highest antibiotic prescribing rate and were close in volume to office visits, emphasizing the importance of optimizing antibiotic prescribing practices in this setting. Antibiotic prescribing occurred at a higher rate for non-Hispanic White beneficiaries than for those from other racial and ethnic groups. Although described in pediatrics, this racial difference has not been well characterized in older adults and warrants further evaluation because it may indicate more services are being provided to White beneficiaries, even if not indicated.
April 7, 2022
After over a billion of vaccinations with messenger RNA-lipid nanoparticle (mRNA-LNP) based SARS-CoV-2 vaccines, anaphylaxis and other manifestations of hypersensitivity can be considered as very rare adverse events. Although current recommendations include avoiding a second dose in those with first-dose anaphylaxis, the underlying mechanisms are unknown; therefore, the risk of a future reaction cannot be predicted. Given how important new mRNA constructs will be to address the emergence of new viral variants and viruses, there is an urgent need for clinical approaches that would allow a safe repeated immunization of high-risk individuals and for reliable predictive tools of adverse reactions to mRNA vaccines. In many aspects, anaphylaxis symptoms experienced by the affected vaccine recipients resemble those of infusion reactions to nanomedicines. Here we share lessons learned over a decade of nanomedicine research and discuss the current knowledge about several factors that individually or collectively contribute to infusion reactions to nanomedicines. We aim to use this knowledge to inform the SARS-CoV-2 lipid-nanoparticle-based mRNA vaccine field.
Three in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.
April 6, 2022
The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.
It is now clear from meta-analyses of case series, cohort studies, and self-controlled case series that the risk of venous thromboembolism is increased after SARS-CoV-2 infection. However, two important questions remain: for how long post-infection is the risk increased, and does mild infection also increase risk? In a linked paper, Katsoularis and colleagues (doi:10.1136/bmj-2021-069590) address these questions by applying two complementary study designs to data from several Swedish registries.
In this systematic review and bayesian meta-analysis of 3 clinical trials, which accounted for varying prior probabilities coupled with a frequentist sensitivity analysis, there was a high probability (94.1%-98.6%) that fluvoxamine was associated with a reduced risk for hospitalization, with a frequentist risk ratio of 0.75 (95% CI, 0.58-0.97). These findings suggest that fluvoxamine, a widely available and inexpensive treatment for outpatients with COVID-19, was associated with a reduction in hospitalizations.
To our knowledge, this cross-sectional study is the first to examine the association of the FDA’s full approval of the BNT162b2 mRNA COVID-19 vaccine with subsequent US COVID-19 vaccinations. We estimated that approval was significantly associated with an increase in the overall number of vaccines administered; however, this appears to be largely related to an increase in series completions after approval. Our analysis suggests that approval may have been associated with a decrease in the number of first doses administered compared with what would have been expected without approval. Potential limitations of this study include the possibility of spillover effects and the relative shortness of the postintervention period considered.
In this retrospective cohort study of 471 791 rural US veterans with a history of mental health care use, receipt of a video-enabled tablet was associated with increased use of mental health care via video, increased psychotherapy visits (across all modalities), and reduced suicide behavior and ED visits.
Early in the pandemic, the World Health Organization stated that SARS-CoV-2 was not transmitted through the air. That mistake and the prolonged process of correcting it sowed confusion and raises questions about what will happen in the next pandemic.
SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD), leading to inflammatory death (pyroptosis) and release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on uptake of antibody-opsonized virus by Fcγ receptors. Vaccine recipient plasma does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in infected monocyte culture supernatants. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from COVID-19 lung autopsies have activated inflammasomes. These findings taken together suggest that antibody-mediated SARS-CoV-2 uptake by monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.
April 5, 2022
These findings suggest that in high-income settings, adults aged 60 years and older who are not fully vaccinated should be given priority to receive REGEN-COV for treating recently diagnosed COVID-19, particularly when supply is limited. It should be noted, however, that clinical trials on the use of REGEN-COV as PEP2 or for treatment3 were conducted before widespread circulation of the SARS-CoV-2 Delta and Omicron variants; therefore, a limitation of this analysis is that the estimated cost-effectiveness may be influenced if the efficacy of REGEN-COV differs by variant. Care must be taken to prevent the availability of monoclonal antibodies from deterring vaccination, which should remain the preferred means of preventing severe COVID-19.
The US Food and Drug Administration (FDA) instructions accompanying at-home SARS-CoV-2 rapid self-tests often confused people in a recent trial reported in JAMA Internal Medicine, causing them to incorrectly decide not to quarantine.
A study in Israel found that individuals who received an mRNA COVID-19 vaccine during pregnancy delivered infants with no increased risk for morbidity or mortality compared with infants whose birthing parents weren’t vaccinated.
The apparent increased COVID-19 deaths reported on weekends might confound projections and create a false sense of security on subsequent weekdays. The apparent increased mortality on weekends might be preventable with more consistent clinical care and public health documentation on all days of the week.
We found that COVID-19 diagnosis in ≥50-year-olds was associated with a significantly increased risk of developing HZ, highlighting the relevance of maintaining HZ vaccination.
April 4, 2022
In this survey study, 3 themes emerged from our analysis. First, translation from evidence to practice guidelines was remarkably complete for interventions supported by aligned national guidelines and high-quality studies. A striking example is the near universal adoption of dexamethasone among patients requiring at least 4 L of supplementary oxygen only 6 to 8 months after the RECOVERY trial demonstrated a survival benefit. The lone exception to this trend was baricitinib; however, new evidence and guidelines were released within 1 week of survey distribution. Practice convergence was also observed when evidence and guidelines aligned against interventions, as seen in the infrequent recommendation of dexamethasone for patients with oxygen saturation greater than 94%, as measured by pulse oximetry. However, clear opportunity for improvement still exists.
Approximately 3% of patients with pneumonia associated with SARS-CoV-2 infection developed new-onset dementia, which was significantly higher than the rate seen with other pneumonias.
April 1, 2022
Data from 40 health care systems participating in a large network found that the risk for cardiac complications was significantly higher after SARS-CoV-2 infection than after mRNA COVID-19 vaccination for both males and females in all age groups. These findings support continued use of recommended mRNA COVID-19 vaccines among all eligible persons aged ≥5 years.
March 31, 2022
However, SARS-CoV-2, the virus that causes COVID-19, is so different from polio and measles that classical herd immunity may not readily apply to it. Important differences include the phenotypic stability of polio and measles viruses, and their ability to elicit long-term protective immunity, compared to SARS-CoV-2. For these and other reasons, controlling COVID-19 by increasing herd immunity may be an elusive goal.
Overall, in a national database study in Qatar, we found that the effectiveness of previous infection in preventing reinfection with the alpha, beta, and delta variants of SARS-CoV-2 was robust (at approximately 90%), findings that confirmed earlier estimates. Such protection against reinfection with the omicron variant was lower (approximately 60%) but still considerable. In addition, the protection of previous infection against hospitalization or death caused by reinfection appeared to be robust, regardless of variant.
March 30, 2022
Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19.
March 29, 2022
Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S (Janssen [Johnson & Johnson]) Vaccine Dose Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults — VISION Network, 10 States, December 2021–March 2022
VE against COVID-19–associated emergency department/urgent care visits was 24% after 1 Jansen dose, 54% after 2 Jansen doses, and 79% after 1 Janssen/1 mRNA dose, compared to 83% after 3 mRNA doses. VE for the same strategies against COVID-19–associated hospitalization was 31%, 67%, 78%, and 90% respectively. All eligible persons should receive recommended COVID-19 booster doses to prevent moderate to severe COVID-19. Adult Janssen primary vaccine recipients should preferentially receive a heterologous mRNA vaccine booster dose ≥2 months later.
CDC Recommends Additional Boosters for Certain Individuals
Following FDA’s regulatory actionexternal icon today, CDC is updating its recommendations to allow certain immunocompromised individuals and people over the age of 50 who received an initial booster dose at least 4 months ago to be eligible for another mRNA booster to increase their protection against severe disease from COVID-19. Separately and in addition, based on newly published data, adults who received a primary vaccine and booster dose of Johnson & Johnson’s Janssen COVID-19 vaccine at least 4 months ago may now receive a second booster dose using an mRNA COVID-19 vaccine.
March 28, 2022
Our data indicate that the immune escape from BA.2 is not as severe as from BA.1, suggesting that other viral or host factors are driving the rapid spread of BA.2. Since NAb titres correlate with vaccine effectiveness, our data suggest that currently available vaccines might be more effective against BA.2 than BA.1.
Whole-genome sequencing (WGS) can identify variants that cause genetic disease, but the time required for sequencing and analysis has been a barrier to its use in acutely ill patients. In the present study, we develop an approach for ultra-rapid nanopore WGS that combines an optimized sample preparation protocol, distributing sequencing over 48 flow cells, near real-time base calling and alignment, accelerated variant calling and fast variant filtration for efficient manual review. Application to two example clinical cases identified a candidate variant in <8 h from sample preparation to variant identification. We show that this framework provides accurate variant calls and efficient prioritization, and accelerates diagnostic clinical genome sequencing twofold compared with previous approaches.
Here, we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of >10 at inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids. In Calu-3 cells it inhibits entry of SARS-CoV-2 VOCs, B.1.1.7, B.1.351, P.1 and B.1.617.2. Importantly, in the K18-human ACE2 transgenic mouse model of severe SARS-CoV-2 disease, we found that N-0385 affords a high level of prophylactic and therapeutic benefit following either multiple or even a single administration. This demonstrates that TTSP-mediated proteolytic maturation of spike is critical for SARS-CoV-2 infection in vivo and suggests that N-0385 provides a novel effective early treatment option against COVID-19 and emerging SARS-CoV-2 VOCs.
China’s hard-line approach to eliminating COVID-19 seems to be softening. In his speech, Xi also flagged a more pragmatic strategy, asking that officials limit the economic impact of control measures. In practice, this means that people with asymptomatic cases of COVID-19 are being sent to dedicated isolation centres rather than hospitals, and are monitored for shorter periods than previously required. But some researchers are divided about whether the virus will spread out of control before the government has time to prepare.
March 27, 2022
The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1. and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lung. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.
Throughout the SARS-CoV-2 pandemic, multiple waves of variants of concern have swept across populations, leading to a chain of new and yet more contagious lineages dominating COVID-19 cases. Here, we tracked the remarkably rapid shift from Omicron BA.1 to BA.2 sub-variant dominance in the Swedish population during January-March 2022. By analysis of 174,933 clinical nasopharyngeal swab samples using a custom variant-typing RT-PCR assay, we uncover nearly two-fold higher levels of viral RNA in cases with Omicron BA.2. Importantly, increased viral load in the upper pharynx upon BA.2 infection may provide part of the explanation why Omicron BA.2 is more transmissible and currently outcompetes the BA.1 variant across populations.
The direction of change in disease severity between successively emerging SARS-CoV-2 variants of concern was inconsistent. This heterogeneity in virulence between variants, coupled with independent evolutionary emergence, demonstrates that severity associated with future SARS-CoV-2 variants is inherently unpredictable.
March 25, 2022
A rapid increase in U.S. at-home test use occurred between the SARS-CoV-2 Delta- and Omicron-predominant periods; at-home test use was lower among persons who self-identified as Black, were aged ≥75 years, had lower incomes, and had a high school level education or less. Commonly reported reasons for using at-home tests included exposure concerns and symptoms.
For all isolates, the virus infected ciliated but not goblet epithelial cells. Key SARS-CoV-2 entry molecules, ACE2 and TMPRSS2, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistently, extracellular virions were seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion where tomography showed that the viral membrane was continuous with the apical plasma membrane and the nucleocapsids diluted, compared with unfused virus, demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein. Tomography showed concentration of nucleocapsids round the periphery of profiles strongly suggestive of viral budding into these compartments and this may explain how virions gain their S glycoprotein containing envelope.
Our findings support that the outcomes of KT after COVID-19 recovery are excellent with absence of COVID-19 sequelae during follow-up. Additionally, there does not seem to be a need for changes in the induction/immunosuppression regimen based on the severity of COVID-19.
This decision analytical model study used CICT program data from 23 jurisdictions and estimated that CICT programs averted 1.11 to 1.36 million cases and 27 231 to 33 527 hospitalizations over 60 days during the 2020 to 2021 winter peak of the pandemic. The upper estimate assumes that all interviewed cases and monitored contacts complied with isolation and quarantine guidelines, whereas the lower estimate assumes that fractions of interviewed cases and monitored or notified contacts did so.
Among 6076 participants (median age 64 years, interquartile range 55–75) included in this analysis, breakthrough infections due to the Delta variant were observed in 127 participants and in 363 due to the Omicron variant. The incidence rate ratio (IRR) for breakthrough infection with the Delta variant decreased with higher levels of anti-spike IgG yielding an IRR of 0.28 (95% CI 0·15–0·55) when comparing the highest and lowest quintiles of anti-spike IgG. For the Omicron variant, no significant differences in IRR of breakthrough infection between quintiles of anti-spike IgG was observed. Notably, 1 of 127 (0·8%) SARS-CoV-2 Delta variant and 0 of 336 (0%) Omicron variant breakthrough infections resulted in severe COVID-19.
March 24, 2022
In this population-based retrospective cohort study that included 157 521 deliveries in Sweden and Norway, SARS-CoV-2 vaccination during pregnancy, compared with no SARS-CoV-2 vaccination during pregnancy, was not significantly associated with risk of preterm birth (adjusted hazard ratio [aHR], 0.98), stillbirth (aHR, 0.86), small for gestational age (adjusted odds ratio [aOR], 0.97), low Apgar score (aOR, 0.97), or neonatal care admission (aOR, 0.97).
ARS-CoV-2 infection during pregnancy is associated with increased risk for maternal morbidity and adverse birth outcomes. COVID-19 vaccines are effective for preventing severe disease, including in pregnant populations. Although more than 100 countries recommend COVID-19 vaccination during pregnancy, COVID-19 vaccination in pregnant people has lagged behind that for age-matched, nonpregnant adults. As of February 2022, the US Vaccine Safety Datalink estimated that 68% of pregnant individuals have completed the primary COVID-19 vaccine series.6 Persistent wide disparities in COVID-19 vaccination during pregnancy by race or ethnicity are likely to exacerbate longstanding disparities in maternal morbidity and mortality.
SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980 for mRNA-1273 boost and 2670 and 1930 for mRNA-Omicron. Similar increases against BA.2 were observed. Following either boost, 70-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge one month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.
A fourth dose of the BNT162b2 vaccine provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, effectiveness of the fourth dose against infection wanes sooner than that of the third dose.
In a cohort study of 112 269 patients with moderate COVID-19, early aspirin use during the first day of hospitalization was associated with lower 28-day in-hospital mortality and pulmonary embolism incidence when compared with patients who did not receive early aspirin.
This retrospective cohort study included all members of Clalit Health Services, aged 60 to 100, eligible for the second-booster. Mortality due to Covid-19 among participants who received the second-booster was compared with participants who received one booster dose. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association between the second-booster and death due to Covid-19 while adjusting for demographic factors and coexisting illnesses. A total of 563,465 participants met the eligibility criteria. Of those, 328,597 (58%) received a second-booster dose during the 40-day study period. Death due to Covid-19 occurred in 92 second-booster recipients and in 232 participants who received one booster dose (adjusted hazard ratio 0.22; 95% confidence interval 0.17 to 0.28). This study demonstrates a substantial reduction in Covid-19 mortality by the second-booster in eligible subjects.
March 23, 2022
Establishing correlates of protection (COP) for vaccine preventable infections is an important public health priority. COP are specific, measurable components of a pathogen-specific immune response that are statistically proven to surpass a quantitative threshold required for protection, and they may be identified after natural infection or vaccination. COP are typically validated with symptomatic illness as an endpoint, but they can also be applied to other outcomes, such as asymptomatic infection, severe disease or transmissibility. Validated COP are used as surrogate endpoints in vaccine trials; such surrogate endpoints are useful because they allow rapid ascertainment of vaccine efficacy without having to rely on clinical infection endpoints, which occur in only a fraction of participants.
We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations.
All treated individuals displayed elevated antibody levels in their sera, which efficiently neutralized the Delta variant. Sera from Ronapreve recipients did not neutralize BA.1 and weakly inhibited BA.2. Neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 Evusheld recipients, respectively. As compared to the Delta variant, neutralizing titers were more markedly decreased against BA.1 (344-fold) than BA.2 (9-fold). We further report 4 breakthrough Omicron infections among the 29 individuals, indicating that antibody treatment did not fully prevent infection. Collectively, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron neutralizing activity of Ronapreve, and to a lesser extent that of Evusheld, is reduced in patients’ sera.
The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome. These are evident more than a month after infection, and are labeled as Post-Acute Sequelae of CoV-2 (PASC) or commonly referred to as long-COVID. Metabolic dysfunction (i.e., obesity, insulin resistance, and diabetes mellitus) is a predisposing risk factor for severe acute COVID-19, and there is emerging evidence that this factor plus a chronic inflammatory state may predispose to PASC. In this article, we explore the potential pathogenic metabolic mechanisms that could underly both severe acute COVID-19 and PASC, and then consider how these might be targeted for future therapeutic approaches.
March 22, 2022
The Swedish response to this pandemic was unique and characterised by a morally, ethically, and scientifically questionable laissez-faire approach, a consequence of structural problems in the society. There was more emphasis on the protection of the “Swedish image” than on saving and protecting lives or on an evidence-based approach. A strategy was never discussed among all relevant parties, and never implemented nor communicated to the public. In addition, there was an unwillingness and incapacity to admit any failures at all governmental levels; or to take any responsibility for the clearly detrimental outcomes for Swedish society. There were even attempts to revise history by changing, or deleting official documents, communication, and websites, and gaslighting the public. The Swedish authorities involved were not self-critical and did not engage in any official and open dialogue and misled the public by withholding correct information and even spreading misleading information. A small group of so-called experts with a narrow disciplinary focus received a disproportionate and unquestioned amount of power in the discussion, nationally and internationally. There was no intellectual/scientific discussion between stakeholders (including independent experts from different disciplines), and the international advice of WHO, ECDC and the scientific community was ignored and/or discredited.
In this bayesian randomized clinical trial that included 1557 patients, antiplatelet therapy with either aspirin or a P2Y12 inhibitor, compared with no antiplatelet therapy, resulted in a 95.7% posterior probability of futility with regard to the odds of improvement in organ support–free days within 21 days.
March 21, 2022
In the post-acute phase, we report increased risks and 12-month burdens of incident diabetes and antihyperglycaemic use in people with COVID-19 compared with a contemporary control group of people who were enrolled during the same period and had not contracted SARS-CoV-2, and a historical control group from a pre-pandemic era. Post-acute COVID-19 care should involve identification and management of diabetes.
The intrinsic severity of Omicron BA.2 is not mild as evident by the fatality and severe complications of the uninfected and unvaccinated children.
March 18, 2022
Receiving 2 or 3 doses of an mRNA COVID-19 vaccine was associated with a 90% reduction in risk for COVID-19–associated IMV or death. Protection of 3 mRNA vaccine doses during the period of Omicron predominance was 94%.
In January 2022, unvaccinated adults and those vaccinated with a primary series, but no booster or additional dose, were 12 and three times as likely to be hospitalized, respectively, as were adults who received booster or additional doses. Hospitalization rates among non-Hispanic Black adults increased more than rates in other racial/ethnic groups.
The Advisory Committee on Immunization Practices’ Recommendation for Use of Moderna COVID-19 Vaccine in Adults Aged ≥18 Years and Considerations for Extended Intervals for Administration of Primary Series Doses of mRNA COVID-19 Vaccines — United States, February 2022
On February 4, 2022, after a systematic review of the evidence, the Advisory Committee on Immunization Practices issued a standard recommendation for use of the Moderna COVID-19 vaccine in persons aged ≥18 years. CDC provided guidance that an 8-week interval between primary series doses of mRNA vaccines might be optimal for some persons.
March 17, 2022
Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.
We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. While additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4+ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.
March 16, 2022
Overall, these data show that neutralizing antibody titers against BA.2 were similar to those against BA.1, with median titers against BA.2 that were lower than those against BA.1 by a factor of 1.3 to 1.4. A third dose of the BNT162b2 vaccine was needed for induction of consistent neutralizing antibody titers against either BA.1 or BA.2. Moreover, in vaccinated persons who had presumably been infected with BA.1, robust neutralizing antibody titers against BA.2 developed, which suggests a substantial degree of cross-reactive natural immunity. These findings have important public health implications and suggest that the increasing frequency of BA.2 in the context of the BA.1 surge is probably related to increased transmissibility rather than to enhanced immunologic escape.
Our data provide evidence that a fourth dose of mRNA vaccine is immunogenic, safe, and somewhat efficacious (primarily against symptomatic disease). A comparison of the initial response to the fourth dose with the peak response to a third dose did not show substantial differences in humoral response or in levels of omicron-specific neutralizing antibodies. Along with previous data showing the superiority of a third dose to a second dose, our results suggest that maximal immunogenicity of mRNA vaccines is achieved after three doses and that antibody levels can be restored by a fourth dose. Furthermore, we observed low vaccine efficacy against infections in health care workers, as well as relatively high viral loads suggesting that those who were infected were infectious. Thus, a fourth vaccination of healthy young health care workers may have only marginal benefits. Older and vulnerable populations were not assessed.
March 15, 2022
During Omicron variant predominance beginning in late December 2021, U.S. infants and children aged 0–4 years were hospitalized at approximately five times the rate of the previous peak during Delta variant predominance. Infants aged <6 months had the highest rates of hospitalization, but indicators of severity (e.g., respiratory support) did not differ by age group.
