Covid19-Sources

Due to numerous mutations in the spike protein, the SARS-CoV-2 variant of concern Omicron (B.1.1.529) raises serious concerns since it may significantly limit the antibody-mediated neutralization and increase the risk of reinfections. While a rapid increase in the number of cases is being reported worldwide, until now there has been uncertainty about the efficacy of vaccinations and monoclonal antibodies. Our in vitro findings using authentic SARS-CoV-2 variants indicate that in contrast to the currently circulating Delta variant, the neutralization efficacy of vaccine-elicited sera against Omicron was severely reduced highlighting T-cell mediated immunity as essential barrier to prevent severe COVID-19. 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 COVID-19 due to Omicron and other emerging variants of concern. ### Competing Interest Statement S.C. was a member of a clinical advisory board for Biontech. T.W. received speaker and consultancy fees from Gilead Sciences, Merck Sharp Dome, and Janssen Pharmaceuticals. All other authors declare no conflict of interest. ### Funding Statement This study has been performed with the support of the Goethe-Corona-Fund of the Goethe University Frankfurt (MW) and the Federal Ministry of Education and Research (COVIDready; grant 02WRS1621C (MW). We are thankful for the numerous donations to the Goethe-Corona-Fund and the support of our SARS-CoV-2 research. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of the Ethics Committee of the Faculty of Medicine at Goethe University Frankfurt (2021-201, 20-864 and 250719). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Sequences are available on GISAID (www.gisaid.org, access date 12/2021), under the following accession numbers. Omicron strains used in this study are as follows: B.1.1.529 (EPI\_ISL\_6959868; GenBank ID: [OL800703][1]), B.1.1.529 (EPI\_ISL\_6959871; GenBank ID: [OL800702][2]) . GenBank accession number for the SARS-CoV-2 B.1.617.2 (Delta) isolate IND8424/2021 ( GenBank ID: [MZ315141][3]). [1]: /lookup/external-ref?link_type=GEN&access_num=OL800703&atom=%2Fmedrxiv%2Fearly%2F2021%2F12%2F13%2F2021.12.07.21267432.atom [2]: /lookup/external-ref?link_type=GEN&access_num=OL800702&atom=%2Fmedrxiv%2Fearly%2F2021%2F12%2F13%2F2021.12.07.21267432.atom [3]: /lookup/external-ref?link_type=GEN&access_num=MZ315141&atom=%2Fmedrxiv%2Fearly%2F2021%2F12%2F13%2F2021.12.07.21267432.atom

To estimate the growth of the Omicron variant of concern (1) and its immune escape (2–9) characteristics, we analysed data from all PCR-confirmed SARS-CoV-2 cases in England excluding those with a history of recent international travel. We undertook separate analyses according to two case definitions. For the first definition, we included all cases with a definitive negative S-gene Target Failure (SGTF) result and specimen dates between 29/11/2021 and 11/12/2021 inclusive. For the second definition, we included cases with a positive genotype result and specimen date between 23/11/2021 and 11/12/2021 inclusive. We chose a later start date for the SGTF definition to ensure greater specificity of SGTF for Omicron. We used logistic and Poisson regression to identify factors associated with testing positive for Omicron compared to non-Omicron (mostly Delta) cases. We explored the following predictors: day, region, symptomatic status, sex, ethnicity, age band and vaccination status. Our results suggest rapid growth of the frequency of the Omicron variant relative to Delta, with the exponential growth rate of its frequency estimated to be 0.34/day (95% CI: 0.33-0.35) [2.0 day doubling time] over the study period from both SGTF and genotype data. The distribution of Omicron by age, region and ethnicity currently differs markedly from Delta, with 18–29-year-olds, residents in the London region, and those of African ethnicity having significantly higher rates of infection with Omicron relative to Delta. Hospitalisation and asymptomatic infection indicators were not significantly associated with Omicron infection, suggesting at most limited changes in severity compared with Delta. To estimate the impact of Omicron on vaccine effectiveness (VE) for symptomatic infection we used conditional Poisson regression to estimate the hazard ratio of being an Omicron case (using SGTF definition) compared with Delta, restricting our analysis to symptomatic cases and matching by day, region, 10-year age band, sex and ethnicity. We found a significant increased risk of an Omicron case compared to Delta for those with vaccine status AZ 2+weeks post-dose 2 (PD2) , Pfizer 2+w PD2, AZ 2+w post-dose 3 (PD3) and PF 2+w PD3 vaccine states with hazard ratios of 1.86 (95%CI: 1.67-2.08), 2.68 (95%CI: 2.54-2.83), 4.32 (95%CI: 3.84-4.85) and 4.07 (95%CI: 3.66-4.51), respectively, where PD3 states are categorised by the dose 1/2 vaccine used. Depending on the Delta VE estimates used (10), these estimates translate into Omicron VE estimates of between 0% and 20% PD2 and between 55% and 80% PD3 against Omicron, consistent with other estimates (11). Similar estimates were obtained using genotype data, albeit with greater uncertainty. To assess the impact of Omicron on reinfection rates we relied on genotype data, since SGTF is associated with a higher observed rate of reinfection, likely due to reinfections typically having higher Ct values than primary infections and therefore being subject to a higher rate of random PCR target failure. Controlling for vaccine status, age, sex, ethnicity, asymptomatic status, region and specimen date and using conditional Poisson regression to predict reinfection status, Omicron was associated with a 5.41 (95% CI: 4.87-6.00) fold higher risk of reinfection compared with Delta. This suggests relatively low remaining levels of immunity from prior infection.