March 14, 2022
Viruses evolve to maximize their transmissibility and sometimes this may correlate with higher virulence, for example, if high viral loads promote transmission but also increase severity. If so, pathogens may evolve towards higher virulence. If severity manifests late in infection, only after the typical transmission window, as in SARS-CoV-2, but also influenza virus, HIV, hepatitis C virus and many others, it plays a limited role in viral fitness and may not be selected against. Forecasting virulence evolution is a complex task, and the lower severity of Omicron is hardly a good predictor for future variants. The prospect of future VOCs featuring the potentially disastrous combination of the ability to reinfect due to immune escape along with high virulence is unfortunately very real.
Severe acute COVID-19 illness—indicated by extended time bedridden—is associated with long-term mental morbidity among recovering individuals in the general population. These findings call for increased vigilance of adverse mental health development among patients with a severe acute disease phase of COVID-19.
In summary, in hospitalized patients with COVID the antibody response to infection indicates induction of virus-specific ASCs both through extrafollicular and germinal center responses that predict a more durable immune response in patients recovering from severe disease.
March 11, 2022
Effectiveness of 2-Dose BNT162b2 (Pfizer BioNTech) mRNA Vaccine in Preventing SARS-CoV-2 Infection Among Children Aged 5–11 Years and Adolescents Aged 12–15 Years — PROTECT Cohort, July 2021–February 2022
Children and adolescents aged 5–15 years were tested for SARS-CoV-2 weekly, irrespective of symptoms, during July 2021–February 2022. Approximately one half of Omicron infections in unvaccinated children and adolescents were asymptomatic. Two doses of Pfizer-BioNTech COVID-19 vaccine reduced the risk of Omicron infection by 31% among children aged 5–11 years and by 59% among persons aged 12–15 years.
March 10, 2022
Scientists have identified a host of genetic variants that are linked to an increased risk of developing severe COVID-191. These variants affect processes ranging from immune-system signalling to blood clotting, and understanding them could help researchers to target new therapies for people who are critically ill.
March 9, 2022
The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively). Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.
The messenger RNA (mRNA) boosters were highly effective against symptomatic delta infection, but they were less effective against symptomatic omicron infection. However, with both variants, mRNA boosters led to strong protection against Covid-19–related hospitalization and death.
These data show the persistence of viable SARS-CoV-2 in patients after sotrovimab infusions and the rapid development of spike gene mutations associated with high-level sotrovimab resistance in vitro. These findings underscore the importance of stewardship of monoclonal antibodies, particularly because sotrovimab is one of the few monoclonal antibodies with retained activity against the B.1.1.529 (omicron) variant. Postmarketing genomic surveillance of patients who receive monoclonal antibodies for the treatment of SARS-CoV-2 infection is prudent in order to minimize the risk of both treatment failure and the transmission of potentially resistant SARS-CoV-2 variants in health care settings and the community, given that SARS-CoV-2 may be isolated up to 24 days after sotrovimab treatment.
1,112,899 students and 157,069 staff attended 61 K–12 districts across 9 states that met inclusion criteria. The districts reported 40,601 primary and 3,085 secondary infections. Six districts had optional masking policies, 9 had partial masking policies, and 46 had universal masking. Districts that optionally masked throughout the study period had 3.6 times the rate of secondary transmission as universally masked districts. For every 100 community-acquired cases, universally masked districts had 7.3 predicted secondary infections, while optionally masked districts had 26.4.
Despite the success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there remains a need for more prevention and treatment options for individuals remaining at risk of coronavirus disease 2019 (COVID-19). Monoclonal antibodies (mAbs) against the viral spike protein have potential to both prevent and treat COVID-19 and reduce the risk of severe disease and death. Here, we describe AZD7442, a combination of two mAbs, AZD8895 (tixagevimab) and AZD1061 (cilgavimab), that simultaneously bind to distinct, nonoverlapping epitopes on the spike protein receptor binding domain to neutralize SARS-CoV-2. Initially isolated from individuals with prior SARS-CoV-2 infection, the two mAbs were designed to extend their half-lives and reduce effector functions. The AZD7442 mAbs individually prevent the spike protein from binding to angiotensin-converting enzyme 2 receptor, blocking virus cell entry, and neutralize all tested SARS-CoV-2 variants of concern. In a nonhuman primate model of SARS-CoV-2 infection, prophylactic AZD7442 administration prevented infection, whereas therapeutic administration accelerated virus clearance from the lung. In an ongoing phase 1 study in healthy participants (NCT04507256), a 300-mg intramuscular injection of AZD7442 provided SARS-CoV-2 serum geometric mean neutralizing titers greater than 10-fold above those of convalescent serum for at least 3 months, which remained threefold above those of convalescent serum at 9 months after AZD7442 administration. About 1 to 2% of serum AZD7442 was detected in nasal mucosa, a site of SARS-CoV-2 infection. Extrapolation of the time course of serum AZD7442 concentration suggests AZD7442 may provide up to 12 months of protection and benefit individuals at high-risk of COVID-19.
March 8, 2022
In Arkansas during August–October 2021, districts with universal mask requirements had a 23% lower incidence of COVID-19 among staff members and students compared with districts without mask requirements. Masks remain an important part of a multicomponent approach to prevent COVID-19 in K–12 settings, especially in communities with high levels of COVID-19.
March 7, 2022
We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.
Safety data from more than 298 million doses of mRNA COVID-19 vaccine administered in the first 6 months of the US vaccination programme show that most reported adverse events were mild and short in duration.
Secondary attack rate of SARS-CoV-2 in Norwegian households was moderately higher when the index case had the Omicron variant rather than the Delta variant.
March 4, 2022
This cross-sectional study found an association between different SDOH measures and COVID-19 mortality that varied across racial and ethnic groups and community types. Future research is needed that explores the different dimensions and regional patterns of SDOH to address health inequity and guide policies and programs.
COVID-19 vaccination coverage with the first dose of the primary vaccination series was lower in rural (58.5%) than in urban counties (75.4%); disparities have increased more than twofold since April 2021. Receipt of booster or additional doses was similarly low in both rural and urban counties.
March 3, 2022
In this cohort study, COVID-19–dedicated hospitals had multiple benefits, including providing high-volume repetitive treatment and isolating patients with the infection. This experience suggests improved in-hospital mortality for patients treated at dedicated hospitals owing to improved processes of care and supports the use of establishing cohorts for future pandemics.
In this retrospective case-control study of US adolescents, 2 doses of BNT162b2 vaccine appeared to provide excellent protection for at least 4 months after immunization against both symptomatic and asymptomatic SARS-CoV-2 infections.
March 2, 2022
SARS-CoV-2 VOCs appear to be associated with increased relative virulence of infection in all age groups, though low absolute numbers of outcomes in younger individuals make estimates in these groups imprecise.
Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time.
This study found that the Ad26.COV2.S vaccine is less effective against COVID-19–related hospitalization than the BNT162b2 vaccine. These results strengthen the evidence supporting a second dose in people who received the Ad26.COV2.S vaccine by an mRNA vaccine as recommended in both France and the US.
The absolute survival rate we observed for US patients with IHCA and COVID-19 (11.9%) was higher than the survival rates reported initially (0%,1 2.9%,2 and 3.0%3), which likely represented the isolated experience of health systems overwhelmed early during the pandemic. Our findings are consistent with those of Hayek et al5 (12.0% survival in 400 patients with COVID-19 in 68 ICUs) and Mitchell et al6 (11.9% survival in 260 patients with COVID-19 at 11 hospitals) and extend the previous findings by adding a comparison group of patients without COVID and including non-ICU patients from a larger group of hospitals. We believe that these data will be relevant to health care providers and hospital administrators as the COVID-19 pandemic continues. Because IHCA survival among patients with COVID-19 in this study was not as poor as reported previously, we believe that COVID-19 infection alone should not be used as a criterion for withholding resuscitation care from hospitalized patients.
Drug overdose mortality is increasingly becoming a racial justice issue in the US. Our results suggest that drug overdose mortality has been exacerbated during the COVID-19 pandemic. Providing individuals with a safer supply of drugs, closing gaps in health care access (eg, harm reduction services and medications for opioid use disorder), ending routine incarceration of individuals with substance use disorders, and addressing the social conditions of people who use drugs represent urgently needed, evidence-based strategies that can be used to reduce increasing inequalities in overdose rates.
An analysis of data from nearly 154 000 US veterans with SARS-CoV-2 infection provides a grim preliminary answer to the question: What are COVID-19’s long-term cardiovascular outcomes? The study, published in Nature Medicine by researchers at the Veterans Affairs (VA) St Louis Health Care System, found that in the year after recovering from the illness’s acute phase, patients had increased risks of an array of cardiovascular problems, including abnormal heart rhythms, heart muscle inflammation, blood clots, strokes, myocardial infarction, and heart failure. What’s more, the heightened risks were evident even among those who weren’t hospitalized with acute COVID-19.
March 1, 2022
Among persons aged 12–17 years, reactions after Pfizer-BioNTech booster vaccination were generally mild to moderate and transient; the frequency of local and systemic reactions reported to v-safe after a booster dose were equal to or slightly higher than after the second primary dose. Myocarditis was less frequently reported after a booster dose than a second primary dose.
Effectiveness of COVID-19 Pfizer-BioNTech BNT162b2 mRNA Vaccination in Preventing COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Nonimmunocompromised Children and Adolescents Aged 5–17 Years — VISION Network, 10 States, April 2021–January 2022
Two doses protect against COVID-19–associated emergency department and urgent care encounters among children and adolescents. However, vaccine effectiveness (VE) was lower during Omicron predominance and decreased with time since vaccination; a booster dose restored VE to 81% among adolescents aged 16–17 years. Overall, 2-dose VE against COVID-19–associated hospitalization was 73%–94%.
Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism.
Cumulatively, we confirmed 1,508 individuals diagnostically, 62% of these through the surveillance program and the remainder through diagnostic tests of symptomatic individuals administered on or off campus. The total strategy, including intensification of testing given case clusters early in the semester, was associated with reduced transmission following rapid case increases upon entry in Fall semester in August 2020, again in early November 2020, and upon re-entry for Spring semester in January 2021. During the Fall semester daily asymptomatic test positivity initially peaked at 4.1% but fell below 0.5% by mid-semester, averaging 0.84% across the Fall semester, with similar levels of control in Spring 2021.
February 28, 2022
At the population-level, where the majority of test-positives (96.0%) were not hospitalized during acute infection, a considerable proportion experience post-acute symptoms and sequelae 6-12 months after infection. Six to twelve months after the test date, the risks of 18 out of 21 physical symptoms were elevated among test-positives and one third (29.6%) of the test-positives experienced at least one physical post-acute symptom.
In this bayesian reanalysis of a previous meta-analysis of 15 randomized clinical trials comprising 5339 hospitalized patients with COVID-19 treated with tocilizumab and corticosteroids, those receiving simple oxygen only or noninvasive ventilation were associated with a clinically meaningful mortality benefit. In contrast, for those receiving invasive mechanical ventilation, an association with benefit was uncertain.
Pediatric medicine has long promoted the benefits of vaccination. An approach to caregivers who visit a pediatric hospital and are unvaccinated against COVID-19 must respect that hospital’s mission to promote COVID-19 vaccination as an important means to safeguard children’s health. Such an approach may include strategies to engage with vaccine-hesitant caregivers and facilitate vaccination. Unvaccinated caregivers can be accommodated in a manner that ensures the safety of other inpatient children, caregivers, and health care workers (eg, via symptom screening, masking, and avoidance of common spaces) and that ensures that no child’s care is compromised by the absence of a caregiver at such a vulnerable time. In facilities that provide adult and pediatric care, unvaccinated caregivers of children and adults should be treated differently. Exclusion of a child’s caregiver on the basis of vaccination status is not ethically permissible except under grave circumstances because such an exclusion would violate a child’s right to health care, for which their caregiver is indispensable under most circumstances. Similarly, measures that ignore caregiver vaccination status and fail to promote vaccination fall short of the mission of pediatric institutions to promote vaccination to safeguard children’s health within and beyond the hospital. Thus, in the balance of accountabilities, care of the sick child requires continued inclusion of caregivers, whereas accountability for broader public health requires continued attention to and encouragement of wide-scale COVID-19 vaccination.
Less than about half of states requiring COVID-19 vaccination or routine testing of schoolteachers included childcare professionals, suggesting an unwarranted disparity between childcare and school settings in states’ efforts to promote vaccination. Several arguments favor vaccinating childcare professionals. First, both staff and children in childcare programs may be at higher risk for contracting COVID-19 than those in schools, because very young children are currently ineligible for vaccination and possibly less adherent to nonpharmaceutical interventions (eg, masking, social distancing). Second, childcare professionals have lower COVID-19 vaccine uptake compared with schoolteachers (78% vs 90% as of late spring 20213). Third, childcare professionals are disproportionately more racial and ethnic minority individuals, and therefore may be at greater risk for COVID-19–related morbidity and mortality (17.3% and 19.3% are Black and Hispanic individuals vs 12.1% and 13.0% of school personnel, respectively4).
In the Omicron era, the effectiveness against cases of BNT162b2 declined rapidly for children, particularly those 5-11 years. However, vaccination of children 5-11 years was protective against severe disease and is recommended. These results highlight the potential need to study alternative vaccine dosing for children and the continued importance layered protections, including mask wearing, to prevent infection and transmission.
The 64Cu-CR3022-probe also demonstrated dynamic changes occurring between 1- and 2-weeks post-infection. Remarkably, a robust signal was seen in the male genital tract (MGT) of all three animals studied. Infection of the MGT was validated by immunofluorescence imaging of infected cells in the testicular and penile tissue and severe pathology was observed in the testes of one animal at 2-weeks post-infection. The results presented here underscore the utility of using immunoPET to study the dynamics of SARS-CoV-2 infection to understand its pathogenicity and discover new anatomical sites of viral replication. We provide direct evidence for SARS-CoV-2 infection of the MGT in rhesus macaques revealing the possible pathologic outcomes of viral replication at these sites.
February 26, 2022
SARS-CoV-2 genomic diversity early in the COVID-19 pandemic points to emergence via repeated zoonotic event.
GeographicalclusteringoftheearliestknownCOVID-19casesandtheproximityofpositiveenvironmentalsamplestolive-animalvendorssuggestthattheHuananSeafoodWholesaleMarketinWuhanwasthesiteof origin of the COVID-19 pandemic.
February 25, 2022
Between 5 and 9 days after symptom onset or after initial diagnosis with SARS-CoV-2 infection, 54% of persons had positive SARS-CoV-2 antigen test results. The proportion of positive results declined over time. Negative follow-up antigen test results were associated with asymptomatic infection, previous infection, and being vaccinated.
Among 173 vaccinated adults with COVID-19 undergoing serial reverse transcription–polymerase chain reaction (RT-PCR) testing during Omicron predominance, 46% received a negative or high cycle threshold RT-PCR test result on or before day 6 postdiagnosis. Although a positive RT-PCR test result does not necessarily indicate infectiousness, these data indicate that persons with COVID-19 should continue to take precautions, including correct and consistent mask use, for a full 10 days after symptom onset or after initial positive test result if they are asymptomatic.
In a study of household transmission in four U.S. jurisdictions, Omicron infection resulted in high transmission among household contacts, particularly among those who lived with index patients who were not vaccinated or who did not take measures to reduce the risk of transmission to household contacts.
Wildlife reservoirs of SARS-CoV-2 can lead to viral adaptation and spillback from wildlife to humans (Oude Munnink et al., 2021). In North America, there is evidence of spillover of SARS-CoV-2 from humans to white-tailed deer (Odocoileus virginianus), but no evidence of transmission from deer to humans (Hale et al., 2021; Kotwa et al., 2022; Kuchipudi et al., 2021). Through a multidisciplinary research collaboration for SARS-CoV-2 surveillance in Canadian wildlife, we identified a new and highly divergent lineage of SARS-CoV-2. This lineage has 76 consensus mutations including 37 previously associated with non-human animal hosts, 23 of which were not previously reported in deer. There were also mutational signatures of host adaptation under neutral selection. Phylogenetic analysis revealed an epidemiologically linked human case from the same geographic region and sampling period. Together, our findings represent the first evidence of a highly divergent lineage of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission.
Herein, we presented the SARS-CoV-2 detection results of 1380 samples collected from the environment and the animals within the market in early 2020. By SARS-CoV-2-specific RT-qPCR, 73 environmental samples tested positive for SARS-CoV-2 and three live viruses were successfully isolated. The viruses from the market shared nucleotide identity of 99.980% to 99.993% with the human isolate HCoV/Wuhan/IVDC-HB-01. In contrast, no virus was detected in the animal swabs covering 18 species of animals in the market. The SARS-COV-2 nucleic acids in the positive environmental samples showed significant correlation of abundance of Homo sapiens with SARS-CoV-2. In summary, this study provided convincing evidence of the prevalence of SARS-CoV-2 in the Huanan Seafood Market during the early stage of COVID-19 outbreak.
February 24, 2022
Global, regional, and national minimum estimates of children affected by COVID-19-associated orphanhood and caregiver death, by age and family circumstance up to Oct 31, 2021: an updated modelling study
Our findings show that numbers of children affected by COVID-19-associated orphanhood and caregiver death almost doubled in 6 months compared with the amount after the first 14 months of the pandemic. Over the entire 20-month period, 5·0 million COVID-19 deaths meant that 5·2 million children lost a parent or caregiver. Our data on children's ages and circumstances should support pandemic response planning for children globally.
February 23, 2022
Widespread underlying SARS-CoV-2 seropositivity was observed in Gauteng before the omicron-dominant wave of Covid-19. Epidemiologic data showed a decoupling of hospitalizations and deaths from infections while omicron was circulating.
The first peer-reviewed clinical trial evidence that a Covid-19 vaccine provided robust protection against SARS-CoV-2 infection was published in the Journal in December 2020, less than a year after the sequence of the viral genome was reported. This unprecedentedly rapid development of vaccines was a scientific triumph. In the year since, about 62% of the world’s population has received at least one dose of a Covid-19 vaccine, and 54% have completed the primary vaccine series. This would appear to be a landmark success in global health mobilization.
February 22, 2022
Using surveillance results from Dec 14, 2020, to Aug 31, 2021, we identified 21 individuals with MIS-C after COVID-19 vaccination. Of these 21 individuals, median age was 16 years (range 12–20); 13 (62%) were male and eight (38%) were female. All 21 were hospitalised: 12 (57%) were admitted to an intensive care unit and all were discharged home. 15 (71%) of 21 individuals had laboratory evidence of past or recent SARS-CoV-2 infection, and six (29%) did not. As of Aug 31, 2021, 21 335 331 individuals aged 12–20 years had received one or more doses of a COVID-19 vaccine, making the overall reporting rate for MIS-C after vaccination 1·0 case per million individuals receiving one or more doses in this age group. The reporting rate in only those without evidence of SARS-CoV-2 infection was 0·3 cases per million vaccinated individuals.
February 21, 2022
This study suggests that there is a low risk of a severe immediate allergic reaction associated with a second SARS-CoV-2 mRNA vaccine dose among persons who had an immediate allergic reaction to their first dose.
COVID-19 vaccine efficacy or effectiveness against severe disease remained high, although it did decrease somewhat by 6 months after full vaccination. By contrast, vaccine efficacy or effectiveness against infection and symptomatic disease decreased approximately 20–30 percentage points by 6 months. The decrease in vaccine efficacy or effectiveness is likely caused by, at least in part, waning immunity, although an effect of bias cannot be ruled out. Evaluating vaccine efficacy or effectiveness beyond 6 months will be crucial for updating COVID-19 vaccine policy.
Forty-five long COVID patients, mean age 45 (6-71), 73.3% female, with prolonged symptoms evolving for a mean of 15.2 months (5-22) were tested. Dogs discriminated in a positive way 23/45 (51.1%) long COVID patients versus 0/188 (0%) control healthy individuals (p<.0001). Our data provide arguments for the persistence of viral antigens at least in some long COVID patients and raise the possibility of future therapeutic options.
February 18, 2022
Weekly ED visits among adolescent females (aged 12–17 years) increased for two MHCs (eating and tic disorders) during 2020, four (depression, eating, tic, and obsessive-compulsive disorders) during 2021, and five (anxiety; trauma and stressor-related; eating; tic; and obsessive-compulsive disorders) and overall MHC visits during January 2022, compared with 2019. The proportion of ED visits with eating disorders doubled among adolescent females; those for tic disorders approximately tripled during the pandemic.
Compared with 2019, overall pediatric emergency department visits decreased by 51%, 22%, and 23% during 2020, 2021, and January 2022, respectively. COVID-19 visits predominated across all pediatric ages; visits for other respiratory illnesses mostly declined. Number and proportion of visits increased for certain injuries (e.g., firearm injuries, self-harm, and drug poisonings), some chronic diseases, and behavioral health concerns, with variations by age group.
Attack rates among a cohort of persons attending a convention were high, but lower among infected attendees’ household members. There were fewer infections among vaccinated attendees who had received a COVID-19 vaccine booster dose.
Despite multiple introductions as evidenced by detection of at least three sublineages of SARS-CoV-2, this investigation did not find evidence of widespread transmission among a highly vaccinated population at a large event in an indoor setting where mask use was required and monitored.
On July 27, 2021, a fully vaccinated* crew member on a U.S. Navy ship who had been symptomatic with cough and congestion for 4 days was evaluated in the ship’s onboard medical department and received a positive test result† for SARS-CoV-2, the virus that causes COVID-19. The ship had approximately 350 personnel on board§; COVID-19 vaccination rate was >98%.
SARS-CoV-2 omicron (B.1.1.529) was designated a variant of concern by WHO because of specific mutations that might increase transmissibility, risk of reinfection, or vaccine breakthrough infection. Many of these mutations affect the receptor-binding domain and N-terminal domain of the spike protein, which might, paradoxically, increase binding to ACE-2 while evading antibody recognition.
In this open-label randomized clinical trial of high-risk patients with COVID-19 in Malaysia, a 5-day course of oral ivermectin administered during the first week of illness did not reduce the risk of developing severe disease compared with standard of care alone. The study findings do not support the use of ivermectin for patients with COVID-19.
Public opinion about the COVID-19 pandemic in the US is deeply divided by political affiliation, including beliefs about the value of ineffective COVID-19 treatments such as hydroxychloroquine sulfate, an antimalarial drug, and ivermectin, an antiparasitic drug. There is increased prescribing of these treatments despite evidence against their effectiveness. We hypothesized that the county-level volume of prescriptions for hydroxychloroquine and ivermectin—but not other, similar medications—would be associated with county-level political voting patterns in the 2020 US presidential election.
Although several studies have shown that the omicron wave is associated with a lower hospitalisation rate per infection than previous COVID-19 waves, primarily because of milder illness, the number of paediatric patients with omicron in many countries is surpassing the number of paediatric COVID-19 cases seen in those previous waves. The current study, consistent with previous research, shows the possibility that a large increase in the number of COVID-19 cases, even if milder on average, can increase the absolute number of paediatric patients with severe outcomes. These conditions can overwhelm an already strained health-care system, and be further exacerbated during seasonal increases of expected respiratory illness among children.
Between Oct 31 and Dec 11, 2021, 6287 children and adolescents in Tshwane District were recorded as having COVID-19. During this period, 2550 people with COVID-19 were hospitalised, of whom 462 (18%) were aged 19 years or younger. The number of paediatric cases was higher than in the three previous SARS-CoV-2 waves, uncharacteristically increasing ahead of adult hospitalisations. 75 viral samples from adults and children in the district were sequenced, of which 74 (99%) were of the omicron variant. Detailed clinical notes were available for 138 (75%) of 183 children aged ≤13 years with COVID-19 who were hospitalised. 87 (63%) of 138 children were aged 0–4 years. In 61 (44%) of 138 cases COVID-19 was the primary diagnosis, among whom symptoms included fever (37 [61%] of 61), cough (35 [57%]), shortness of breath (19 [31%]), seizures (19 [31%]), vomiting (16 [26%]), and diarrhoea (15 [25%]). Median length of hospital stay was 2 days [IQR 1–3]). 122 (88%) of 138 children with available data needed standard ward care and 27 (20%) needed oxygen therapy. Seven (5%) of 138 children were ventilated and four (3%) died during the study period, all related to complex underlying copathologies. All children and 77 (92%) of 84 parents or guardians with available data were unvaccinated to COVID-19.
February 17, 2022
Altogether, the findings suggest that people with covid-19 are experiencing increased rates of mental health outcomes, which could have far-reaching consequences. The increased risk of opioid use is of particular concern, especially considering the high rates of opioid use disorders pre-pandemic. The increased risks of mental health outcomes in people with covid-19 demands greater attention now to mitigate much more serious downstream consequences in the future.
Active genomic surveillance and transparent communication by South African scientists and public health practitioners recently heralded a new, rapidly circulating SARS-CoV-2 variant, now called omicron. Scientists and the public have been closely monitoring the clinical effects of the omicron-variant wave that has rapidly swept through the population in order to estimate the variant’s relative transmissibility, capability for immune evasion, and severity as compared with previous variants.
Serum and plasma from patients with COVID-19 increased surface expression of cell adhesion molecules. Furthermore, levels of soluble ICAM-1 and E-selectin were elevated in patient serum and tracked with disease severity. The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium. Depletion of total IgG from antiphospholipid antibody-positive serum markedly restrained upregulation of cell adhesion molecules. Conversely, supplementation of control serum with patient IgG was sufficient to trigger endothelial activation.
February 16, 2022
The animal reservoir of SARS-CoV-2 is unknown despite reports of various SARS-CoV-2-related viruses in Asian Rhinolophus bats1–4, including the closest virus from R. affinis, RaTG135,6 and in pangolins7–9. SARS-CoV-2 presents a mosaic genome, to which different progenitors contribute. The spike sequence determines the binding affinity and accessibility of its receptor-binding domain (RBD) to the cellular angiotensin-converting enzyme 2 (ACE2) receptor and is responsible for host range10–12. SARS-CoV-2 progenitor bat viruses genetically close to SARS-CoV-2 and able to enter human cells through a human ACE2 pathway have not yet been identified, though they would be key in understanding the origin of the epidemics. Here we show that such viruses indeed circulate in cave bats living in the limestone karstic terrain in North Laos, within the Indochinese peninsula. We found that the RBDs of these viruses differ from that of SARS-CoV-2 by only one or two residues at the interface with ACE2, bind more efficiently to the hACE2 protein than the SARS-CoV-2 Wuhan strain isolated in early human cases, and mediate hACE2-dependent entry and replication in human cells, which is inhibited by antibodies neutralizing SARS-CoV-2. None of these bat viruses harbors a furin cleavage site in the spike. Our findings therefore indicate that bat-borne SARS-CoV-2-like viruses potentially infectious for humans circulate in Rhinolophus spp. in the Indochinese peninsula.
The findings suggest that people who survive the acute phase of covid-19 are at increased risk of an array of incident mental health disorders. Tackling mental health disorders among survivors of covid-19 should be a priority.
Two doses of BNT162b2 vaccine were associated with high short-term protection against SARS-CoV-2 infection; this protection waned considerably after 6 months. Infection-acquired immunity boosted with vaccination remained high more than 1 year after infection.
A total of 149,032 patients who had recovered from SARS-CoV-2 infection met the eligibility criteria. Of these patients, 83,356 (56%) received subsequent vaccination during the 270-day study period. Reinfection occurred in 354 of the vaccinated patients (2.46 cases per 100,000 persons per day) and in 2168 of 65,676 unvaccinated patients (10.21 cases per 100,000 persons per day). Vaccine effectiveness was estimated at 82% (95% confidence interval [CI], 80 to 84) among patients who were 16 to 64 years of age and 60% (95% CI, 36 to 76) among those 65 years of age or older. No significant difference in vaccine effectiveness was found for one dose as compared with two doses.
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns.
February 15, 2022
Soon after the emergence and global spread of a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) Omicron lineage, BA.1, another Omicron lineage, BA.2, has initiated outcompeting BA.1. Statistical analysis shows that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralisation experiments show that the vaccine-induced humoral immunity fails to function against BA.2 like BA.1, and notably, the antigenicity of BA.2 is different from BA.1. Cell culture experiments show that BA.2 is more replicative in human nasal epithelial cells and more fusogenic than BA.1. Furthermore, infection experiments using hamsters show that BA.2 is more pathogenic than BA.1. Our multiscale investigations suggest that the risk of BA.2 for global health is potentially higher than that of BA.1.
Effectiveness of maternal completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy against COVID-19 hospitalization among infants aged <6 months was 61% (95% CI = 31% to 78%). Effectiveness of completion of the primary COVID-19 vaccine series early and later in pregnancy was 32% (95% CI = –43% to 68%) and 80% (95% CI = 55% to 91%), respectively.
Coinciding with increased circulation of the Omicron variant, COVID-19–associated hospitalization rates among children and adolescents aged 0–17 years increased rapidly in late December 2021, especially among children aged 0–4 years who are not yet eligible for vaccination. Throughout the periods of Delta and Omicron predominance, hospitalization rates remained lower among fully vaccinated adolescents aged 12–17 years than among unvaccinated adolescents.
The fourth COVID-19 mRNA dose restores antibody titers to peak post-third dose titers. Low efficacy in preventing mild or asymptomatic Omicron infections and the infectious potential of breakthrough cases raise the urgency of next generation vaccine development.
February 14, 2022
Between February and August, 2021, 227 households consisting of 559 participants were recruited to the UKHSA study. The alpha variant was detected or assumed to be responsible for infections in 131 households (243 infections in 334 participants) recruited in February–May, and the delta variant in 96 households (174 infections in 225 participants) in May–August. The mean intrinsic generation time was shorter for the delta variant (4·7 days, 95% credible interval [CI] 4·1–5·6) than the alpha variant (5·5 days, 4·7–6·5), with 92% posterior probability. The mean household generation time was 28% (95% CI 0–48%) shorter for the delta variant (3·2 days, 95% CI 2·5–4·2) than the alpha variant (4·5 days, 3·7–5·4), with 97·5% posterior probability.
February 13, 2022
Extrapolated to the US population we estimated approximately 135,000 excess deaths during the study period in persons >= 18 years old. Our estimates are an underestimate of all excess deaths that have occurred since vaccine became available because our analysis period was limited to May 30 to December 4, 2021 and many excess deaths occurred before and after this period. In summary, we used retrospective data to provide an estimate of the substantial number of COVID-19 deaths among the unvaccinated illustrating the importance of vaccination to prevent further unnecessary mortality during this pandemic.
Among 39 766 employees, 8037 (20%) previously infected and the remaining previously vaccinated, COVID-19 occurred in 6230 (16%) during the study. Risk of COVID-19 increased with time since POIC. In multivariable analysis, boosting was independently associated with lower risk of COVID-19 among those with vaccine-induced immunity (HR, .43; 95% CI, .41-.46) as well as those with natural immunity (HR, .66; 95% CI, .58-.76). Among those with natural immunity, receiving 2 compared to 1 dose of vaccine was associated with higher risk of COVID-19 (HR, 1.54; 95% CI, 1.21-1.97).
February 12, 2022
The novel severe acute respiratory syndrome coronavirus 2 caused the coronavirus 2019 (COVID-19) pandemic that resulted in more than 150 million infections and 3.5 million deaths globally. COVID-19 affected men more than women, emerging with more severe disease and higher mortality rates. Androgens may be responsible for the underlying reason of more severe disease, as androgen receptors have been implicated to mediate viral cell entry and infection. Besides, male reproductive organs have been reported to be affected by the especially severe disease, resulting in erectile dysfunction (ED). In this narrative review, we aimed to gather possible mechanisms of the development of ED led by COVID-19. Current evidence illuminates endothelial dysfunction, direct testicular damage, and the psychological burden of COVID-19 that are of the pathways of ED. Although the proposed underlying mechanisms partly fail to answer the questions by which COVID-19 leads to ED, it is important to monitor men who recovered from COVID-19 regarding the sexual dysfunction sequelae of infection and address the long‐term consequences.
Hans Kluge, WHO's Regional Director for Europe, has been reported as saying that European nations could soon be entering a “long period of tranquillity” as the pandemic abates. Pointing out that mortality from COVID-19 seemed to be plateauing, he suggested the continent was approaching a “plausible endgame” and an “enduring peace”. As WHO's chief spokesperson for the 53 countries that make up his regional responsibility, Kluge was no doubt seeking to strike an optimistic and encouraging note. But it is disappointing that he took such a narrow geographical perspective about a global pandemic. His words promote a false reassurance that could breed complacency, even conceit.
February 11, 2022
Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022
Vaccine effectiveness (VE) against COVID-19–associated emergency department/urgent care (ED/UC) visits and hospitalizations was higher after the third dose than after the second dose but waned with time since vaccination. During the Omicron-predominant period, VE against COVID-19–associated ED/UC visits and hospitalizations was 87% and 91%, respectively, during the 2 months after a third dose and decreased to 66% and 78% by the fourth month after a third dose. Protection against hospitalizations exceeded that against ED/UC visits.
Review of surveillance data found that local and systemic reactions were less frequent after a homologous COVID-19 mRNA vaccine booster dose than after the second primary vaccine dose. Myocarditis was rarely reported following an mRNA vaccine booster dose.
The dynamic landscape of SARS-CoV-2 variants in 2021, including Delta- and Omicron-driven resurgences of SARS-CoV-2 transmission across the United States, underscores the importance of robust genomic surveillance efforts to inform public health planning and practice.
February 10, 2022
Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.
Vaccines must be the primary mode of protection against SARS-CoV-2; however, orally bioavailable medications will become an essential tool for physicians in the management of this horrible disease. Of note, although the data have not been peer-reviewed, Pfizer has announced the efficacy of its orally bioavailable protease inhibitor, Paxlovid, and Gilead has reported a benefit of ambulatory therapy with remdesivir. Data for both medications demand peer review. The availability of medications with different mechanisms of action offers the opportunity for creating combination therapies that are potentially synergistic and less likely to lead to resistance.
NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains.
Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms.
Even a mild case of COVID-19 can increase a person’s risk of cardiovascular problems for at least a year after diagnosis, a new study shows. Researchers found that rates of many conditions, such as heart failure and stroke, were substantially higher in people who had recovered from COVID-19 than in similar people who hadn’t had the disease.
February 9, 2022
We used an innovative multiple instance learning-based ML approach and droplet segmentation to analyze droplets. Amongst all confounding factors, we discriminated between COVID-positive and COVID-negative individuals yielding receiver operating coefficient curves with an area under curve (AUC) of 0.8 in both males (79% sensitivity and 75% specificity) and females (84% sensitivity and 64% specificity). Taking the sex of the saliva donor into account increased the AUC by 5%.
In this randomized clinical trial that included 73 adults with mild to moderate COVID-19, the proportion of participants achieving oropharyngeal clearance of SARS-CoV-2 at 3 days postenrollment was not statistically significantly different between patients given placebo and those given niclosamide. Niclosamide was well-tolerated.
In this cross-sectional study using data for 555 372 student athlete and 3 482 845 nonathlete student SARS-CoV-2 tests reported from 12 National Collegiate Athletic Association Division I institutions, participation in collegiate athletics was not associated with increased test positivity in student athletes compared with nonathlete students.
Overall, in a national database study in Qatar, we found that the effectiveness of previous infection in preventing reinfection with the alpha, beta, and delta variants of SARS-CoV-2 was robust (at approximately 90%), findings that confirmed earlier estimates. Such protection against reinfection with the omicron variant was lower (approximately 60%) but still considerable. In addition, the protection of previous infection against hospitalization or death caused by reinfection appeared to be robust, regardless of variant.
A single dose of Ad26.COV2.S provided 52.9% protection against moderate to severe–critical Covid-19. Protection varied according to variant; higher protection was observed against severe Covid-19, medical intervention, and death than against other end points and lasted for 6 months or longer.
Overall, documented infections, including moderate and severe or critical disease, were uncommon among veterans who had received either homologous or heterologous boosters. Heterologous mRNA boosting may better protect against incident infection in persons who were initially vaccinated with an adenoviral-vector vaccine.
Researchers, policy makers and science communicators have become increasingly been interested in factors that affect public’s trust in science. Recently, one such potentially important driving factor has emerged, the COVID-19 pandemic. Have trust in science and other science-related beliefs changed in Germany from before to during the pandemic? To investigate this, we re-analyzed data from a set of representative surveys conducted in April, May, and November 2020, which were obtained as part of the German survey Science Barometer, and compared it to data from the last annual Science Barometer survey that took place before the pandemic, (in September 2019). Results indicate that German’s trust in science increased substantially after the pandemic began and slightly declined in the months thereafter, still being higher in November 2020 than in September 2019. Moreover, trust was closely related to expectations about how politics should handle the pandemic. We also find that increases of trust were most pronounced among the higher-educated. But as the pandemic unfolded, decreases of trust were more likely among supporters of the populist right-wing party AfD. We discuss the sustainability of these dynamics as well as implications for science communication.
February 8, 2022
The emerging SARS-CoV-2 variants of concern (VOC) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.
The coronavirus disease 2019 (COVID-19) pandemic sparked an explosion of interest in wastewater-based epidemiology (WBE; also known as wastewater monitoring or wastewater surveillance). Much has been said, in the scientific literature and popular press alike, about the public health value of tracking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in wastewater. Emergence and spread of the omicron variant has recently pushed WBE for COVID-19 management back into headlines. Unfortunately, coverage of the potential of WBE is rarely balanced by a practical discussion of limitations and tradeoffs, especially when it comes to issues beyond technical challenges encountered in the lab.
One of the best ways the world has to get a clear view of COVID-19 is going underused. It’s time to exploit the power of random sampling.
As SARS-CoV-2 transmission continues to evolve, understanding how location-specific variations in non-pharmaceutical interventions and behaviors contributed to disease transmission during the initial epidemic wave will be key for future control strategies. We offer a rigorous statistical analysis of the relative effectiveness of the timing of both official stay-at-home orders and population mobility reductions during the initial stage of the US epidemic. We use a Bayesian hierarchical regression to fit county-level mortality data from the first case on Jan 21 2020 through Apr 20 2020 and quantify associations between the timing of stay-at-home orders and population mobility with epidemic control. We find that among 882 counties with an early local epidemic, a 10-day delay in the enactment of stay-at-home orders would have been associated with 14,700 additional deaths by Apr 20 (95% credible interval, 9,100, 21,500), whereas shifting orders 10 days earlier would have been associated with nearly 15,700 fewer lives lost (95% credible interval, 11,350, 18,950). Analogous estimates are available for reductions in mobility—which typically occurred before stay-at-home orders—and are also stratified by county urbanicity, showing significant heterogeneity. Results underscore the importance of timely policy and behavioral action for early-stage epidemic control.
Long COVID is a term devised by patients to describe the lingering symptoms they experience well after an initial bout of COVID-19. The symptoms vary widely, but some of the most common are fatigue, shortness of breath, cognitive dysfunction (also called brain fog) and post-exertional malaise, in which even minor physical activity leads to lasting exhaustion. Between one-fifth and one-third of those with long COVID remain ill at least 12 weeks after a diagnosis of COVID-19, and a significant number continue to experience symptoms many months later. Many want the condition to be considered a disability.
Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram —an FDA-approved drug for alcohol use disorder— dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for COVID-19 patients. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in two rodent models of lung injury for which treatment options are limited.
Viral RNA may be edited by enzymes of the ADAR family that deaminate adenosine residues with ensuing A→G mutations. We found multiple A→G mutations in minor viral populations of the SARS-CoV-2 genome. A→G mutations accumulated in the receptor binding domain of the spike gene, which may cause structural changes by altering binding to the ACE2 receptor. Presence of A→G mutations in minor viral populations was associated with reduced viral load, implying that ADAR may limit viral replication. Analyses of >250,000 European samples from 2020 revealed that A→G mutations in SARS-CoV-2 RNA were inversely correlated with mortality as a reflection of incidence. ADAR may thus be important in providing new variants of SARS-CoV-2 with altered infectivity and transmissibility.
February 7, 2022
In this retrospective cohort study that included 14 104 patients, a composite outcome of maternal death or serious morbidity related to hypertensive disorders of pregnancy, postpartum hemorrhage, or infection other than SARS-CoV-2 occurred significantly more frequently in individuals with SARS-CoV-2 infection compared with individuals without SARS-CoV-2 infection (13.4% vs 9.2%, respectively).
This study found that the majority of infants born to COVID-vaccinated mothers had persistent anti-S antibodies at 6 months, compared with infants born to mothers with SARS-CoV-2 infection. Understanding the persistence of maternal antibody levels in infants is important because COVID-19 infections in this age group account for a disproportionate burden of pediatric SARS-CoV-2–associated morbidity6 and because COVID-19 vaccines are not currently planned for administration to infants younger than 6 months. Study limitations include the small number of infants, the longer mean time to follow-up in the infected group (due to pragmatic constraints related to timing of COVID-19 surges in Boston and the availability of participants for timely follow-up), and the reporting of antibody titers rather than clinical outcomes. Although the antibody titer known to be protective against COVID-19 in infants is unknown, these findings provide further incentive for pregnant individuals to pursue COVID-19 vaccination.
We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.
We developed the mCARMEN respiratory virus panel (RVP) to test for up to 21 viruses, including SARS-CoV-2, other coronaviruses and both influenza strains, and demonstrated its diagnostic-grade performance on 525 patient specimens in an academic setting and 166 specimens in a clinical setting. We further developed an mCARMEN panel to enable identification of 6 SARS-CoV-2 variant lineages, including Delta and Omicron, and evaluated it on 2,088 patient specimens, with near-perfect concordance to sequencing-based variant classification. Lastly, we implemented a combined Cas13 and Cas12 approach that enables quantitative measurement of SARS-CoV-2 and influenza A viral copies in samples. The mCARMEN platform enables high-throughput surveillance of multiple viruses and variants simultaneously, enabling rapid detection of SARS-CoV-2 variants.
Looking back, the initial spread of COVID-19 in early 2020 illustrates that clinicians, epidemiologists and behavioral scientists around the world greatly underestimated the scope and intensity of resistance to mitigation measures that would follow. Many in the medical community have remained wedded to the view that direct observation of the soaring volume of death and morbidity associated with coronavirus infections will convert most people into adherents of mitigation measures. Hence, most public health communications on mask-wearing, social distancing, and vaccination stubbornly focus on and attempt to leverage efficacy data, patient testimonies, and the clout of clinicians, politicians, athletes and social media influencers, to increase public uptake.
There were 4,248 (39.7%) COVID-19 patients with ACI, with most (93%) developed ACI on or within a day after admission. In-hospital mortality odds ratio of ACI patients was 4.45 [95%CI: 3.92, 5.05, p<0.001] compared to non-ACI patients. Of the 2,880 ACI survivors, 1,114 (38.7%) returned to our hospitals 2.5 months on average post-discharge, of which only 302 (44.9%) out of 673 patients recovered from ACI. There were no significant differences in demographics, race, ethnicity, major commodities, and length of hospital stay between groups. Prediction of ACI recovery post-discharge using the top predictors (troponin, creatinine, lymphocyte, sodium, lactate dehydrogenase, lymphocytes and hematocrit) at discharge yielded 63.73%-75.73% accuracy.