Alte und neue Seuchen bedrohen auch Deutschland - und das liegt nicht nur am Klimawandel

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity to Delta32 and Omicron SARS-CoV-2 variants in 239 samples from 125 fully vaccinated individuals. In uninfected, non-boosted individuals, VLP neutralization titers to Delta and Omicron were reduced 2.7-fold and 15.4-fold, respectively, compared to wild-type (WT), while boosted individuals (n=23) had 18-fold increased titers. Delta breakthrough infections (n=39) had 57-fold and 3.1-fold titers whereas Omicron breakthrough infections (n=14) had 5.8-fold and 0.32-fold titers compared to uninfected non-boosted and boosted individuals, respectively. The difference in titers (p=0.049) was related to a higher proportion of moderate to severe infections in the Delta cohort (p=0.014). Correlation of neutralizing and spike quantitative antibody titers was decreased with Delta or Omicron compared to WT. Neutralizing antibodies in Delta and Omicron breakthrough infections increase overall, but the relative magnitude of increase is greater in more clinically severe infection and against the specific infecting variant.

There is considerable variation in disease severity among patients infected with SARS-CoV-2, the virus that causes COVID-19. Human genetic variation can affect disease outcome, and the coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize human ACE2 ...

A 58-year-old woman who died of COVID infection was included as a control subject in an ongoing autopsy study of the neuropathology of military traumatic brain

This study examines the antibody responses to a third dose (100 μg) of the mRNA-1273 SARS-CoV-2 vaccine among kidney transplant recipients in France who had not responded to 2 doses of the vaccine.

Correspondence from The New England Journal of Medicine — Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients

An Covid-19 sterben Menschen. Aber warum eigentlich genau? Wieso hat der Großteil der Betroffenen kaum oder nur leichte Symptome, während andere so sc

OK ich wage mich nochmal an ein schwieriges Thema. Bitte erst zu Ende lesen und dann kommentieren.Wenn es darum geht, dass wir irgendwann Infektionen zulassen müssen damit die Normalität wieder einkehren kann wird oft darauf hingewiesen, dass es Patienten mit Immunsuppression— ECMO_Doc (@doc_ecmo) January 29, 2022

Wer eine Infektion mit SARS-CoV-2 überstanden hat, kann erneute Attacken des Virus erstaunlich effektiv abwenden. Dies gilt auch für den Fall, dass der Verlauf nur milde oder sogar asymptomatisch war. Das Potenzial der Genesenen könnte sich zudem als...

📌Not a good signal—somehow in the original 🇿🇦 epicenter of #Omicron, #BA2 subvariant has suddenly become dominant ~58% now, displacing old BA1 strain. Same thing happened in Denmark 🇩🇰 where BA2 is now over 65% dominant. HT @JosetteSchoenma #COVID19 pic.twitter.com/Mf0bChrc89— Eric Feigl-Ding (@DrEricDing) January 28, 2022

Nature Medicine - High levels of neutralizing antibodies are successfully elicited against SARS-CoV-2 variants of concern, including omicron, after three exposures to the viral spike protein,...