Adolescents who tested positive for SARS-CoV-2 had similar symptoms to those who tested negative, but had a higher prevalence of single and, particularly, multiple symptoms at the time of PCR testing and 3 months later. Clinicians should consider multiple symptoms that affect functioning and recognise different clusters of symptoms. The multiple and varied symptoms show that a multicomponent intervention will be required, and that mental and physical health symptoms occur concurrently, reflecting their close relationship.
February 5, 2022
A WHO report published on Feb 1, has found serious shortfalls in COVID-19 health-care waste practices, following an analysis of waste generated through a UN initiative to supply countries with personal protective equipment (PPE) and diagnostic kits for their COVID-19 pandemic response. “Evidence on the amount of health care waste generated, the lack of resourcing to safely manage waste, and the incomplete attention to environmental and climate impacts demonstrates that a more holistic approach is needed” the report concluded.
February 4, 2022
Consistent use of a face mask or respirator in indoor public settings was associated with lower odds of a positive SARS-CoV-2 test result (adjusted odds ratio = 0.44). Use of respirators with higher filtration capacity was associated with the most protection, compared with no mask use.
SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and protection.Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing antibody titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron.Significant and equivalent control of virus replication in lower airways was observed following either boost. Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.
In this cohort study of 338 024 persons younger than 20 years and 1 790 886 persons 20 years or older who were tested for SARS-CoV-2, new diagnoses of shortness of breath, nonspecific heart rate abnormalities, and type 2 diabetes were more common among those hospitalized after positive compared with negative test results; fatigue was more common among those aged 20 years or older.
Clinical Characteristics and Outcomes Among Adults Hospitalized with Laboratory-Confirmed SARS-CoV-2 Infection During Periods of B.1.617.2 (Delta) and B.1.1.529 (Omicron) Variant Predominance — One Hospital, California, July 15–September 23, 2021, and December 21, 2021–January 27, 2022
Among adults hospitalized with SARS-CoV-2 infection during Omicron predominance, COVID-19 vaccination, including with a booster dose, was associated with lower likelihood of intensive care unit admission. Compared with patients during the period of Delta predominance, Omicron-period patients had less severe illness, largely driven by an increased proportion who were fully vaccinated. Approximately 20% of early Omicron-period hospitalizations were for non–COVID-19 conditions, particularly among young and vaccinated adults.
During March 1, 2020–October 26, 2021, approximately 2,500,000 COVID-19 cases and 58,000 COVID-19–associated deaths occurred in the state of New York.* New York has the highest U.S. per capita rate of persons living with diagnosed HIV infection (PLWDH), and population-level analyses adjusting for age, sex, and region have shown that PLWDH are more likely to be hospitalized for and to experience an in-hospital death from COVID-19 than are those not known to be PLWDH (1). CDC considers PLWDH who have a low CD4 cell count or who are not receiving HIV treatment to be at elevated risk for severe COVID-19–associated outcomes.
COVID-19 vaccination coverage and vaccine confidence were higher among gay or lesbian adults than among heterosexual adults and higher among gay men than gay or lesbian women. There were no significant differences in vaccination coverage among persons based on gender identity. Vaccination coverage was lowest among non-Hispanic Black LGBT persons across all categories of sexual orientation and gender identity.
Humans have extensive contact with wildlife known to harbor vast numbers of viruses, many of which have not yet spilled into humans. We compute the annualized damages from emerging viral zoonoses. We explore three practical actions to minimize the impact of future pandemics: better surveillance of pathogen spillover and development of global databases of virus genomics and serology, better management of wildlife trade, and substantial reduction of deforestation. We find that these primary pandemic prevention actions cost less than 1/20th the value of lives lost each year to emerging viral zoonoses and have substantial cobenefits.
Among nonhospitalized Medicare beneficiaries with a COVID-19 diagnosis between November 2020 and August 2021, only 7.2% received mAb therapy. In many cases, patients at the highest risk of severe disease were the least likely to receive mAb therapy. There was also extreme variation geographically.
February 3, 2022
In early November 2021, the B.1.1.529 (omicron) variant was first identified in South Africa and has rapidly become the dominant variant in Gauteng province, where a third wave of coronavirus disease 2019 (Covid-19) driven by the B.1.617.2 (delta) variant had largely subsided. As of November 15, the omicron variant was being detected in more than 75% of Covid-19–positive tests that were sequenced in South Africa.
This case series leveraged more than 190 000 COVID-19 surveillance tests for 14 894 individuals, including 1603 positive test results, at a midsized Midwestern university from January 6 to May 20, 2021. By April 2021, the highly transmissible Alpha (B.1.1.7) variant was the only variant resulting in persistent numbers of positive cases. An increase in vaccination coverage was associated with a decrease in COVID-19 cases in the campus population.
Of 1176 patients admitted, 253 had records of a 25(OH)D level prior to COVID-19 infection. A lower vitamin D status was more common in patients with the severe or critical disease (<20 ng/mL [87.4%]) than in individuals with mild or moderate disease (<20 ng/mL [34.3%] p < 0.001). Patients with vitamin D deficiency (<20 ng/mL) were 14 times more likely to have severe or critical disease than patients with 25(OH)D ≥40 ng/mL (odds ratio [OR], 14; 95% confidence interval [CI], 4 to 51; p < 0.001).
In this cross-sectional study of unvaccinated US adults, antibodies were detected in 99% of individuals who reported a positive COVID-19 test result, in 55% who believed they had COVID-19 but were never tested, and in 11% who believed they had never had COVID-19 infection. Anti-RBD levels were observed after a positive COVID-19 test result up to 20 months, extending previous 6-month durability data. Although evidence of natural immunity in unvaccinated healthy US adults up to 20 months after confirmed COVID-19 infection is encouraging, it is unclear how these antibody levels correlate with protection against future SARS-CoV-2 infections, particularly with emerging variants. The public health implications and long-term understanding of these findings merit further consideration.
Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial
In critically ill hospitalised patients with COVID-19 who were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, treatment with baricitinib compared with placebo (in combination with standard of care, including corticosteroids) reduced mortality, which is consistent with the mortality reduction observed in less severely ill patients in the hospitalised primary COV-BARRIER study population. However, this was an exploratory trial with a relatively small sample size; therefore, further phase 3 trials are needed to confirm these findings.
The improved outcomes of SARS-CoV-2 infections in the UK, especially compared with France and Germany, have been suggested to be a consequence of use of the ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccine. From April, 2021, those older than 40 years in the UK received the ChAdOx1 nCoV-19 vaccine, whereas in the EU, BNT162b2 (Pfizer–BioNTech) was the predominant vaccine used. Supporting this contention, the role of T cells in the response to SARS-CoV-2 infection and vaccination has been highlighted, with an enhanced cellular response reported after ChAdOx1 nCoV-19 compared with BNT162b2 vaccination in people aged 80 years or older, potentially related to an adjuvant effect from the adenovirus vector. In this Correspondence, we report results of a prospective study of vaccination responses in a different group of vulnerable individuals known to have a reduced antibody response to vaccines; namely, patients with rheumatoid arthritis on disease modifying antirheumatic drugs (DMARDs).
February 2, 2022
Patients who are hospitalized with COVID-19 have elevated rates of postdischarge thrombotic events, but uncertainty exists about whether thromboprophylaxis should continue beyond the hospital stay. In a recent phase 3 trial, continuing thromboprophylaxis after patients hospitalized with COVID-19 were discharged reduced major and fatal thromboembolic events without increasing major bleeding.
Viruses don’t inevitably evolve toward being less virulent; evolution simply selects those that excel at multiplying. In the case of Covid-19, in which the vast majority of transmission occurs before disease becomes severe, reduced severity may not be directly selected for at all. Indeed, previous SARS-CoV-2 variants with enhanced transmissibility (e.g., alpha and delta) appear to have greater intrinsic severity than their immediate ancestors or the previously dominant variant. Although the reduced CFR seen in the early weeks of South Africa’s omicron-variant wave is better than the alternative, much of the observed difference relates to increased immunity among the people being infected. More time and careful comparisons controlling for age, preexisting immunity, detection bias, lag time, hospital capacity, and other factors will be required to determine omicron’s intrinsic virulence. Given the remarkable pace at which omicron has spread, its societal effects will probably be substantial, particularly considering an intrinsic severity that is higher than crude comparisons might suggest. Our collective intuition regarding how a population-level CFR or IFR relates to a variant’s intrinsic severity needs to be recalibrated over time as immunity accrues — especially with a variant with the immune-evasion capabilities of omicron.
The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T-cell recognition is unknown. Here we show that T-cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼21%) with a >50% reduction in T-cell reactivity to the Omicron spike. Evaluation of functional CD4+ and CD8+ memory T cell responses confirmed these findings and reveal that reduced recognition to Omicron spike is primarily observed within the CD8+ T cell compartment potentially due to escape from HLA binding. Booster vaccination enhanced T-cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T-cell responses to the Omicron variant, although with reduced reactivity in some individuals.
February 1, 2022
SARS-CoV-2 Infection and Hospitalization Among Adults Aged ≥18 Years, by Vaccination Status, Before and During SARS-CoV-2 B.1.1.529 (Omicron) Variant Predominance — Los Angeles County, California, November 7, 2021–January 8, 2022
As of January 8, 2022, during Omicron predominance, COVID-19 incidence and hospitalization rates in Los Angeles County among unvaccinated persons were 3.6 and 23.0 times, respectively, those of fully vaccinated persons with a booster, and 2.0 and 5.3 times, respectively, those among fully vaccinated persons without a booster. During both Delta and Omicron predominance, incidence and hospitalization rates were highest among unvaccinated persons and lowest among vaccinated persons with a booster.
To establish a novel SARS-CoV-2 human challenge model, 36 volunteers aged 18-29 years without evidence of previous infection or vaccination were inoculated with 10 TCID50 of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) intranasally. Two participants were excluded from per protocol analysis due to seroconversion between screening and inoculation. Eighteen (~53%) became infected, with viral load (VL) rising steeply and peaking at ~5 days post-inoculation. Virus was first detected in the throat but rose to significantly higher levels in the nose, peaking at ~8.87 log10 copies/ml (median, 95% CI [8.41,9.53). Viable virus was recoverable from the nose up to ~10 days post-inoculation, on average. There were no serious adverse events. Mild-to-moderate symptoms were reported by 16 (89%) infected individuals, beginning 2-4 days post-inoculation. Anosmia/dysosmia developed more gradually in 12 (67%) participants. No quantitative correlation was noted between VL and symptoms, with high VLs even in asymptomatic infection, followed by the development of serum spike-specific and neutralising antibodies. However, lateral flow results were strongly associated with viable virus and modelling showed that twice-weekly rapid tests could diagnose infection before 70-80% of viable virus had been generated. Thus, in this first SARS-CoV-2 human challenge study, no serious safety signals were detected and the detailed characteristics of early infection and their public health implications were shown.
The NIH continues to support the development of some very innovative therapies to control SARS-CoV-2, the coronavirus that causes COVID-19. One innovative idea involves a molecular decoy to thwart the coronavirus.
Globally, during the week of 24 to 30 January 2022, the number of new COVID-19 cases remained similar to that reported during the previous week, while the number of new deaths increased by 9%. Across the six WHO regions, over 22 million new cases and over 59 000 new deaths were reported. As of 30 January 2022, over 370 million confirmed cases and over 5.6 million deaths have been reported globally.
Patients with COVID-19 breakthrough infections had a significantly higher proportion of CT scans without pneumonia compared to unvaccinated patients. Vaccinated patients with breakthrough infections had lower likelihood of requiring supplemental oxygen or ICU admission.
We estimate that there is a large volume of undetected cancer cases related to the pandemic, with incidence rates not yet having returned to prepandemic levels and with some cancers more impacted than others. The population profile of those diagnosed with cancer was not different during the pandemic compared with before. Public health messaging and advisories are required to highlight the importance of early presentation with new symptoms to physicians. Ongoing urgent vaccination of the population to achieve herd immunity will allow safe cancer care. Although this pandemic is ongoing, a cancer recovery plan needs to be initiated. Physicians should encourage continued screening and early biopsy for suspected cancers despite the ongoing pandemic.
This cross-sectional study of 386 711 patients in community clinics in Israel found an increase in incidence rates of various infections among children aged 0 to 3 years and in respiratory infections among all age groups during 3 months after the easing of COVID-19–related social restrictions. These findings suggest that as global COVID-19 vaccination rates increase and social restrictions are lifted, patterns of non–SARS-CoV-2 infection transmission observed late spring in Israel may be seen elsewhere, requiring early preparation.
The rate of confirmed infection was lower in people 12 or more days after their fourth dose than among those who received only three doses and those 3 to 7 days after vaccination by factors of 2.0 (95% confidence interval [CI], 2.0 to 2.1) and 1.9 (95% CI, 1.8 to 2.0), respectively. The rate of severe illness was lower by factors of 4.3 (95% CI, 2.4 to 7.6) and 4.0 (95% CI, 2.2 to 7.5).
Results demonstrate considerable variation in the sex disparity in COVID-19 cases and mortalities over time and between states. These data suggest that the sex disparity, when present, is modest, and likely varies in relation to context-sensitive variables, which may include health behaviors, preexisting health status, occupation, race/ethnicity, and other markers of social experience.
Much of the harm wrought in patients with cancer by COVID-19 has not been the direct result of infection, but rather has been inflicted indirectly by delayed diagnoses and suspended or aborted treatments.14 This harm is compounded for patients with cancer who have refused vaccination. Our data, in combination with those from other sources, show that the mRNA COVID-19 vaccine is well tolerated by patients with a history of cancer, including those receiving active treatment. Adverse events occurring shortly after vaccination closely resemble those seen in patients without cancer. As noted, our vaccination program, which targeted a sizable population of patients in fragile health, encountered no obstacles of either an administrative or clinical nature to the timely delivery of the vaccine.
New data provide perspective for appreciating the COVID-19 experience for patients with cancer at greatest risk. Patients with cancer may be more resilient to COVID-19 stressors than has been assumed or suggested. Although not immune to the stresses of COVID-19, data show resilience for otherwise heavily burdened patients with NSCLC—ones unable to “shelter in place” but leaving home regularly to receive treatment. Although recent data from >260,000 cancer survivors show patients with LC experience greater distress and disability and poorer quality of life than those with other common cancers, the latter studies do not necessarily capture the whole story. The present data show that, in the face of multiple health stressors and COVID-19, patients with NSCLC demonstrated resilience.
January 31, 2022
The results of this comparative effectiveness study suggest that a low-cost, easy-to-manufacture elastomeric harness may improve the fit and protection of a standard surgical mask. Infrared imaging and OSHA-approved fit testing were used to improve the harness design and optimize both fit and user comfort. The use of rubber-band harnesses with surgical masks has been reported, but they lack the consistency and comfort that can be achieved with manufactured harnesses.
January 30, 2022
We found BA.2 to be associated with an increased susceptibility of infection for unvaccinated individuals (Odds Ratio (OR) 2.19; 95%-CI 1.58-3.04), fully vaccinated individuals (OR 2.45; 95%-CI 1.77-3.40) and booster-vaccinated individuals (OR 2.99; 95%-CI 2.11-4.24), compared to BA.1. We also found an increased transmissibility from unvaccinated primary cases in BA.2 households when compared to BA.1 households, with an OR of 2.62 (95%-CI 1.96-3.52). The pattern of increased transmissibility in BA.2 households was not observed for fully vaccinated and booster-vaccinated primary cases, where the OR of transmission was below 1 for BA.2 compared to BA.1.
January 28, 2022
In a study of hospitalized adults, compared with receipt of 2 mRNA COVID-19 vaccine doses, receipt of a third dose increased vaccine effectiveness against hospitalization among adults without and with immunocompromising conditions, from 82% to 97% and from 69% to 88%, respectively.
Here, we report neutralizing antibody dynamics in a longitudinal cohort of COVID-19 convalescent and infection-naive individuals vaccinated with mRNA BNT162b2 by quantifying anti-SARS-CoV-2-spike antibodies and determining their avidity and neutralization capacity in serum. Using live-virus neutralization assays, we show that a superior infection-neutralizing capacity against all VoCs, including omicron, developed after either two vaccinations in convalescents or after a third vaccination or breakthrough infection of twice-vaccinated, naive individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. We conclude that an infection-plus-vaccination-induced hybrid immunity or a triple immunization can induce high-quality antibodies with superior neutralization capacity against VoCs, including omicron.
Over 50% of individually tested Syrian hamsters in the pet shop (8/16) and warehouse (7/12) were positive for SARS-CoV-2 infection in RT-PCR or serological tests. None of dwarf hamsters (n=77), rabbits (n=246), Guinea pigs (n=66), chinchilla (n=116) and mice (n=2) were confirmed positive in RT-PCR tests. SARS-CoV-2 viral genomes deduced from human and hamster cases in this incident all belong to Delta variant of concern (AY.127) that had not been circulating locally prior. These sequences are highly similar, but distinct. The viral genomes obtained from hamsters are phylogenetically related with some sequence heterogeneity and phylogenetic dating suggest infection in these hamsters occurred around 21 November 2021. Two separate transmission events to humans are documented, one leading to onward household spread.
January 27, 2022
The individual-level effectiveness of vaccines against COVID-19 is well established. However, few studies have examined vaccine effectiveness against transmission. We used a chain binomial model to estimate the effectiveness of vaccination with BNT162b2 (Pfizer-BioNTech mRNA-based vaccine) against household transmission of SARS-CoV-2 in Israel before and after the Delta variant emerged. Vaccination reduced susceptibility to infection by 89.4% [95% confidence interval (CI): 88.7%, 90.0%], whereas vaccine effectiveness against infectiousness given infection was 23.0% (95% CI: −11.3%, 46.7%) during days 10 to 90 after the second dose before June 1, 2021. Total vaccine effectiveness was 91.8% (95% CI: 88.1%, 94.3%). However, vaccine effectiveness is reduced over time as a result of the combined effect of waning of immunity and the emergence of the Delta variant.
Children unvaccinated against SARS-CoV-2 may still benefit through protection from vaccinated contacts. We estimated the protection provided to children through parental vaccination with the BNT162b2 vaccine. We studied households without prior infection, consisting of two parents and unvaccinated children, estimating the effect of parental vaccination on the risk of infection for unvaccinated children. We studied two periods separately– an early period (January 17, 2021 - March 28, 2021, Alpha variant, two doses vs. no vaccination) and a late period (July 11, 2021 - September 30, 2021, Delta variant, booster dose vs. two-vaccine doses). We found that having a single vaccinated parent was associated with a 26.0% and 20.8% decreased risk, and having two vaccinated parents was associated with a 71.7% and 58.1% decreased risk, in the early and late periods, respectively. To conclude, parental vaccination confers substantial protection for unvaccinated children in the household.
Four coronavirus (COVID-19) vaccines have now been approved for use in the UK. Rigorous clinical trials have been undertaken to understand the immune response, safety profile and efficacy of these vaccines as part of the regulatory process. Ongoing monitoring of the vaccines as they are rolled out in the population is important to continually ensure that clinical and public health guidance on the vaccination programme is built upon the best available evidence.
In this commentary, we discuss themes that emerged from the symposium about what modern epidemiology as a science may learn from the coronavirus disease 19 (COVID-19) pandemic. We reflect on the successes and limitations of this discipline from multiple perspectives, including junior and senior epidemiologists and scientists on the front lines of generating evidence for the COVID-19 pandemic response from Wuhan, China to Ontario, Canada. These themes include: the role of the traditional scientific process in a public health emergency; epidemiologic methods and data that are critical for an effective pandemic response; the interventions that epidemiologists recommended and interventions that we may explore in the future; inequitable impacts of the COVID-19 pandemic contrasted with homogeneity in epidemiologists’ workforce; effective and honest communication of uncertainty; trust and collaboration; and the extent to which these themes are currently reflected in our training programs and discipline. We look forward to insights from field epidemiologists directly involved in the ongoing response to the COVID-19 pandemic and further reflection from epidemiologists throughout our discipline.
January 26, 2022
Long COVID symptoms of any severity were reported by 9.5% of double-vaccinated study participants, compared with 14.6% of socio-demographically similar participants who were unvaccinated when infected; the corresponding estimates for long COVID symptoms severe enough to result in limitation to day-to-day activities were 5.5% and 8.7% respectively.
In November 2021, the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in South Africa. Since then, omicron has rapidly spread around the world. On November 26, 2021, the World Health Organization designated omicron as a variant of concern. The omicron variant was found to have at least 33 mutations (29 amino acid substitutions, 1 insertion of three amino acids, and 3 small deletions) in its spike (S) protein, as compared with early SARS-CoV-2 strains identified in Wuhan, China.
The highly transmissible omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of mounting concern globally. The omicron variant carries a large number of spike mutations, including at least 15 mutations in the receptor-binding domain, which is a major target of neutralizing antibodies.
The coronavirus disease 2019 (Covid-19) pandemic is still ongoing, and the B.1.1.529 (or omicron) variant, first detected in November 2021, has already spread globally. The ability of the omicron variant to escape vaccine-elicited immunity is of great concern. Inactivated vaccines, such as CoronaVac and BBIBP-CorV, and protein subunit vaccines, such as ZF2001, have been widely used in China and several other countries.
Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients.
We used a test-negative, case–control study design to estimate vaccine effectiveness, applying the same methods used recently to assess waning effectiveness of the BNT162b2 (Pfizer–BioNTech) vaccine in the same population. Case participants (persons with a positive polymerase-chain-reaction [PCR] test for SARS-CoV-2) and controls (PCR-negative persons) were matched one to one according to sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test. Effectiveness was estimated against documented infection (a PCR-positive swab, regardless of the presence of symptoms) and against any severe Covid-19 cases (acute-care hospitalizations), critical Covid-19 cases (intensive care unit hospitalizations), or fatal Covid-19 cases (Covid-19–related deaths).
These findings support the use of multiple vaccine boosts and prolonged intervals between vaccine doses to protect against highly mutated variants such as omicron in persons who had previously received two priming doses of vaccine or who had previously recovered from SARS-CoV-2. Our results are in accordance with those of previous studies involving messenger RNA vaccine recipients.5Next-generation vaccines that stimulate broad protection against SARS-CoV-2 variants are also needed.
The omicron variant has mutations in both the RNA-dependent RNA polymerase (RdRp) and the main protease of SARS-CoV-2, which are targets for antiviral drugs such as RdRp inhibitors (remdesivir and molnupiravir) and the main protease inhibitor PF-07304814, which arouses concern regarding the decreased effectiveness of these drugs against omicron. Thus, we tested three different antiviral compounds (i.e., remdesivir, molnupiravir, and PF-07304814) for their efficacy against omicron. The in vitro 50% inhibitory concentration (IC50) values of each compound were determined against NC928, NC002, HP127, HP01542, TY7-503, and UW5250. The susceptibilities of omicron to the three compounds were similar to those of the early strain (i.e., IC50 values for remdesivir, molnupiravir, and PF-07304814 that differed by factors of 1.2, 0.8, and 0.7, respectively) (Table 1). These results suggest that all three of these compounds may show efficacy for treating patients infected with the omicron variant.
January 25, 2022
Although disease severity appears lower with the Omicron variant, the high volume of hospitalizations can strain local health care systems and the average daily number of deaths remains substantial. This underscores the importance of national emergency preparedness, specifically, hospital surge capacity and the ability to adequately staff local health care systems. In addition, being up to date on vaccinations and following other recommended prevention strategies are critical to preventing infections, severe illness, or death from COVID-19.
The SARS-CoV-2 Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and X-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.
Researchers in Israel report that people who have had both SARS-CoV-2 infection and doses of Pfizer–BioNTech vaccine were much less likely to report any of a range of common long-COVID symptoms than were people who were unvaccinated when infected. In fact, vaccinated people were no more likely to report symptoms than people who’d never caught SARS-CoV-2. The study has not yet been peer reviewed.
Our results show that Omicron had higher positivity rates than Delta among those who received two doses within five months (Omicron = 4.7% vs. Delta = 2.6%), two doses more than five months ago (4.2% vs. 2.9%), and three vaccine doses (2.2% vs. 0.9%). Our estimates of Omicron positivity rates in persons receiving one or two vaccine doses were not significantly lower than unvaccinated persons but were 49.7% lower after three doses. In comparison, the reduction in Delta positivity rates from unvaccinated to 2 vaccine doses was 45.6-49.6% and to 3 vaccine doses was 83.2%. Despite the higher positivity rates for Omicron in vaccinated persons, we still found that 91.2% of the Omicron infections in our study occurred in persons who were eligible for 1 or more vaccine doses at the time of PCR testing. In conclusion, escape from vaccine-induced immunity likely contributed to the rapid rise in Omicron infections.
We find that human immune sera following breakthrough infection and vaccination following natural infection, broadly neutralize SARS-CoV-2 variants to a similar degree. While age negatively correlates with antibody response after vaccination alone, no correlation with age was found in breakthrough or hybrid immune groups. Together, our data suggest that the additional antigen exposure from natural infection substantially boosts the quantity, quality, and breadth of humoral immune response regardless of whether it occurs before or after vaccination.
In this meta-analysis of 8 randomized clinical trials enrolling 2341 participants, individual patient data were monitored in real time and analyzed using a robust bayesian framework and advanced statistical modeling. No association of convalescent plasma with clinical outcomes was found.
There may be a relationship between COVID-19 associated AIS and severe disability or death. We identified several factors that predict worse outcomes, and these outcomes were more frequent compared with global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-dimer, predicted both morbidity and mortality.
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
January 24, 2022
The best way to prevent more, more-dangerous or more-transmissible variants from emerging is to stop unconstrained spread, and that requires many integrated public-health interventions, including, crucially, vaccine equity. The more a virus replicates, the greater the chance that problematic variants will arise, most probably where spread is highest. The Alpha variant was first identified in the United Kingdom, Delta was first found in India and Omicron in southern Africa — all places where spread was rampant. Thinking that endemicity is both mild and inevitable is more than wrong, it is dangerous: it sets humanity up for many more years of disease, including unpredictable waves of outbreaks. It is more productive to consider how bad things could get if we keep giving the virus opportunities to outwit us. Then we might do more to ensure that this does not happen.
During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including 3rd dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is less after infection compared to all vaccines evaluated, but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks post-vaccination in some cases. SARS-CoV-2 antibody specificity, breadth and maturation are affected by imprinting from exposure history, and distinct histological and antigenic contexts in infection compared to vaccination.
ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.
In September, 2021, at the start of the autumn school term in England, infections were increasing exponentially in children aged 5–17 years, at a time when vaccination rates were low in this age group. In adults, compared to those who received their second dose less than 3 months ago, the higher prevalence of swab positivity at 3–6 months following two doses of the COVID-19 vaccine suggests an increased risk of breakthrough infections during this period. The vaccination programme needs to reach children as well as unvaccinated and partially vaccinated adults to reduce SARS-CoV-2 transmission and associated disruptions to work and education.
The estimated transmission bottleneck size of the Delta variant was generally narrow, with 1-3 virions in 29 donor-recipient transmission pairs. However, the transmission of minor iSNVs resulted in at least 3 of the 34 substitutions that were identified in the outbreak, highlighting the contribution of intra-host variants to population-level viral diversity during rapid spread.
Here, we show that it is possible to generate ultra-potent (IC50 < 2 ng/ml) human neutralizing antibodies directly from a unique semisynthetic naïve antibody library format with affinities, developability properties and neutralization activities comparable to the best from hyperimmune sources. This demonstrates that appropriately designed and constructed naïve antibody libraries can effectively compete with immunization to directly provide therapeutic antibodies against a viral pathogen, without the need for immune sources or downstream optimization.
We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
In this exploratory multicenter prospective cohort study that included 246 patients who were alive 1 year following ICU treatment for COVID-19, 74.3% reported physical symptoms, 26.2% reported mental symptoms, and 16.2% reported cognitive symptoms.
January 22, 2022
We report the antibody neutralization against Omicron SARS-CoV-2 after 2 and 3 doses of BNT162b2 mRNA vaccine. Vaccinated individuals were serially tested for their neutralization against wild-type SARS-CoV-2 (strain USA-WA1/2020) and an engineered USA-WA1/2020 bearing the Omicron spike glycoprotein. Plaque reduction neutralization results showed that at 2 or 4 weeks post-dose-2, the neutralization geometric mean titers (GMTs) were 511 and 20 against the wild-type and Omicron-spike viruses, respectively, suggesting that two doses of BNT162b2 were not sufficient to elicit robust neutralization against Omicron; at 1 month post-dose-3, the neutralization GMTs increased to 1342 and 336, respectively, indicating that three doses of vaccine increased the magnitude and breadth of neutralization against Omicron; at 4 months post-dose-3, the neutralization GMTs decreased to 820 and 171, respectively, suggesting similar neutralization decay kinetics for both variants. The data support a three-dose vaccine strategy and provide the first glimpse of the neutralization durability against Omicron.
January 21, 2022
COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence — 25 U.S. Jurisdictions, April 4–December 25, 2021
In 25 U.S. jurisdictions, decreases in case incidence rate ratios for unvaccinated versus fully vaccinated persons with and without booster vaccine doses were observed when the Omicron variant emerged in December 2021. Protection against infection and death during the Delta-predominant period against infection during Omicron emergence were higher among booster vaccine dose recipients, and especially among persons aged 50–64 and ≥65 years.
Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19–Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance — VISION Network, 10 States, August 2021–January 2022
VE was significantly higher among patients who received their second mRNA COVID-19 vaccine dose <180 days before medical encounters compared with those vaccinated ≥180 days earlier. During both Delta- and Omicron-predominant periods, receipt of a third vaccine dose was highly effective at preventing COVID-19–associated emergency department and urgent care encounters (94% and 82%, respectively) and preventing COVID-19–associated hospitalizations (94% and 90%, respectively).
In this test-negative case-control analysis that included 70 155 tests from symptomatic adults, the likelihood of vaccination with 3 mRNA vaccine doses (vs unvaccinated) was significantly lower among both Omicron (odds ratio, 0.33) and Delta (odds ratio, 0.065) cases than SARS-CoV-2–negative controls; a similar pattern was observed with 3 vaccine doses vs 2 doses (Omicron odds ratio, 0.34; Delta odds ratio, 0.16). These findings suggest that vaccination with 3 doses of mRNA COVID-19 vaccine, compared with being unvaccinated and with receipt of 2 doses, was associated with protection against both the Omicron and Delta variants, although higher odds ratios for the association with Omicron infection suggest less protection for Omicron than for Delta.
Pfizer-BioNTech or Moderna mRNA COVID-19 vaccines are preferred over the Janssen COVID-19 vaccine for primary and booster vaccination. The Janssen COVID-19 vaccine may be considered in some situations, including for persons with a contraindication to receipt of mRNA COVID-19 vaccines.
This survey study of 1200 US adults found that COVID-19 vaccine hesitancy decreased more rapidly among Black individuals than among White individuals since December 2020. A key factor associated with this pattern seems to be the fact that Black individuals more rapidly came to believe that vaccines were necessary to protect themselves and their communities.
As the US enters the third year of the global coronavirus pandemic, vaccination remains the most effective tool against infections and symptomatic illness. Layered on other public health mitigation tools such as testing and masks, vaccination is central to a larger strategy of control and management of COVID-19 as the pandemic shifts toward endemicity.1 However, emergence of new variants of concern, vaccine hesitancy, and barriers to global vaccine equity have created challenges to containing the pandemic.
The nature and extent of the novel COVID-19 pandemic has been unprecedented, touching all aspects of society. An emerging body of literature has highlighted the substantial mental health toll affecting broad swaths of the general population during the pandemic.
Omicron replication is markedly attenuated in both the upper and lower respiratory tract of infected K18-hACE2 mice in comparison to that of WT and Delta variant, which results in its dramatically ameliorated lung pathology. When compared with SARS-CoV-2 WT, Alpha, Beta, and Delta variant, infection by the Omicron variant causes the least body weight loss and mortality rate. Overall, our study demonstrates that the Omicron variant is attenuated in virus replication and pathogenicity in mice in comparison with WT and previous variants.
Despite modeling data suggesting that B.1.1.529 spike can bind more avidly to murine ACE23,4, we observed less infection in 129, C57BL/6, BALB/c, and K18-hACE2 transgenic mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.
These results demonstrate COH04S1-mediated vaccine protection in animal models through different vaccination routes and dose regimens, complementing ongoing investigation of this multiantigen SARS-CoV-2 vaccine in clinical trials.
Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.
January 20, 2022
Although infections among vaccinated individuals lead to milder COVID-19 symptoms relative to those in unvaccinated subjects, the specificity and durability of antibody responses elicited by breakthrough cases remain unknown. Here, we demonstrate that breakthrough infections induce serum-binding and -neutralizing antibody responses that are markedly more potent, durable, and resilient to spike mutations observed in variants than those in subjects who received only 2 doses of vaccine. However, we show that breakthrough cases, subjects who were vaccinated after infection, and individuals vaccinated three times have serum-neutralizing activity of comparable magnitude and breadth, indicating that an increased number of exposures to SARS-CoV-2 antigen(s) enhance the quality of antibody responses. Neutralization of SARS-CoV was moderate, however, underscoring the importance of developing vaccines eliciting broad sarbecovirus immunity for pandemic preparedness.
These findings indicate that male SARS-CoV-2 infection may be associated with a short-term decline in fertility and that COVID-19 vaccination does not impair fertility in either partner.
January 19, 2022
The Ad26.COV2.S and mRNA boosters had an acceptable safety profile and were immunogenic in health care workers who had received a priming dose of Ad26.COV2.S vaccine. The strongest responses occurred after boosting with mRNA-based vaccines. Boosting with any available vaccine was better than not boosting.
Although the epidemiology of COVID-19 might change as new variants emerge, vaccination remains the safest strategy for averting future SARS-CoV-2 infections, hospitalizations, long-term sequelae, and death. Primary vaccination, additional doses, and booster doses are recommended for all eligible persons. Additional future recommendations for vaccine doses might be warranted as the virus and immunity levels change.
SARS-CoV-2 RNA can be found infrequently in the breastmilk after recent infection, but we found no evidence that breastmilk contains an infectious virus or that breastfeeding represents a risk factor for transmission of infection to infants.
One of the rate-limiting steps in analyzing immune responses to vaccines or infections is the isolation and characterization of monoclonal antibodies. Here, we present a hybrid structural and bioinformatic approach to directly assign the heavy and light chains, identify complementarity-determining regions, and discover sequences from cryoEM density maps of serum-derived polyclonal antibodies bound to an antigen. When combined with next-generation sequencing of immune repertoires, we were able to specifically identify clonal family members, synthesize the monoclonal antibodies, and confirm that they interact with the antigen in a manner equivalent to the corresponding polyclonal antibodies. This structure-based approach for identification of monoclonal antibodies from polyclonal sera opens new avenues for analysis of immune responses and iterative vaccine design.
Today’s MMWR study finds that during the Delta wave, both COVID-19 vaccination and surviving a prior infection provided protection against infection and hospitalization from COVID-19. Scientists reviewed data from New York and California to determine the level of protection offered by COVID-19 vaccines, previous infection, and both. Between May and November 2021, people who were unvaccinated and did not have a prior COVID-19 infection remained at the highest risk of infection and hospitalization, while those who were previously infected, both with or without prior vaccination, had the greatest protection.
Cognitive post-acute sequelae of SARS-CoV-2 (PASC) can occur after mild COVID-19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS-CoV-2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre-existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.
Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples of COVID-19 patients with prominent tissue destruction and associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, SARS-CoV-2 infection activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, leading to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a novel principle for the development of host-directed therapeutics.
Pfizer aims to have an Omicron-specific COVID-19 vaccine ready by March. Assuming it gains approval, it will mark the first revision of its mRNA vaccine Comirnaty since the initial Emergency Use Authorization of the vaccine by the US Food and Drug Administration (FDA) on 11 December 2020. The variant-specific booster will also test the responsiveness of the FDA and other major regulators in turning around applications for vaccine revisions.
January 18, 2022
In-vitro data suggest lower titres of neutralising antibodies against omicron compared to other SARS-CoV-2 lineages following BNT162b2 vaccination but increased titres after a third dose,10, 11, 12 supporting calls for booster doses while the omicron variant appears to be spreading globally. Our study, however, demonstrates insufficient prevention of symptomatic infection in otherwise healthy individuals who had received three doses of COVID-19 mRNA vaccines.
The performance of current antigen tests in paediatric populations under real-life conditions varies broadly. Relevant data were only identified for very few antigen tests on the market, and the risk of bias was mostly unclear due to poor reporting. Additionally, the most common uses of these tests in children (eg, self-testing in schools or parents testing their toddlers before kindergarten) have not been addressed in clinical performance studies yet. The observed low diagnostic sensitivity may impact the planned purpose of the broad implementation of testing programmes.
January 17, 2022
Vaccination with at least two doses of COVID-19 vaccine was associated with a substantial decrease in reporting the most common post-acute COVID-19 symptoms, bringing it back to baseline. Our results suggest that, in addition to reducing the risk of acute illness, COVID-19 vaccination may have a protective effect against long COVID.
A fourth shot of COVID-19 vaccine boosts antibodies to even higher levels than the third jab but it is not enough to prevent Omicron infections, according to a preliminary study in Israel.
Israel's Sheba Medical Center has given second booster shots in a trial among its staff and is studying the effect of the Pfizer booster in 154 people after two weeks and the Moderna booster in 120 people after one week, said Gili Regev-Yochay, director of the Infectious Diseases Unit.
Using online surveys, we collected data regarding COVID-19-related loss of smell or taste from 69,841 individuals. We performed a multi-ancestry genome-wide association study and identified a genome-wide significant locus in the vicinity of the UGT2A1 and UGT2A2 genes. Both genes are expressed in the olfactory epithelium and play a role in metabolizing odorants. These findings provide a genetic link to the biological mechanisms underlying COVID-19-related loss of smell or taste.
SARS-CoV-2 RNA can be detected in exhaled aerosol, sampled during a limited number of breathing and coughing procedures. Detection in aerosol seemed independent of viral load in the upper airway swab as well as of the exhaled number of particles. The infectious potential of the amount of virus detected in aerosol needs to be further explored.
January 14, 2022
Equitable receipt of COVID-19 treatments by race and ethnicity along with vaccines and other prevention practices are essential to reduce inequities in severe COVID-19–associated illness and death.
CDC is the nation’s premier health promotion, prevention, and preparedness agency. As such, CDC is an important source of public health and clinical guidelines. If CDC guidelines are to be trusted by partners and the public, they must be clear, valid, and reliable. Methods and processes used in CDC guideline development should follow universally accepted standards. This report describes the standards required by CDC for the development of evidence-based guidelines. These standards cover topics such as guideline scoping, soliciting external input, summarizing evidence, and crafting recommendations. Following these standards can help minimize bias and enhance the quality and consistency of CDC guidelines.
January 13, 2022
Patients with the omicron variant of covid-19 shed virus for longer after symptoms emerge, show data from Japan, potentially jeopardising hopes that the period of isolation for people testing positive could be shortened.
Vaccine coverage was substantially lower in pregnant women than in the general female population of 18−44 years; 32.3% of women giving birth in October 2021 had two doses of vaccine compared to 77.4% in all women. The extended perinatal mortality rate for women who gave birth within 28 d of a COVID-19 diagnosis was 22.6 per 1,000 births (95% CI 12.9−38.5; pandemic background rate 5.6 per 1,000 births; 452 out of 80,456; 95% CI 5.1−6.2). Overall, 77.4% (3,833 out of 4,950; 95% CI 76.2−78.6) of SARS-CoV-2 infections, 90.9% (748 out of 823; 95% CI 88.7−92.7) of SARS-CoV-2 associated with hospital admission and 98% (102 out of 104; 95% CI 92.5−99.7) of SARS-CoV-2 associated with critical care admission, as well as all baby deaths, occurred in pregnant women who were unvaccinated at the time of COVID-19 diagnosis. Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic.
The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance.
January 12, 2022
We observed limited waning in vaccine effectiveness against Covid-19–related hospitalization and death at 20 weeks or more after vaccination with two doses of the ChAdOx1-S or BNT162b2 vaccine. Waning was greater in older adults and in those in a clinical risk group.
Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19–related hospitalization and ICU admission or the receipt of life support.
All three Covid-19 vaccines had durable effectiveness in reducing the risks of hospitalization and death. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant.
During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, several new viral variants have emerged, leading to the virus becoming more contagious. However, efficient immune escape has not been observed, and vaccines have remained effective. Most recently, the B.1.1.529 (omicron) variant has been described, which the World Health Organization classified as a variant of concern on November 26, 2021.
There is an urgent need to understand how SARS-CoV-2 infects the airway epithelium and in a subset of individuals leads to severe illness or death. Induced pluripotent stem cells (iPSCs) provide a near limitless supply of human cells that can be differentiated into cell types of interest, including airway epithelium, for disease modeling. We present a human iPSC-derived airway epithelial platform, composed of the major airway epithelial cell types, that is permissive to SARS-CoV-2 infection. Subsets of iPSC-airway cells express the SARS-CoV-2 entry factors ACE2 and TMPRSS2. Multiciliated cells are the primary initial target of SARS-CoV-2 infection. Upon infection with SARS-CoV-2, iPSC-airway cells generate robust interferon and inflammatory responses and treatment with remdesivir or camostat methylate causes a decrease in viral propagation and entry, respectively. In conclusion, iPSC-derived airway cells provide a physiologically relevant in vitro model system to interrogate the pathogenesis of, and develop treatment strategies for, COVID-19 pneumonia.
January 11, 2022
Rates of ICU admission and mortality after an outpatient positive test were 0.26 (0.10-0.73) and 0.09 (0.01-0.75) fold as high among cases with Omicron variant infection as compared to cases with Delta variant infection. Zero cases with Omicron variant infection received mechanical ventilation, as compared to 11 cases with Delta variant infections throughout the period of follow-up (two-sided p<0.001). Median duration of hospital stay was 3.4 (2.8-4.1) days shorter for hospitalized cases with Omicron variant infections as compared to hospitalized patients with Delta variant infections, reflecting a 69.6% (64.0-74.5%) reduction in hospital length of stay. Conclusions: During a period with mixed Delta and Omicron variant circulation, SARS-CoV-2 infections with presumed Omicron variant infection were associated with substantially reduced risk of severe clinical endpoints and shorter durations of hospital stay.
Plasma SARS-CoV-2 viral RNA (vRNA) levels are predictive of COVID-19 outcomes in hospitalized patients, but whether plasma vRNA reflects lower respiratory tract (LRT) vRNA levels is unclear. We compared plasma and LRT vRNA levels in simultaneously collected longitudinal samples from mechanically-ventilated patients with COVID-19. LRT and plasma vRNA levels were strongly correlated at first sampling (r=0.83, p<10-8) and then declined in parallel except in non-survivors who exhibited delayed vRNA clearance in LRT samples. Plasma vRNA measurement may offer a practical surrogate of LRT vRNA burden in critically ill patients, especially early in severe disease.