European Journal of Pediatrics - Most children have a mild course of acute COVID-19. Only few mainly non-controlled studies with small sample size have evaluated long-term recovery from SARS-CoV-2...

Omicron has been shown to be highly transmissible and have extensive evasion of neutralizing antibody immunity elicited by vaccination and previous SARS-CoV-2 infection. Omicron infections are rapidly expanding worldwide often in the face of high levels of Delta infections. Here we characterized developing immunity to Omicron and investigated whether neutralizing immunity elicited by Omicron also enhances neutralizing immunity of the Delta variant. We enrolled both previously vaccinated and unvaccinated individuals who were infected with SARS-CoV-2 in the Omicron infection wave in South Africa soon after symptom onset. We then measured their ability to neutralize both Omicron and Delta virus at enrollment versus a median of 14 days after enrollment. Neutralization of Omicron increased 14-fold over this time, showing a developing antibody response to the variant. Importantly, there was an enhancement of Delta virus neutralization, which increased 4.4-fold. The increase in Delta variant neutralization in individuals infected with Omicron may result in decreased ability of Delta to re-infect those individuals. Along with emerging data indicating that Omicron, at this time in the pandemic, is less pathogenic than Delta, such an outcome may have positive implications in terms of decreasing the Covid-19 burden of severe disease.

Conflicting recommendations exist related to whether masks have a protective effect on the spread of respiratory viruses.The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was consulted to report this systematic ...

Middle East Respiratory Syndrome coronavirus (MERS-CoV) and several bat coronaviruses employ Dipeptidyl peptidase-4 (DPP4) as their functional receptors[1][1]–[4][2]. However, the receptor for NeoCoV, the closest MERS-CoV relative yet discovered in bats, remains enigmatic[5][3]. In this study, we unexpectedly found that NeoCoV and its close relative, PDF-2180-CoV, can efficiently use some types of bat Angiotensin-converting enzyme 2 (ACE2) and, less favorably, human ACE2 for entry. The two viruses use their spikes’ S1 subunit carboxyl-terminal domains (S1-CTD) for high-affinity and species-specific ACE2 binding. Cryo-electron microscopy analysis revealed a novel coronavirus-ACE2 binding interface and a protein-glycan interaction, distinct from other known ACE2-using viruses. We identified a molecular determinant close to the viral binding interface that restricts human ACE2 from supporting NeoCoV infection, especially around residue Asp338. Conversely, NeoCoV efficiently infects human ACE2 expressing cells after a T510F mutation on the receptor-binding motif (RBM). Notably, the infection could not be cross-neutralized by antibodies targeting SARS-CoV-2 or MERS-CoV. Our study demonstrates the first case of ACE2 usage in MERS-related viruses, shedding light on a potential bio-safety threat of the human emergence of an ACE2 using “MERS-CoV-2” with both high fatality and transmission rate. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-4 [3]: #ref-5

This report describes COVID-19 cases and hospitalizations by vaccination status and previous COVID-19 diagnosis before and after the Delta variant became predominant.

This filtered @Nextstrain build gives a nice visual display of how distant the Omicron family is from everything else, & how different BA.1 (21K) & BA.2 (21L) are from each other. Distance is in mutations.https://t.co/mrPRngyQFv pic.twitter.com/IXOOFZ9yy4— Dr Emma Hodcroft (@firefoxx66) January 27, 2022

County and statewide data to help people understand the spread of COVID-19.

As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin. ### Competing Interest Statement W.M.S. and A.I. are cofounders of Xanadu Bio. A.I., B.I., and T.M. are listed as inventors on patent applications relating to intranasal spike-based SARS-CoV-2 vaccines filed by the Yale University. A.I., W.M.S., B.I., T.M, A.S., and M.H. are listed as inventors on patent applications relating to intranasal PACE nanoparticle delivery-based vaccines filed by Yale University.