One Health genomic surveillance identified transmission of a Delta variant from a zookeeper to the three lions, similar to those circulating in humans in South Africa. One lion developed pneumonia while the other cases had mild infection. Both the puma and lions remained positive for SARS-CoV-2 RNA for up to 7 weeks.
January 10, 2022
Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.
The aerosol microenvironment is highly dynamic exposing pathogens, such as the SARS-CoV-2 virus when exhaled in respiratory aerosol, to extreme conditions of solute concentration, pH and evaporative cooling. Yet surviving this environment is a key step in the transmission of such pathogens. Understanding the impact that airborne transport has on pathogens and the influence of environmental conditions on pathogen survival can inform the implementation of strategies to mitigate the spread of diseases such as COVID-19. We report changes in the infectivity of the airborne virus over timescales spanning from 5 s to 20 minutes and demonstrate the role of two microphysical processes in this infectivity loss: particle crystallisation and aerosol droplet pH change.
Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.
In this cohort study of 1928 health care workers in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was significantly associated with lower risk of SARS-CoV-2 infection during a median of 39 days of follow-up (adjusted hazard ratio, 0.07).
January 7, 2022
Among 1,228,664 persons who completed primary vaccination during December 2020–October 2021, severe COVID-19–associated outcomes (0.015%) or death (0.0033%) were rare. Risk factors for severe outcomes included age ≥65 years, immunosuppressed, and six other underlying conditions. All persons with severe outcomes had at least one risk factor; 78% of persons who died had at least four.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.
Receipt of 2 doses of Pfizer-BioNTech vaccine is highly effective in preventing MIS-C in persons aged 12–18 years. These findings further reinforce the COVID-19 vaccination recommendation for eligible children.
The increased diabetes risk among persons aged <18 years following COVID-19 highlights the importance of COVID-19 prevention strategies in this age group, including vaccination for all eligible persons and chronic disease prevention and treatment.
Here, we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.
The overall rate of false-positive results among the total rapid antigen test screens for SARS-CoV-2 was very low, consistent with other, smaller studies. The cluster of false-positive results from 1 batch was likely the result of manufacturing issues rather than implementation. These results inform the discussion of whether rapid antigen tests will result in too many false-positives that could overwhelm PCR testing capacity in other settings. Also, the results demonstrate the importance of having a comprehensive data system to quickly identify potential issues. With the ability to identify batch issues within 24 hours, workers could return to work, problematic test batches could be discarded, and the public health authorities and manufacturer could be informed. Aside from issues with the batch, false-positives are possible due to the timing of the test (ie, too early or too late in the infectious stage) or quality issues in how the self-test was completed.
In this cohort study including 163 patients, a third vaccine dose strengthened the immune response in 75% of the patients treated with chemotherapy or targeted therapy presenting a weak humoral response after the second dose. The data of this study appear to support the use of a third vaccine dose as a booster dose among patients with active cancer treatment for solid tumors.
Therefore, we have established the NP purification method, which completely eliminates the RNA in the NP preparation. Two stages of RNA removal were used: treatment of the crude lysate of E. coli with RNase A and subsequent selective RNA elution with 2 M NaCl solution. The resulting NP without RNA has a significantly better signal-to-noise ratio when used as an ELISA antigen and tested with a control panel of serum samples with antibodies to SARS-CoV-2; therefore, it is preferable for in vitro diagnostic use. The same increase of the signal-to-noise ratio was detected for the free N-terminal domain of the NP. Complete removal of RNA complexed with NP during purification will significantly improve its antigenic properties, and the absence of RNA in NP preparations should be controlled during the production of this antigen.
January 6, 2022
A newly isolated antibody that blocks SARS-CoV-2 from infecting cells could one day be used to treat infections caused by current and future variants of the virus that causes COVID-19, and even infections from related viruses.
The US needs a strategy for a “new normal” of living that includes COVID-19. This “new normal” will occur when total respiratory viral infections, hospitalizations, and deaths inclusive of those from COVID-19 are no higher than what typically occurred in the most severe influenza years before the current pandemic. Integral to achieving and sustaining this “new normal” are both faster development and more efficient deployment of vaccines and therapeutics. While COVID-19 has ushered in new vaccine platforms, repurposed existing therapies, and stimulated rapid development of monoclonal antibody and oral antiviral treatments in record time, much remains to be done to ensure these life-saving medicines are accessible to all.
It is widely believed that self-reported loss of taste can be an indirect consequence of retronasal olfactory dysfunction6; indeed, our study found that even when specifically asked about basic tastes, more than half of patients self-reporting an altered taste perception exhibited a normal gustatory function, while most of them had an olfactory impairment. However, 42% were found to have true hypogeusia. Following evaluation of the scores in relation to age, still 29% exhibited hypogeusia, which has largely been overlooked to date. While olfactory training may help the former group, additional strategies may be needed for those with gustatory impairment.
January 5, 2022
Vaccination was associated with a smaller reduction in transmission of the delta variant than of the alpha variant, and the effects of vaccination decreased over time. PCR Ct values at diagnosis of the index patient only partially explained decreased transmission.
January 4, 2022
These data support the safety of COVID-19 vaccination during pregnancy. CDC recommends COVID-19 vaccination for women who are pregnant, recently pregnant, who are trying to become pregnant now, or who might become pregnant in the future.
In this cohort study of 255 infants born between March and December 2020, exposure to maternal SARS-CoV-2 infection was not associated with differences on any Ages & Stages Questionnaire, 3rd Edition, subdomain at age 6 months, regardless of infection timing or severity. However, both exposed and unexposed infants born during that period had significantly lower scores on gross motor, fine motor, and personal-social subdomains compared with a historical cohort of infants born before the onset of the COVID-19 pandemic.
As the COVID-19 pandemic grinds toward the end of another year, it makes sense to wonder about the effect on children conceived and born in its shadow. Some of the consequences can be seen in the increasing rates of COVID-19 among infants and young children, particularly among those with comorbid medical conditions. But we must also consider less obvious sequelae: are infants born during the pandemic at greater risk for behavioral or neurodevelopmental problems, either due to exposure to maternal SARS-CoV-2 infection or to the more global effects of trauma and stress? Pregnant women and their infants are vulnerable to the effects of disasters, and evidence suggests that disaster affects maternal mental health and some perinatal health outcomes, particularly among highly exposed women. Prenatal exposure to some viral infections, such as rubella and HIV, increases the risk of neurobehavioral problems in children, and some have hypothesized that SARS-CoV-2 infection could have a similar outcome via in utero exposure to maternal fever, hypoxia, or inflammation.
Mortality rates for US residents 15 years or older increased sharply in 2020, fueled by nearly 351 000 deaths attributed to COVID-19 during the year. As a result, average US life expectancy at birth declined by nearly 2 years from that in 2019, according to a data brief from the Centers for Disease Control and Prevention’s National Center for Health Statistics (NCHS).
Healthcare workers (HCWs) in the United Kingdom (UK) have been prioritised in the SARS-CoV-2 vaccination agenda, including the ongoing booster programme. We previously reported that 23% of 11,584 HCWs who completed the baseline UK-REACH (UK Research study into Ethnicity And Covid-19 outcomes in Healthcare workers) cohort study questionnaire were hesitant about receiving a SARS-CoV-2 vaccine between 4th December 2020 and 28th February 2021. Vaccine hesitancy was more likely amongst certain ethnic minority groups and was associated with lower trust in employing healthcare organisations and in vaccines themselves. HCWs who were hesitant also reported concerns about vaccine safety and side effects, especially given the speed of vaccine development and roll-out, and expressed a desire to delay vaccination until more people had been vaccinated.
January 3, 2022
COVID-19 infection and symptoms may be more common among those experiencing elevated psychological distress. Further research to elucidate the mechanisms underlying these associations is needed.
January 1, 2022
As coronavirus disease 2019 (COVID-19) vaccination is undoubtedly a key to controlling the transmission of COVID-19, owing to its effectiveness, increasing the willingness to receive COVID-19 vaccines is a crucial mission for both vaccine coverage and subsequent global infection control. In this context, COVID-19 vaccine hesitancy, the reluctance to receive COVID-19 vaccines, has become a significant growing public health concern. Although COVID-19 vaccine hesitancy varies across cultural and geographical contexts, general mistrust for vaccines and fear of future adverse events are major concerns among the hesitant. Such mistrust, fear, and the unwillingness to vaccinate, based on misinformation or disinformation, are often cultivated by mass and social media. Since individuals generally use multiple media channels, identifying specific media use, including combinations of media use among the hesitant, is essential to prevent the development of COVID-19 vaccine hesitancy.
We read with interest the news that the UK Government has announced deals to procure the oral antivirals for SARS-CoV-2, molnupiravir (Lagevrio, Merck [Branchburg, NJ, USA]) and ritonavir in combination with PF-07321332 (Paxlovid, Pfizer [New York, NY, USA]). Although we welcome further partnership between the government and pharmaceutical industry in the provision of effective agents to manage the COVID-19 pandemic, we urge caution with the widescale use of ritonavir, given its propensity for causing clinically significant drug–drug interactions with commonly prescribed and over-the-counter medications.
December 31, 2021
Parents and guardians of children aged 5–11 years should be advised that local and systemic reactions are expected after vaccination with Pfizer-BioNTech COVID-19 vaccine and are more common after the second dose.
In real-world conditions among adolescents aged 12–17 years, the Pfizer-BioNTech vaccine was highly effective in preventing SARS-CoV-2 infection.
COVID-19 vaccination and other prevention strategies are important to protect children from COVID-19, particularly children with obesity and other underlying health conditions.
Here, we investigated the neutralizing and binding activity of sera from convalescent, mRNA double vaccinated, mRNA boosted, convalescent double vaccinated, and convalescent boosted individuals against wild type, B.1.351 and B.1.1.529 SARS-CoV-2 isolates. Neutralizing activity of sera from convalescent and double vaccinated participants was undetectable to very low against B.1.1.529 while neutralizing activity of sera from individuals who had been exposed to spike three or four times was maintained, albeit at significantly reduced levels. Binding to the B.1.1.529 receptor binding domain (RBD) and N-terminal domain (NTD) was reduced in convalescent not vaccinated individuals, but was mostly retained in vaccinated individuals.
December 30, 2021
The newly emerged B.1.1.159 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a large number of changes — 32 — in its spike protein relative to that of the original virus (Wuhan-hu-1), particularly in the receptor-binding domain and the N-terminal domain, the primary targets of neutralizing antibodies. Previously, we showed that approximately 20 changes introduced into a synthetic polymutant spike protein (PMS20) are sufficient for substantial evasion of the polyclonal neutralizing antibodies elicited in the majority of persons who have recovered from coronavirus disease 2019 (Covid-19) or have received two doses of an mRNA vaccine. Of note, several changes in the PMS20 spike protein are the same as or similar to changes in the omicron variant.
Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.
December 29, 2021
Thus, during the proxy omicron period, we saw a maintenance of effectiveness of the BNT162b2 vaccine (albeit at a reduced level) against hospital admission for Covid-19 that was presumed to have been caused by the omicron variant as compared with the rate associated with the delta variant earlier in the year. The addition of a booster dose of vaccine may mitigate this reduction in vaccine effectiveness.
Nevertheless, we found low neutralization efficiency with two doses of the BNT162b2 vaccine against the wild-type virus and the delta variant, assessed more than 5 months after receipt of the second dose, and no neutralization efficiency against the omicron variant. The importance of a third vaccine dose is clear, owing to the higher neutralization efficiency (by a factor of 100) against the omicron variant after the third dose than after the second dose; however, even with three vaccine doses, neutralization against the omicron variant was lower (by a factor of 4) than that against the delta variant. The durability of the effect of the third dose of vaccine against Covid-19 is yet to be determined.
Fourteen amino acid substitutions, including N501Y and E484K, and 9 deletions are located in the spike protein. This genotype pattern led to create a new Pangolin lineage named B.1.640.2, which is a phylogenetic sister group to the old B.1.640 lineage renamed B.1.640.1. Both lineages differ by 25 nucleotide substitutions and 33 deletions. The mutation set and phylogenetic position of the genomes obtained here indicate based on our previous definition a new variant we named “IHU”. These data are another example of the unpredictability of the emergence of SARS-CoV-2 variants, and of their introduction in a given geographical area from abroad.
December 28, 2021
The B.1.1.529 (Omicron) variant of SARS-CoV-2 (the virus that causes COVID-19) was first detected in specimens collected on November 11, 2021, in Botswana and on November 14 in South Africa; the first confirmed case of Omicron in the United States was identified in California on December 1, 2021 (1). On November 29, the Nebraska Department of Health and Human Services was notified of six probable cases of COVID-19 in one household, including one case in a man aged 48 years (the index patient) who had recently returned from Nigeria.
December 23, 2021
Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.
Omicron was totally or partially resistant to neutralization by all mAbs tested. Sera from Pfizer or AstraZeneca vaccine recipients, sampled 5 months after complete vaccination, barely inhibited Omicron. Sera from COVID-19 convalescent patients collected 6 or 12 months post symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titers 6 to 23 fold lower against Omicron than against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and to a large extent vaccine-elicited antibodies. Omicron remains however neutralized by antibodies generated by a booster vaccine dose.
Here we used unbiased abundance proteomics, phosphoproteomics, RNAseq and viral replication assays to show that isolates of the Alpha (B.1.1.7) variant more effectively suppress innate immune responses in airway epithelial cells, compared to first wave isolates. We found that Alpha has dramatically increased subgenomic RNA and protein levels of N, Orf9b and Orf6, all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein required for RNA sensing adaptor MAVS activation. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful Alpha transmission, and may increase in vivo replication and duration of infection. The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.
By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, we noted that the activity of 17 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients. In addition, we also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.
In total, over 85% of the tested NAbs are escaped by Omicron. Regarding NAb drugs, the neutralization potency of LY-CoV016/LY-CoV555, REGN10933/REGN10987, AZD1061/AZD8895, and BRII-196 were greatly reduced by Omicron, while VIR-7831 and DXP-604 still function at reduced efficacy. Together, data suggest Omicron would cause significant humoral immune evasion, while NAbs targeting the sarbecovirus conserved region remain most effective. Our results offer instructions for developing NAb drugs and vaccines against Omicron and future variants.
Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein required for RNA sensing adaptor MAVS activation. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful Alpha transmission, and may increase in vivo replication and duration of infection4. The importance of mutations outside Spike in adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the Delta and Omicron N/Orf9b regulatory regions.
The B.1.2 viruses, dominant in humans in Ohio at the time, infected deer in four locations. Probable deer-to-deer transmission of B.1.2, B.1.582, and B.1.596 viruses was observed, allowing the virus to acquire amino acid substitutions in the spike protein (including the receptor-binding domain) and ORF1 that are infrequently seen in humans. No spillback to humans was observed, but these findings demonstrate that SARS-CoV-2 viruses have the capacity to transmit in US wildlife, potentially opening new pathways for evolution. There is an urgent need to establish comprehensive “One Health” programs to monitor deer, the environment, and other wildlife hosts globally.
Omicron was totally or partially resistant to neutralization by all mAbs tested. Sera from Pfizer or AstraZeneca vaccine recipients, sampled 5 months after complete vaccination, barely inhibited Omicron. Sera from COVID-19 convalescent patients collected 6 or 12 months post symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titers 6 to 23 fold lower against Omicron than against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and to a large extent vaccine-elicited antibodies. Omicron remains however neutralized by antibodies generated by a booster vaccine dose.
Neutralization of ancestral virus was much higher in infected and vaccinated versus vaccinated only participants but both groups showed a 22-fold escape from vaccine elicited neutralization by the Omicron variant. However, in the previously infected and vaccinated group, the level of residual neutralization of Omicron was similar to the level of neutralization of ancestral virus observed in the vaccination only group. These data support the notion that, provided high neutralization capacity is elicited by vaccination/boosting approaches, reasonable effectiveness against Omicron may be maintained.
A total of 843,208 participants met the eligibility criteria, of whom 758,118 (90%) received the booster during the 54-day study period. Death due to Covid-19 occurred in 65 participants in the booster group (0.16 per 100,000 persons per day) and in 137 participants in the nonbooster group (2.98 per 100,000 persons per day). The adjusted hazard ratio for death due to Covid-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% confidence interval, 0.07 to 0.14; P<0.001).
Across the age groups studied, rates of confirmed Covid-19 and severe illness were substantially lower among participants who received a booster dose of the BNT162b2 vaccine than among those who did not.
Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured the neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild-type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that received their primary series recently (<3 months), distantly (6–12 months), or an additional “booster” dose, while accounting for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinees. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron, only 4–6-fold lower than wild type, suggesting enhanced cross-reactivity of neutralizing antibody responses. In addition, we find that Omicron pseudovirus infects more efficiently than other variants tested. Overall, this study highlights the importance of additional mRNA doses to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.
December 22, 2021
In our cohort of PLWHIV with well-controlled ART, stable viral suppression and robust CD4+ T cell count, inoculation with mRNA-1273 vaccine given 4 weeks apart produced detectable humoral immune response, similar to individuals without HIV infection, supporting vaccination in PLWHIV.
Memory B cells (MBCs) represent a second layer of immune protection against SARS-CoV-2. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant is of major concern. We used bio-layer interferometry to assess the affinity against the receptor-binding-domain (RBD) of Omicron spike of 313 naturally expressed monoclonal IgG that were previously tested for affinity and neutralization against VOC prior to Omicron. We report here that Omicron evades recognition from a larger fraction of these antibodies than any of the previous VOCs. Additionally, whereas 30% of these antibodies retained high affinity against Omicron-RBD, our analysis suggest that Omicron specifically evades antibodies displaying potent neutralizing activity against the D614G and Beta variant viruses. Further studies are warranted to understand the consequences of a lower memory B cell potency on the overall protection associated with current vaccines.
Our study provides evidence of protection against infection with the Omicron variant after completion of a primary vaccination series with the BNT162b2 or mRNA-1273 vaccines; in particular, we found a VE against the Omicron variant of 55.2% (95% confidence interval (CI): 23.5 to 73.7%) and 36.7% (95% CI: 69.9 to 76.4%) for the BNT162b2 and mRNA-1273 vaccines, respectively, in the first month after primary vaccination. However, the VE is significantly lower than that against Delta infection and declines rapidly over just a few months. The VE is re-established upon revaccination with the BNT162b2 vaccine (54.6%, 95% CI: 30.4 to 70.4%).
Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo
December 21, 2021
Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.
A domain with three sitting female passengers was defined. Dynamics of droplets released from the mouth of the different passengers during the vocalization of vowel /ɑ/ were investigated in detail. For the conditions evaluated, the droplets were initially driven by the exhaled jet and buoyancy and mainly occupied the back region of a hypothetical front row. This effect was more noticeable when droplets were released from positions closer to the ventilation system such as window and middle seat positions. The droplets from the passenger located farthest from the ventilation inlet, such as the one in the aisle, were more affected by the flow from the beginning of the exhalation, and many of the droplets were initially moved to the bottom of the domain. The droplets then encountered primary and secondary flows, which were responsible for the longitudinal and transverse migration. The combination of both these effects made local particle concentrations lower near the mouth or nose regions of other occupants, at the expense of contaminating other rows. Between 19.5% and 27.4% of drops were removed through the outlet during the first 40 s and none of the droplets hit the mouth of the passengers. During their trajectory, the distance of drops to the mouth of the passengers was evaluated, showing that the majority of them passed at a relatively safe distance. However, a few of them passed at a close distance of the order of magnitude of 1 cm.
The marked magnitude and global scale of immunisation disruption evokes the dangers of vaccine-preventable disease outbreaks in the future. Trends indicating partial resumption of services highlight the urgent need for ongoing assessment of recovery, catch-up vaccination strategy implementation for vulnerable populations, and ensuring vaccine coverage equity and health system resilience.
Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting.
December 20, 2021
We found waning vaccine protection of ChAdOx1 nCoV-19 against COVID-19 hospital admissions and deaths in both Scotland and Brazil, this becoming evident within three months of the second vaccine dose. Consideration needs to be given to providing booster vaccine doses for people who have received ChAdOx1 nCoV-19.
December 17, 2021
During fall 2021, 90 Lake County, Illinois, schools implemented Test to Stay (TTS), permitting eligible close contacts with masked COVID-19 exposures to remain in school. Secondary transmission among TTS participants was 1.5%; no tertiary transmission was observed among school-based contacts; however, tertiary cases were identified among household contacts. Implementation of TTS preserved up to 8,152 in-person learning days. Although vaccination remains the leading recommendation to protect against COVID-19, TTS allows close contacts to remain in the classroom as an alternative to home quarantine.
One in five LAC public schools adopted TTS. In TTS schools, student case rates did not increase, and tertiary transmission was not identified. A higher percentage of disadvantaged schools did not implement TTS. TTS does not appear to increase transmission risk in public schools and might greatly reduce loss of in-person school days. Implementation requires resources that might be currently unavailable for some schools. Vaccination remains the leading recommendation to protect against COVID-19; TTS allows students with a school exposure to remain in the classroom as an alternative to home quarantine.
Adults who reported a provider COVID-19 vaccination recommendation were more likely to have been vaccinated, to be concerned about COVID-19, to have confidence that COVID-19 vaccines are important and safe, and to perceive that family and friends had been vaccinated. A health care provider recommendation for COVID-19 vaccines at every visit could increase coverage and confidence in vaccines, particularly among groups with lower COVID-19 vaccination coverage, including younger adults, racial/ethnic minorities, and rural residents.
December 16, 2021
We find strong evidence of immune evasion, both from natural infection, where the risk of reinfection
is 5.41 (95% CI: 4.87-6.00) fold higher for Omicron than for Delta, and from vaccine-induced
protection. Our VE estimates largely agree with those from UKHSA’s TNCC study (11) and predictions
from predicting VE from neutralising antibody titres (4,14), suggesting very limited remaining
protection against symptomatic infection afforded by two doses of AZ, low protection afforded by two doses of Pfizer, but moderate to high (55-80%) protection in people boosted with an mRNA vaccine.
We find no evidence (for both risk of hospitalisation attendance and symptom status) of Omicron
having different severity from Delta, though data on hospitalisations are still very limited.
Our analysis reinforces the still emerging but increasingly clear picture that Omicron poses an
immediate and substantial threat to public health in England and more widely.
Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.
The Covid-19 pandemic has resulted in substantial global morbidity and mortality as well as disruption of the economies of virtually every country. Some of this tragedy could have been averted with the development of deliverable, orally bioavailable, direct-acting antiviral therapeutics. Molnupiravir, the orally bioavailable prodrug of N4-hydroxycytidine (NHC), begins to address this need.
Researchers are racing to detect Omicron, the latest SARS-CoV-2 variant of concern, by sequencing the genomes of coronaviruses infecting people. But surveillance through genomic sequencing can be slow and patchy, complicating the picture of how and where Omicron spreads.
We developed a mathematical model to predict symptom order of symptomatic COVID-19 cases from patient characteristics data in the USA and China. Surprisingly, our model predicted that cough occurs first in the USA, while fever occurs first in China.
Understanding the burden of coronavirus disease (COVID-19) among children is essential for evidence-based decision-making regarding the vaccination of children and for assessing the importance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mitigation measures in specific settings, such as schools. Here, we report on the burden and severity of symptomatic notified COVID-19 cases among children in the European Union (EU)
December 15, 2021
A study led by researchers from the LKS Faculty of Medicine at The University of Hong Kong (HKUMed) provides the first information on how the novel Variant of Concern (VOC) of SARS-CoV-2, the Omicron SARS-CoV-2 infect human respiratory tract. The researchers found that Omicron SARS-CoV-2 infects and multiplies 70 times faster than the Delta variant and original SARS-CoV-2 in human bronchus, which may explain why Omicron may transmit faster between humans than previous variants. Their study also showed that the Omicron infection in the lung is significantly lower than the original SARS-CoV-2, which may be an indicator of lower disease severity. This research is currently under peer review for publication.
The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in a pseudovirus assay in two different laboratories. Omicron was 49-84-fold less sensitive to neutralization than D614G and 5.3-6.2-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 µg mRNA-1273. A 50 µg boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.
In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) showed susceptibility to diverse animal species. We conducted this study to understand the spatial epidemiology, genetic diversity, and statistically significant genetic similarity along with per-gene recombination events of SARS-CoV-2 and related viruses (SC2r-CoVs) in animals globally.
The past 20 years have witnessed four fatal coronavirus outbreaks: SARS (severe acute respiratory syndrome, 2002 and 2003), MERS (Middle East respiratory syndrome, since 2012), and now Covid-19 (since 2019). Scientific evidence and ecologic reality suggest that coronaviruses will emerge again in the future, potentially posing an existential threat.
December 14, 2021
Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals
Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant
(BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of vaccine-induced
neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we
measured neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40
Ad26.COV2.S vaccine recipients against wild type, Delta, and Omicron SARS-CoV-2
pseudoviruses. We included individuals that were vaccinated recently (<3 months), distantly (6-
12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection. Remarkably,
neutralization of Omicron was undetectable in most vaccinated individuals. However, individuals
boosted with mRNA vaccines exhibited potent neutralization of Omicron only 4-6-fold lower than
wild type, suggesting that boosters enhance the cross-reactivity of neutralizing antibody
responses. In addition, we find Omicron pseudovirus is more infectious than any other variant
tested. Overall, this study highlights the importance of boosters to broaden neutralizing antibody
responses against highly divergent SARS-CoV-2 variants.
We found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine over the 1–28 days postvaccination period, and after a SARS-CoV-2 positive test. We estimated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test. We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associations were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose of mRNA-1273.
Discovery Health, South Africa’s largest private health insurance administrator, releases at-scale, real-world analysis of Omicron outbreak based on 211 000 COVID-19 test results in South Africa, including collaboration with the South Africa
The Omicron variant of SARS-CoV-2 was first identified in Southern Africa during November 2021. It was brought to the world’s attention by scientists in South Africa and Botswana and declared a Variant of Concern by the World Health Organization shortly thereafter. South Africa experienced rapid community spread (concentrated in the Gauteng), dominated by the Omicron variant, fuelling South Africa’s fourth wave of COVID-19.
There’s been great concern about the new Omicron variant of SARS-CoV-2, the coronavirus that causes COVID-19. A major reason is Omicron has accumulated over 50 mutations, including about 30 in the spike protein, the part of the coronavirus that mRNA vaccines teach our immune systems to attack. All of these genetic changes raise the possibility that Omicron could cause breakthrough infections in people who’ve already received a Pfizer or Moderna mRNA vaccine.
December 13, 2021
COVID-19 certification led to increased vaccinations 20 days before implementation in anticipation, with a lasting effect up to 40 days after. Countries with pre-intervention uptake that was below average had a more pronounced increase in daily vaccinations compared with those where uptake was already average or higher. In France, doses exceeded 55 672 (95% CI 49 668–73 707) vaccines per million population or, in absolute terms, 3 761 440 (3 355 761–4 979 952) doses before mandatory certification and 72 151 (37 940–114 140) per million population after certification (4 874 857 [2 563 396–7 711 769] doses). We found no effect in countries that already had average uptake (Germany), or an unclear effect when certificates were introduced during a period of limited vaccine supply (Denmark). Increase in uptake was highest for people younger than 30 years after the introduction of certification. Access restrictions linked to certain settings (nightclubs and events with >1000 people) were associated with increased uptake in those younger than 20 years. When certification was extended to broader settings, uptake remained high in the youngest group, but increases were also observed in those aged 30–49 years.
As health-care professionals and researchers worldwide continue to warn of the complications of COVID-19 on cancer, a new US-based study has now further highlighted the link between the pandemic and worsening cancer care. The time-frame study published on Dec 6, 2021, included the pre-pandemic phase and the primary surge of COVID-19 infections.
December 11, 2021
We were encouraged by the results of the PRINCIPLE trial, which in vulnerable individuals showed inhaled budesonide to confer a non-significant –25% (95% CI –45 to 3) relative reduction in the composite coprimary endpoint of hospital admission or death, with the number needed to treat being 50. Notably, the study had 90% power to detect a 50% reduction in the composite endpoint. The investigators appear to have attributed any protective effects of budesonide to its local glucocorticoid activity in the lung.
It is important to understand the illness severity of the study population, such as how many participants were symptomatic versus asymptomatic at enrolment, how many were compliant with treatment versus non-adherent, and if there were any outcome differences among them. We are curious if time from enrolment to treatment initiation differed among participants. The Article's Table 1 includes 833 participants from the inhaled budesonide group and 1126 participants from the usual care group, respectively, which does not coincide with the 787 and 1069 included for primary analysis.
December 10, 2021
Comparative Effectiveness and Antibody Responses to Moderna and Pfizer-BioNTech COVID-19 Vaccines among Hospitalized Veterans — Five Veterans Affairs Medical Centers, United States, February 1–September 30, 2021
These findings from a cohort of older, hospitalized veterans with high prevalences of underlying conditions suggest the importance of booster doses to help maintain long-term protection against severe COVID-19.
The CBTS program demonstrated the value of successful partnerships and collaboration for providing testing services that are responsive to local community needs. These lessons can guide current community-based screening, surveillance, and disease control programs and responses to future public health emergencies.
During December 1–8, 2021, 22 U.S. states reported at least one COVID-19 case attributed to the Omicron variant. Among 43 cases with initial follow-up, one hospitalization and no deaths were reported. Implementation of concurrent prevention strategies, including vaccination, masking, improving ventilation, testing, quarantine, and isolation are recommended to slow transmission of SARS-CoV-2, including variants such as Omicron, to protect against severe illness and death from COVID-19.
During August 13–November 19, 2021, 18.7 million persons aged ≥65 years received a booster or additional primary dose of COVID-19 vaccine, constituting 44.1% of eligible persons aged ≥65 years. Coverage differed by primary series vaccine product and race/ethnicity. Strategic efforts are needed to encourage eligible persons aged ≥18 years, especially those aged ≥65 years and those who are immunocompromised, to receive a booster and/or additional primary dose to ensure maximal protection against COVID-19.
Our findings indicate that 2 doses of vaccination with BNT162b2 or ChAdOx1 are insufficient to give adequate levels of protection against infection and mild disease with the Omicron variant, although we cannot comment on protection against severe disease. Booster doses of BNT162b2 provide a significant increase in protection against mild disease and are likely to offer even greater levels of protection against severe disease. As such our findings support maximising coverage with third doses of vaccine in highly vaccinated populations such as the UK. Further follow-up will be needed to assess the duration of protection of booster vaccination.
December 9, 2021
In this audio interview conducted on December 7, 2021, the editors discuss new studies of the duration of immunity conferred by Covid-19 vaccines.
On Nov 24, South Africa alerted the world to the latest SARS-CoV-2 variant, omicron (B.1.1.529). The omicron variant distinguishes itself from previous variants by harbouring in its genomic sequence 49 mutations (30 of which occur within the spike protein)—a jump from the 13 mutations found within the delta variant (B.1.617.2). More mutations does not intrinsically mean that a variant is more dangerous, but almost immediately omicron generated concern within the global health community regarding its transmissibility and ability to evade both vaccine-induced and natural immunity. The report of the new variant has caused national governments to react with the reintroduction of non-pharmaceutical measures and ramped up vaccine booster programmes in the hope of delaying the spread of omicron. Controversially, however, for some governments the immediate response was to issue travel bans against South Africa. The UK was the first to adopt such a proposal, and was swiftly followed by the USA, Israel, and others.
December 8, 2021
Since SARS-CoV-2 Omicron was resistant to casirivimab and imdevimab genotyping of SARS-CoV-2 may be needed before initiating mAb treatment. Variant-specific vaccines and mAb agents may be required to treat Omicron and other emerging variants of concern.
But the preliminary results — released overnight by teams in South Africa, Germany, and Sweden, as well as the Pfizer-BioNtech collaboration — hint that protection conferred by existing COVID-19 vaccines won’t be totally wiped out, and that boosters should improve immunity to Omicron.
Participants who received a booster at least 5 months after a second dose of BNT162b2 had 90% lower mortality due to Covid-19 than participants who did not receive a booster.
Across the age groups studied, rates of confirmed Covid-19 and severe illness were substantially lower among participants who received a booster dose of the BNT162b2 vaccine than among those who did not.
More than 10.7 million undocumented immigrants and 8 million citizens with at least 1 undocumented family member live in the US. Evidence shows that immigrants are at increased risk for COVID-19 infection and have high levels of distrust in public systems. Contact tracing is an effective way to mitigate disease transmission but requires trust and cooperation among infected persons and their contacts. Using the Centers for Disease Control and Prevention sample contact tracing script as a framework, we describe undocumented immigrants’ attitudes about contact tracing and challenges that may be a factor in their ability to follow contact tracing and public health guidelines.
These findings suggest that health systems learned to adapt and were able to self-regulate, maintaining surgical procedure volume during the largest peak in volume of patients with COVID-19.
December 7, 2021
Omicron, a fast-spreading SARS-CoV-2 variant of concern reported to the World Health Organization on November 24, 2021, has raised international alarm. We estimated there is at least 50% chance that Omicron had been introduced by travelers from South Africa into all of the 30 countries studied by November 27, 2021.
A Randomized Clinical Trial
Among patients with severe COVID-19, treatment with high-flow oxygen therapy compared with conventional oxygen therapy reduced the likelihood of invasive mechanical ventilation and decreased time to clinical recovery.
December 6, 2021
On the backdrop of ongoing Delta variant infection and vaccine-induced immunity, the emergence of the new Variant of Concern, the Omicron, has again fuelled the fears of COVID-19 around the world. Currently, very little information is available about the S glycoprotein mutations, transmissibility, severity, and immune evasion behaviour of the Omicron variant. In the present study, we have performed a comprehensive analysis of the S glycoprotein mutations of 309 strains of the Omicron variant and also discussed the probable effects of observed mutations on several aspects of virus biology based on known available knowledge of mutational effects on S glycoprotein structure, function, and immune evasion characteristics.
On December 1, JAMA convened a panel of experts to discuss what’s known—and unknown—about Omicron, the newest SARS-CoV-2 variant of concern.
In September 2021, one-fourth of the COVID-19 cases in the US were among children. Vaccinating children against COVID-19 is the most effective way to reduce disease burden and ensure safe return to in-person schooling and other social activities. National surveys show hesitancy among parents to vaccinate children, even when they are vaccinated themselves. We measured parental intention to vaccinate children and related sociodemographic factors in a national sample of US parents.
December 5, 2021
Previous studies have reported that a third dose of the BNT162b2 (Pfizer) COVID-19 vaccine increased antibody titers and protective efficacy. Here we compare humoral and cellular immune responses in 65 individuals who were vaccinated with the BNT162b2 vaccine and were boosted after at least 6 months with either Ad26.COV2.S (Johnson & Johnson; N=41) or BNT162b2 (Pfizer; N=24).
December 3, 2021
COVID-19 outbreaks have been reported in homeless shelters across the United States. Many persons experiencing homelessness are older adults or persons with underlying medical conditions, placing them at increased risk for severe COVID-19–associated illness. The proportion of persons experiencing homelessness who are fully vaccinated against COVID-19 in the United States is currently unknown. Many persons experiencing homelessness express a willingness to receive the COVID-19 vaccine.
Standard dosing intervals for BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines are 21 and 28 days, respectively.1 Data suggest improved effectiveness of ChAdOx1 adenoviral2 and other nonreplicating vaccines3 with increased dosing intervals, but little data exist for mRNA vaccines. This study investigated the immunogenicity of extended mRNA vaccine dosing intervals.
Late last year, UK health authorities announced that the second dose of authorized COVID-19 vaccines would be administered up to 12 weeks instead of 3 to 4 weeks after the first dose. The change was intended to free up initial doses for more people, but it also created an opportunity to investigate a vaccine schedule that hadn’t been tested in clinical trials.
December 2, 2021
Population-level evidence suggests that the Omicron variant is associated with substantial ability to evade immunity from prior infection. In contrast, there is no population-wide epidemiological evidence of immune escape associated with the Beta or Delta variants. This finding has important implications for public health planning, particularly in countries like South Africa with high rates of immunity from prior infection. Urgent questions remain regarding whether Omicron is also able to evade vaccine-induced immunity and the potential implications of reduced immunity to infection on protection against severe disease and death.
On 26 November 2021, the World Health Organization designated the SARS-CoV-2 variant B.1.1.529, Omicron, a variant of concern. However, the phylogenetic and evolutionary dynamics of this variant remain unclear. An analysis of the 131 Omicron variant sequences from November 9 to November 28, 2021 reveals that variants have diverged into at least 6 major subgroups. 86.3% of the cases have an insertion at amino acid 214 (INS214EPE) of the spike protein.
Mandates can increase vaccine uptake, but their effectiveness is associated with who is covered, penalties, and exemptions. The US federal government recently required federal employees to be vaccinated against SARS-CoV-2 and developed standards for large employers. However, individual states traditionally take the lead in regulating public health via vaccine mandates. Some states have attempted to introduce requirements to increase uptake of COVID-19 vaccines. However, others have attempted to impede COVID-19 vaccine mandates. Most efforts have been considered by legislatures; also, some governors and regulatory agencies have issued executive orders. We assessed state-level legal interventions to promote or impede COVID-19 vaccine mandates since the beginning of the pandemic.
December 1, 2021
The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance.
The effectiveness of the three vaccines against Covid-19 declined after the delta variant became predominant. The effectiveness against hospitalization remained high, with modest declines limited to BNT162b2 and mRNA-1273 recipients 65 years of age or older.
Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown.
SARS-CoV-2 reinfections were rare in older residents and younger staff. Protection from SARS-CoV-2 was sustained for longer than 9 months, including against the alpha variant. Reinfection was associated with no or low neutralising antibody before reinfection, but significant boosting occurred on reinfection.
In this cross-sectional study of 12 610 HCP at a major US academic hospital, two-thirds received a first dose within the first 4 months; 98% of those received 2 doses. Adjusted for age, sex, job position, and area-level social vulnerability, Black or African American and multiracial HCP were less likely to receive the vaccine compared with White HCP, with narrower disparities observed for nurses and no disparities found among physicians.
In this survey study of 2080 adults, most respondents were willing to use video visits in the future but, when presented with the choice between an in-person or a video visit for nonemergency care, most preferred in-person care. Willingness to pay for preferred visit modality was higher for those who preferred in-person care, and those who preferred video visits were more sensitive to out-of-pocket cost.
Over the past 20 months of the COVID-19 pandemic, a great deal has been crystallised about the ideal therapeutic targets for infected patients. For very sick patients who require hospitalisation, we now know that targeting the dysregulated host response is of greater value than targeting the virus. Through steroids, interleukin(IL)-6 blockade, IL-1 blockade, tyrosine kinase inhibition, or Janus kinase inhibition, we have a breadth of clinical trials that show the possible mortality benefits of both broad and focused immunomodulation in severely ill patients with COVID-19. As the pandemic continues, there is a need to understand whether combinations or different agents that target alternative pathways would continue to improve clinical outcomes, or whether there are ways of identifying specific patients with a higher likelihood of benefit from specific therapies.
In many countries, the availability of vaccines has marked a turning point in the Covid-19 pandemic. Although the vaccines are imperfect, breakthrough infections in fully vaccinated people remain quite rare, even with recently emerging variants. Countries with high vaccination rates have largely been able to reopen, and rates of severe illness and death have dropped dramatically. But this has not been a smooth process.
Two opposing forces that are shaping the coronavirus disease 2019 (Covid-19) pandemic are the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern and the uptake of vaccines. Measurement of SARS-CoV-2 viral load over the course of acute infection can inform hypotheses about the mechanisms that underlie variation in transmissibility according to variant and vaccination status.
In patients with moderate-to-severe COVID-19 pneumonia, an aberrant post-viral alveolitis with excessive inflammatory responses and immunothrombosis underpins use of immunomodulatory therapy (eg, corticosteroids and interleukin-6 receptor antagonism). By contrast, immunosuppression in individuals with mild COVID-19 who do not require oxygen therapy or in those with critical disease undergoing prolonged ventilation is of no proven benefit.
The SEIR model provides a robust method to estimate the total number of infected individuals in a sewershed on the basis of the mass rate of RNA copies released per day. This approach overcomes some of the limitations associated with individual testing campaigns and thereby provides an additional tool that can be used to inform policy decisions.
November 30, 2021
In this case-control study that included 306 710 Israeli adults 40 years and older, there was an estimated significant reduction in the odds of SARS-CoV-2 infection within a few weeks of receiving the booster compared with receiving just the 2 primary doses. Those receiving the booster also had lower odds of hospitalization.
November 29, 2021
In this randomized clinical trial of 487 patients with COVID-19 pneumonia and a partial pressure of arterial oxygen–to–fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg at enrollment, the rate of the primary clinical end point (need for mechanical ventilation, defined as Pao2/Fio2 ratio <150 mm Hg, or death) was not significantly different between the convalescent plasma group and the control group.
November 26, 2021
Analyses of patients have revealed marked dysregulation of the immune system in severe cases of human coronavirus infection, and there is ample evidence that aberrant immune responses to human coronaviruses are typified by impaired induction of interferons, exuberant inflammatory responses and delayed adaptive immune responses. In addition, various viral proteins have been shown to impair interferon induction and signalling and to induce inflammasome activation. This suggests that severe disease associated with human coronaviruses is mediated by both dysregulated host immune responses and active viral interference. Here we discuss our current understanding of the mechanisms involved in each of these scenarios.
Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2–transmission risk, provided a comprehensive preventive intervention was implemented.
November 25, 2021
Effectiveness of ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection during the delta (B.1.617.2) variant surge in India: a test-negative, case-control study and a mechanistic study of post-vaccination immune responses
The ChAdOx1 nCoV-19 vaccine remained effective against moderate-to-severe COVID-19, even during a surge that was dominated by the highly transmissible delta variant of SARS-CoV-2. Spike-specific T-cell responses were maintained against the delta variant. Such cellular immune protection might compensate for waning humoral immunity.
The quest for effective drugs to treat COVID-19 has been a priority since the outbreak of the disease. The clinical application of remdesivir has been greatly restricted by the need for intravenous administration, as well as unstable concentrations in plasma and variable antiviral activity in different organelles.
November 24, 2021
Qatar had a first wave of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from March through June 2020, after which approximately 40% of the population had detectable antibodies against SARS-CoV-2.
In this case series study, our findings were similar to those of the study by Alejo et al,5 in which a fourth dose of SARS-CoV-2 vaccine was associated with slightly improved humoral response among patients with a weak response after 3 doses and with no improvement among those with no response after 3 doses. Neutralizing antibody titers and cellular response were low in both groups.
Moral injury can result from chronic stressors in morally injurious environments; leadership must identify and address these stressors to effectively support health care professionals as COVID-19 continues to strain staff’s physical, mental, and emotional resources.
he pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is incompletely understood, with its effects on multiple organ systems and the syndrome of “long Covid” occurring long after the resolution of infection. The development of multiple efficacious vaccines has been critical in the control of the pandemic, but their efficacy has been limited by the appearance of viral variants, and the vaccines can be associated with rare off-target or toxic effects, including allergic reactions, myocarditis, and immune-mediated thrombosis and thrombocytopenia in some healthy adults. Many of these phenomena are likely to be immune-mediated.