Die Regierung argumentiert mit der hohen Impfquote und sinkenden Krankenhauseinweisungen. Kritiker halten den Schritt für verfrüht

To assess differences in the risk of hospitalisation between the Omicron variant of concern (1) and the Delta variant, we analysed data from all PCR-confirmed SARS-CoV-2 cases in England with last test specimen dates between 1st and 14th December inclusive. Variant was defined using a combination of S- gene Target Failure (SGTF) and genetic data. Case data were linked by National Health service (NHS) number to the National Immunisation Management System (NIMS) database, the NHS Emergency Care (ECDS) and Secondary Use Services (SUS) hospital episode datasets. Hospital attendance was defined as any record of attendance at a hospital by a case in the 14 days following their last positive PCR test, up to and including the day of attendance. A secondary analysis examined the subset of attendances with a length of stay of one or more days. We used stratified conditional Poisson regression to predict hospitalisation status, with demographic strata defined by age, sex, ethnicity, region, specimen date, index of multiple deprivation and in some analyses, vaccination status. Predictor variables were variant (Omicron or Delta), reinfection status and vaccination status. Overall, we find evidence of a reduction in the risk of hospitalisation for Omicron relative to Delta infections, averaging over all cases in the study period. The extent of reduction is sensitive to the inclusion criteria used for cases and hospitalisation, being in the range 20-25% when using any attendance at hospital as the endpoint, and 40-45% when using hospitalisation lasting 1 day or longer or hospitalisations with the ECDS discharge field recorded as “admitted” as the endpoint (Table 1). These reductions must be balanced against the larger risk of infection with Omicron, due to the reduction in protection provided by both vaccination and natural infection. A previous infection reduces the risk of any hospitalisation by approximately 50% (Table 2) and the risk of a hospital stay of 1+ days by 61% (95%CI:55-65%) (before adjustments for under ascertainment of reinfections). High historical infection attack rates and observed reinfection rates with Omicron mean it is necessary to correct hazard ratio estimates to accurately quantify intrinsic differences in severity between Omicron and Delta and to assess the protection afforded by past infection. The resulting adjustments are moderate (typically less than an increase of 0.2 in the hazard ratio for Omicron vs Delta and a reduction of approximately 0.1 in the hazard ratio for reinfections vs primary infections) but significant for evaluating severity overall. Using a hospital stay of 1+ days as the endpoint, the adjusted estimate of the relative risk of reinfections versus primary cases is 0.31, a 69% reduction in hospitalisation risk (Table 2). Stratifying hospitalisation risk by vaccination state reveals a more complex overall picture, albeit consistent with the unstratified analysis. This showed an apparent difference between those who received AstraZenca (AZ) vaccine versus Pfizer or Moderna (PF/MD) for their primary series (doses 1 and 2). Hazard ratios for hospital attendance with Omicron for PF/MD are similar to those seen for Delta in those vaccination categories, while Omicron hazard ratios are generally lower than for Delta for the AZ vaccination categories. Given the limited samples sizes to date, we caution about over-interpreting these trends, but they are compatible with previous findings that while protection afforded against mild infection from AZ was substantially reduced with the emergency of Delta, protection against more severe outcomes was sustained (2,3). We emphasise that these are estimates which condition upon infection; net vaccine effectiveness against hospital attendance may not vary between the vaccines, given that PF/MD maintain higher effectiveness against symptomatic infection with Omicron than AZ (4). Our estimates will assist in refining mathematical models of potential healthcare demand associated with the unfolding European Omicron wave. The hazard ratios provided in Table 3 can be translated into estimates of vaccine effectiveness (VE) against hospitalisation, given estimates of VE against infection (4). In broad terms, our estimates suggest that individuals who have received at least 2 vaccine doses remain substantially protected against hospitalisation, even if protection against infection has been largely lost against the Omicron variant (4,5).

Vaccines that reduce infection & disease are needed to combat the pandemic. Here, @tianyangmao @BenIsraelow et al. describe our new mucosal booster strategy, Prime and Spike, to induce such immunity via nasal delivery of unadjuvanted spike vaccine 🧵 (1/)https://t.co/J4NuUgiI7e pic.twitter.com/bcB5MFph9F— Prof. Akiko Iwasaki (@VirusesImmunity) January 27, 2022

Correspondence from The New England Journal of Medicine — SARS-CoV-2 Omicron Variant Neutralization after mRNA-1273 Booster Vaccination