November 19, 2021
Among 1,249,634 delivery hospitalizations during March 2020–September 2021, U.S. women with COVID-19 were at increased risk for stillbirth compared with women without COVID-19 (adjusted relative risk [aRR] = 1.90; 95% CI = 1.69–2.15). The magnitude of association was higher during the period of SARS-CoV-2 B.1.617.2 (Delta) variant predominance than during the pre-Delta period. Implementing evidence-based COVID-19 prevention strategies, including vaccination before or during pregnancy, is critical to reduce the impact of COVID-19 on stillbirths.
Pregnant and recently pregnant women are at increased risk for severe illness and death from COVID-19 compared with women who are not pregnant or were not recently pregnant. CDC recommends COVID-19 vaccination for women who are pregnant, recently pregnant, trying to become pregnant, or might become pregnant in the future.
Incidence of SARS-CoV-2 Infection, Emergency Department Visits, and Hospitalizations Because of COVID-19 Among Persons Aged ≥12 Years, by COVID-19 Vaccination Status — Oregon and Washington, July 4–September 25, 2021
Among persons aged ≥12 years enrolled in a Pacific Northwest health plan, unvaccinated persons with SARS-CoV-2 infection were approximately twice as likely to receive ED care or to be hospitalized than were vaccinated persons with COVID-19. The findings in this report support CDC’s current recommendation that all persons aged ≥5 years should receive full COVID-19 vaccination, including additional and booster doses, to prevent illness and reduce transmission of SARS-CoV-2.
Among adults with diabetes, those aged 18–29 years reported the most disruption in access to and use of medical care and the least engagement in prevention of COVID-19, including vaccination intent. Efforts are warranted to enhance access to diabetes care during the COVID-19 pandemic, and to deliver public health messages emphasizing the importance of diabetes management and COVID-19 prevention, including vaccination, especially among younger adults with diabetes.
Overall, 56% of patients with a positive SARS-CoV-2 test result were notified by telephone call or digital notification within 24 hours of report in January 2021, compared with 15% during November 23–December 23, 2020. Differences in text notification by age, race, and ethnicity were observed. Automated digital notification can provide a more timely means for reaching persons with COVID-19 and can likely facilitate more rapid patient isolation and increase efficiency of case investigation.
The conditions of hospital strain during July 2020–July 2021, which included the presence of SARS-CoV-2 B.1.617.2 (Delta) variant, predicted that intensive care unit bed use at 75% capacity is associated with an estimated additional 12,000 excess deaths 2 weeks later. As hospitals exceed 100% ICU bed capacity, 80,000 excess deaths would be expected 2 weeks later.
November 18, 2021
The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression.
The overall risk for severe COVID-19 among WRA remains low; however, symptomatic pregnant WRA remain at increased risk for severe outcomes compared with symptomatic nonpregnant WRA during Delta variant predominance. Compared with the pre-Delta period, pregnant and nonpregnant WRA are at increased risk for severe COVID-19 in the Delta period.
SARS-CoV-2 variants of concern exhibit varying degrees of transmissibility and, in some cases, escape from acquired immunity. Much effort has been devoted to measuring these phenotypes, but understanding their impact on the course of the pandemic – especially that of immune escape – has remained a challenge. Here, we use a mathematical model to simulate the dynamics of wildtype and variant strains of SARS-CoV-2 in the context of vaccine rollout and nonpharmaceutical interventions. We show that variants with enhanced transmissibility frequently increase epidemic severity, whereas those with partial immune escape either fail to spread widely, or primarily cause reinfections and breakthrough infections. However, when these phenotypes are combined, a variant can continue spreading even as immunity builds up in the population, limiting the impact of vaccination and exacerbating the epidemic. These findings help explain the trajectories of past and present SARS-CoV-2 variants and may inform variant assessment and response in the future.
The struggle to control the COVID-19 pandemic is made challenging by the emergence of virulent SARS-CoV-2 variants. To gain insight into their replication dynamics, emergent Alpha (A), Beta (B) and Delta (D) SARS-CoV-2 variants were assessed for their infection performance in single variant- and co-infections. The effectiveness of thapsigargin (TG), a recently discovered broad-spectrum antiviral, against these variants was also examined. Of the 3 viruses, the D variant exhibited the highest replication rate and was most able to spread to in-contact cells; its replication rate at 24 h post-infection (hpi) based on progeny viral RNA production was over 4 times that of variant A and 9 times more than the B variant. In co-infections, the D variant boosted the replication of its co-infected partners at the expense of its own initial performance. Furthermore, co-infection with AD or AB combination conferred replication synergy where total progeny (RNA) output was greater than the sum of corresponding single-variant infections. All variants were highly sensitive to TG inhibition.
This systematic review and meta-analysis suggests that several personal protective and social measures, including handwashing, mask wearing, and physical distancing are associated with reductions in the incidence covid-19. Public health efforts to implement public health measures should consider community health and sociocultural needs, and future research is needed to better understand the effectiveness of public health measures in the context of covid-19 vaccination.
November 17, 2021
The analysis suggests that the relative protection of the booster shot against infection is likely to be significantly smaller than the initial estimates of 10-11-fold (over 90%) reported by the MOH, probably around 60% at best. This also implies that the absolute number of infected individuals in the Vaccinated group is likely to be at least as high as in the Unvaccinated, raising serious concerns that the new Green Pass is inefficient in preventing infection spread, and could expose high risk individuals to risk.
November 15, 2021
In a large, multicenter, retrospective cohort study of 83 584 patients with laboratory-confirmed COVID-19 who had an emergency department or urgent care visit or were admitted for observation or hospitalized across 87 health care centers in the US, Oskotsky et al observed an association between selective serotonin reuptake inhibitor (SSRI) administration and reduced mortality in 3401 patients with COVID-19 compared with 6802 matched control patients who were not given SSRIs but shared similar sociodemographic characteristics, medical comorbidities, and medication indication.
Altogether, our findings show increased risks of death and post-acute sequalae in people with breakthrough COVID-19; the risks are evident among those who were not hospitalized during the acute phase of the disease. Our comparative approach provides context for understanding the risks in relation to COVID-19 without prior vaccination and seasonal influenza. The findings will inform the ongoing effort to optimize strategies for prevention of breakthrough SARS-CoV-2 infections and will guide development and optimization of post-acute care pathways for people with breakthrough COVID-19.
In summary, these new data show that fetal exposure to SARS-CoV-2 acutely increases the frequencies of fetal NK cell and γδ T cell immune effector cells, and also accelerates the maturation and non-specific activation of multiple fetal immune cell populations. Although the effect of these changes on neonatal immunity might not be known for many years, fetal exposure to a maternal SARS-CoV-2 infection — even in the absence of a congenital infection — can imprint the fetal immune system.
November 12, 2021
On November 2, 2021, after a systematic review of available data, the Advisory Committee on Immunization Practices made an interim recommendation for use of the Pfizer-BioNTech COVID-19 vaccine in children aged 5–11 years in the United States for prevention of COVID-19. The Pfizer-BioNTech COVID-19 vaccine has high efficacy (>90%) against COVID-19 in children aged 5–11 years, and benefits outweigh risks for vaccination. Vaccination is important to protect children against COVID-19 and reduce community transmission of SARS-CoV-2.
November 5, 2021
On November 2, 2021, after a systematic review of available data, the Advisory Committee on Immunization Practices made an interim recommendation for use of the Pfizer-BioNTech COVID-19 vaccine in children aged 5–11 years in the United States for prevention of COVID-19. The Pfizer-BioNTech COVID-19 vaccine has high efficacy (>90%) against COVID-19 in children aged 5–11 years, and benefits outweigh risks for vaccination. Vaccination is important to protect children against COVID-19 and reduce community transmission of SARS-CoV-2.
November 2, 2021
Effectiveness of mRNA vaccination against laboratory-confirmed COVID-19–associated hospitalization was lower (77%) among immunocompromised adults than among immunocompetent adults (90%). Vaccine effectiveness varied considerably among immunocompromised patient subgroups. Immunocompromised persons benefit from COVID-19 mRNA vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive 3 doses and a booster, consistent with CDC recommendations, practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes.
October 29, 2021
Among COVID-19–like illness hospitalizations among adults aged ≥18 years whose previous infection or vaccination occurred 90–179 days earlier, the adjusted odds of laboratory-confirmed COVID-19 among unvaccinated adults with previous SARS-CoV-2 infection were 5.49-fold higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine who had no previous documented infection (95% confidence interval = 2.75–10.99). All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2.
The Advisory Committee on Immunization Practices issued recommendations for an additional primary mRNA COVID-19 vaccine dose for immunocompromised persons and a COVID-19 vaccine booster dose in eligible groups. Health care professionals play a critical role in COVID-19 vaccination efforts, including for primary, additional primary, and booster vaccination, particularly to protect patients who are at increased risk for severe illness and death.
Our study therefore supports saliva testing as an alternative diagnostic procedure to NPH testing, and that rapid antigen test on saliva provides a potential complement to PCR test to meet increasing screening demand.
Vaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory.
October 27, 2021
Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital.
Our results suggest that despite the prevalence of personal feelings of invincibility across cultures, the effects of perceived invincibility on prosocial beliefs and behaviors depend on the extent to which individuals maintain an interdependent self-construal and feel responsible for the wellbeing of their community members. In turn, health communications should encourage a collectivistic mindset so as to promote prosocial beliefs and behaviors, despite personal feelings of invincibility. In the context of COVID-19, this is especially important in less collectivistic or individualistic cultures such as the U.S., U.K., and France.
Our findings show that the risk of a large wave of COVID-19 hospital admissions resulting from lifting NPIs can be substantially mitigated if the timing of NPI relaxation is carefully balanced against vaccination coverage. However, with the delta variant, it might not be possible to fully lift NPIs without a third wave of hospital admissions and deaths, even if vaccination coverage is high. Variants of concern, their transmissibility, vaccine uptake, and vaccine effectiveness must be carefully monitored as countries relax pandemic control measures.
“It will save lives in that age group,” says Emma McBryde, an infectious-diseases modeller at the Australian Institute of Tropical Health and Medicine in Townsville. But it could also have a broader impact, given that many US children aged 5 to 11 have returned to school unvaccinated in the past few months, and the group now accounts for a significant portion of new COVID-19 cases, capable of transmitting the coronavirus SARS-CoV-2 to others. “For every child’s life you save, you may well save many, many more adult lives,” she says.
October 26, 2021
Damage to the lining of airways from severe SARS-CoV-2 infection allows Aspergillus fungi to invade the tissue, according to a recent consensus guidance from the European Confederation of Medical Mycology and the International Society for Human and Animal Mycology. These secondary fungal infections can worsen patient outcomes, and they’ve raised concern about emerging evidence of Aspergillus resistance to voriconazole and isavuconazole, the first-line therapies.
October 25, 2021
Our work provides the first in vivo evidence of SARS-CoV-2 infection in human adipose tissue and describes the associated inflammation.
The findings of this cross-sectional study suggest that social gatherings among unvaccinated students were associated with increased COVID-19 infections (in this scenario, slowing the previous downward trend and briefly increasing) in a university’s community beginning 8 days after the event, which corresponds with the 75th percentile of time to symptom onset. This study identifies an urgent gap in evidence on the risk of COVID-19 spread at social gatherings among university students, although the increase in transmission was brief. This increase in transmission may have been brief because of increases in the vaccination rate of university students during this time or because some students may have completed their semester before the end of the study period.
October 22, 2021
During December 2020–July 2021, COVID-19 vaccine recipients had lower rates of non–COVID-19 mortality than did unvaccinated persons after adjusting for age, sex, race and ethnicity, and study site. There is no increased risk for mortality among COVID-19 vaccine recipients. This finding reinforces the safety profile of currently approved COVID-19 vaccines in the United States. All persons aged ≥12 years should receive a COVID-19 vaccine.
Analysis of COVID-NET data from 14 states found no significant increases in the proportion of hospitalized COVID-19 patients with severe outcomes during the Delta period. The proportion of hospitalized unvaccinated COVID-19 patients aged 18–49 years significantly increased during the Delta period. Lower vaccination coverage in adults aged 18–49 years likely contributed to the increase in hospitalized patients during the Delta period. COVID-19 vaccination is critical for all eligible adults, including adults aged <50 years who have relatively low vaccination rates compared with older adults.
The association of COVID-19 with executive functioning raises key questions regarding patients’ long-term treatment. Future studies are needed to identify the risk factors and mechanisms underlying cognitive dysfunction as well as options for rehabilitation.
October 21, 2021
In this randomized trial that included 1000 patients with COVID-19 and severe hypoxemia, treatment with 12 mg/d of dexamethasone resulted in 22.0 days alive without life support at 28 days compared with 20.5 days in those receiving 6 mg/d of dexamethasone. This difference was not statistically significant. Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly reduce the number of days alive without life support at 28 days.
October 19, 2021
Infections during pregnancy contribute to high rates of maternal and fetal morbidity and mortality. However, the study of maternal-fetal immune responses to such infections remains underwhelming. The studies by Atyeo et al. and Bordt et al. on the immune responses to SARS-CoV-2 vaccination and infection demonstrate the critical nature of investigating maternal-fetal immune responses during pregnancy, a highly unique biological state. The findings of these studies have direct clinical implications for the COVID-19 pandemic and future maternal-fetal vaccination strategies, as they reveal that pregnant and lactating women have distinct immune responses to immunization and natural infection. Furthermore, these studies echo the call to action to incorporate women at different stages of gestation into clinical trials, thereby increasing their representation in the development of vaccines.
October 8, 2021
During March 4–July 21, 2021, sequencing data from 6,798 SARS-CoV-2–positive specimens were linked to electronic health records among Kaiser Permanente Southern California members. The weekly percentage of all infections attributed to the Delta variant rapidly increased to 95% during this period. Infection with the Delta variant was more common among younger persons and among non-Hispanic Black persons. These findings reinforce the importance of continued monitoring of SARS-CoV-2 variants and implementing multicomponent COVID-19 prevention strategies, particularly during the current period in which Delta is the predominant circulating variant in the United States.
October 7, 2021
Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy.
Covid-19 vaccines in the United States were highly effective against SARS-CoV-2 infection requiring hospitalization, ICU admission, or an emergency department or urgent care clinic visit. This vaccine effectiveness extended to populations that are disproportionately affected by SARS-CoV-2 infection.
Among high-risk ambulatory patients, bamlanivimab plus etesevimab led to a lower incidence of Covid-19–related hospitalization and death than did placebo and accelerated the decline in the SARS-CoV-2 viral load.
We report overall and US state-specific findings, disaggregated by race/ethnicity, for COVID-19-associated orphanhood and death of grandparent caregivers. High rates of orphanhood, marked disparities, and state-specific differences show the overlooked burden among children at greatest risk, in states most affected.
October 6, 2021
Among patients in a large Israeli health care system who had received at least one dose of the BNT162b2 mRNA vaccine, the estimated incidence of myocarditis was 2.13 cases per 100,000 persons; the highest incidence was among male patients between the ages of 16 and 29 years. Most cases of myocarditis were mild or moderate in severity.
The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.
Six months after receipt of the second dose of the BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.
BNT162b2-induced protection against SARS-COV-2 infection appeared to wane rapidly following its peak after the second dose, but protection against hospitalization and death persisted at a robust level for 6 months after the second dose.
Research at a hospital swamped by people with COVID-19 has confirmed that portable air filters effectively remove SARS-CoV-2 particles from the air — the first such evidence in a real-world setting. The results suggest that air filters could be used to reduce the risk of patients and medical staff contracting SARS-CoV-2 in hospitals, the study’s authors say.
Given the association between disability and mortality involving COVID-19, verification of these findings and consideration of recommendations for protective measures are now required.
In this case-control study including 6 647 733 veterans, 23% of veterans received at least 1 COVID-19 vaccination during the first 3 months of vaccine rollout. VE against infection was estimated to be 95% for full vaccination; estimated VE against COVID-19-related hospitalization was 91%, and there were no COVID-19–related deaths among fully vaccinated veterans.
COVID-19 incidence and standardized mortality rates remained consistently higher among the prison population than the overall US population in the first year of the pandemic. While COVID-19 incidence and mortality rates peaked in late 2020 and early 2021 and have since declined, the cumulative toll of COVID-19 has been several times greater among the prison population than the overall US population.
October 5, 2021
Nationwide, average anxiety severity scores increased 13% from August to December 2020 and then decreased 26.8% from December 2020 to June 2021. Similar increases and decreases occurred in depression severity scores.
Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include protected elective surgical pathways and long-term investment in surge capacity for acute care during public health emergencies to protect elective staff and services.
October 4, 2021
Our results provide support for high effectiveness of BNT162b2 against hospital admissions up until around 6 months after being fully vaccinated, even in the face of widespread dissemination of the delta variant. Reduction in vaccine effectiveness against SARS-CoV-2 infections over time is probably primarily due to waning immunity with time rather than the delta variant escaping vaccine protection.
Although the immune correlates of protection from disease have yet to be defined, we show markedly diminished humoral and cellular immune responses to both vector and mRNA SARS-CoV-2 vaccines in kidney transplant recipients. The planning of intervention studies to optimise vaccine platform and dosing are urgently required in this group, and preliminary reports suggest encouraging responses to third vaccine doses. In the interim, strategic planning to protect this susceptible population is required. This planning could include, but is not limited to, educating patients to maintain physical distancing rules and immunising household members, including prioritisation of children older than 12 years.
This international bayesian randomized clinical trial that included 2011 participants treated with 2 units of high-titer convalescent plasma, compared with no convalescent plasma, resulted in a posterior probability of futility of 99.4% for the primary outcome of organ support–free days up to day 21.
October 1, 2021
These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5·1 years after peak antibody response, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans (5–95% quantiles 15 months to 10 years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12 years for HCoV-229E). For SARS-CoV, the 5–95% quantiles were 4 months to 6 years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset.
The increased number of outbreaks and cases observed in Louisiana youth summer camps in 2021 compared with the previous year coincided with the widespread circulation of the highly transmissible Delta variant. This period also coincided with apparent underutilization of preventive measures such as vaccination, masking, and physical distancing. Multicomponent prevention measures, including vaccination of all eligible adults and adolescents, wearing masks indoors, regular screening testing, physical distancing and cohorting, and increasing ventilation can help prevent transmission of SARS-CoV-2 in settings with youths who cannot be vaccinated.
Implementation of high vaccination coverage coupled with multiple prevention strategies is critical to averting COVID-19 outbreaks in congregate settings, including overnight camps. These findings highlight important guiding principles for school and youth-based COVID-19 prevention protocols.
Disparities in COVID-19 Vaccination Status, Intent, and Perceived Access for Noninstitutionalized Adults, by Disability Status — National Immunization Survey Adult COVID Module, United States, May 30–June 26, 2021
Analysis of the National Immunization Survey Adult COVID Module found that, compared with adults without a disability, those with a disability had a lower likelihood of having received COVID-19 vaccination, despite being less likely to report hesitancy about getting vaccinated. Adults with a disability reported more difficulties obtaining a COVID-19 vaccine than did persons without a disability.
September 30, 2021
In this cohort study of 901 samples from 595 patients with hematooncological diseases and a control group of health care workers, anti–SARS-CoV-2 spike antibodies after full immunization could be detected, although antibody levels were lower in patients than in health care workers. However, specific subgroups, such as patients who received B-cell–targeting therapy, showed impaired seroconversion. The study findings suggest that lower SARS-CoV-2 antibody levels in patients with cancer after vaccination compared with vaccinated health care workers, and particularly weak seroconversion in specific subgroups, highlight the need for dedicated vaccination trials in patients with cancer.
In this qualitative study, 70 participants from racial and ethnic minority communities in Los Angeles County described a complex vaccination decision-making process influenced by misinformation and politicization, deep apprehension related to historical inequity and mistreatment, access barriers related to social disadvantage, and a need for community engagement and trusted messengers. This study suggests that COVID-19 vaccine equity will require multifaceted policies and programming that respect community concerns and the need for informed deliberation, invest in community-based engagement, improve accessibility and transparency of information, and reduce structural barriers in vaccination.
In a between-participants survey study of adult Canadian citizens, individuals who were provided information on the death prevention potential of less-preferred vaccines, such as AstraZeneca and Johnson & Johnson, reported more confidence in their effectiveness and a higher likelihood of taking these vaccines if offered compared with those who did not receive this information. Information on the overall effectiveness of these vaccines at preventing symptomatic COVID-19 showed the opposite result. These findings suggest that communication strategies that focus on the death prevention potential of less-preferred COVID-19 vaccines have the potential to improve their uptake, whereas focusing on such metrics as their comparatively less impressive overall effectiveness at preventing symptomatic COVID-19 could undermine these efforts.
Our most notable finding was no difference in adherence rates for patients without diabetes who had telemedicine encounters. This demonstrates the benefit of telemedicine in preventive care—comparable quality with lower cost. Similar to recent literature, during the pandemic, telemedicine met a care demand in our study; but moving forward, telemedicine may be a valuable care venue, especially in primary care.
September 29, 2021
REGEN-COV reduced the risk of Covid-19–related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo.
AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults.
COVID-19 hospitalisations and deaths were uncommon 14 days or more after the first vaccine dose in this national analysis in the context of a high background incidence of SARS-CoV-2 infection and with extensive social distancing measures in place. Sociodemographic and clinical features known to increase the risk of severe disease in unvaccinated populations were also associated with severe outcomes in people receiving their first dose of vaccine and could help inform case management and future vaccine policy