Data from Denmark indicate low risk, with important differences between vaccines The mRNA vaccines from Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) are a stunning success of science. They have saved countless lives and have a demonstrated safety record in a billion administered doses worldwide. No drug in history, however, has been completely free of adverse events. Myocarditis, although rare, is a known side effect of the mRNA vaccines and has been a barrier to uptake primarily because of uncertainty around its severity and frequency. Much of the pharmacovigilance data identifying myocarditis has been from passive reports and could be incomplete. There have also been a handful of case reports. What has been missing are complete population based studies that can give a less biased assessment of incidence. It is in this context that the linked study by Husby and colleagues (doi:10.1136/bmj-2021-068665) is considered.1 These authors reviewed data from all five million residents of Denmark age 12 and older, four million of whom received one of the mRNA vaccines from October 2020 to October 2021. They identified all cases of myocarditis or myopericarditis, defined as a hospital diagnosis of myocarditis or pericarditis plus an increased troponin level and admission lasting 24 hours. The …

What can lead to impaired neurogenesis in hippocampus? We looked into a chemokine called CCL11 (eotaxin-1) which was shown to reduce neurogenesis (Villeda et al). In our mice, CCL11 was elevated in the CSF 7 weeks after mild respiratory infection. (10/)https://t.co/yYKCdqhdMf pic.twitter.com/jtBfByh74z— Prof. Akiko Iwasaki (@VirusesImmunity) January 16, 2022

Objectives We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. Methods In this cohort study, we included public sector patients aged ≥20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. Results We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). Conclusions In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledge funding for the Western Cape Provincial Health Data Centre from the Western Cape Department of Health, the US National Institutes for Health (R01 HD080465, U01 AI069924), the Bill and Melinda Gates Foundation (1164272, 119327), the United States Agency for International Development (72067418CA00023), the European Union (101045989), the Wellcome Trust (203135/Z/16/Z, 222574) and the Medical Research Council of South Africa. RJW receives support from the Francis Crick Institute which is funded by Wellcome (FC0010218), MRC (UK) (FC0010218) and Cancer Research UK (FC0010218). He also receives support from Wellcome (203135, 222574) and the Medical Research Council of South Africa. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Ethics Committee, University of Cape Town Faculty of Health Sciences, South Africa I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Background Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition associated with antecedent SARS-CoV-2 infection. In the United States, reporting of MIS-C after vaccination is required under COVID-19 vaccine emergency use authorizations. This case series describes persons aged 12–20 years with MIS-C following COVID-19 vaccination reported to passive surveillance systems or through clinician outreach to CDC. Methods We investigated potential cases of MIS-C after COVID-19 vaccination reported to CDC’s health department-based national MIS-C surveillance, the Vaccine Adverse Event Reporting System (VAERS, co-administered by CDC and the U.S. FDA), and CDC’s Clinical Immunization Safety Assessment Project (CISA) from December 14, 2020, to August 31, 2021. We describe cases meeting the CDC MIS-C case definition. Any positive SARS-CoV-2 serology test satisfied the case criteria although anti-nucleocapsid antibody indicates SARS-CoV-2 infection, while anti-spike protein antibody indicates either infection or COVID-19 vaccination. Findings We identified 21 persons with MIS-C after COVID-19 vaccination. Of these 21 persons, median age was 16 years (range, 12–20 years); 13 (62%) were male. All were hospitalized; 12 (57%) had intensive care unit admission, and all were discharged home. Fifteen (71%) of the 21 had laboratory evidence of past or recent SARS-CoV-2 infection, and six (29%) did not. Through August 2021, 21,335,331 persons aged 12–20 years had received ≥1 dose of COVID-19 vaccine, making the overall reporting rate for MIS-C following vaccination 1·0 case per million persons receiving ≥1 vaccine dose in this age group. The reporting rate for those without evidence of SARS-CoV-2 infection was 0·3 cases per million vaccinated persons. Interpretation In our case series, we describe a small number of persons with MIS-C who had received ≥1 COVID-19 vaccine dose before illness onset. Continued reporting of potential cases and surveillance for MIS-C illnesses after COVID-19 vaccination is warranted. Funding This work was supported by the Centers for Disease Control and Prevention Clinical Immunization Safety Assessment (CISA] Project contracts 200-2012-50430-0005 to Vanderbilt University Medical Center and 200-2012-53661 to Cincinnati Children’s Hospital Medical Center. Evidence before this study Multisystem inflammatory syndrome in children (MIS-C), also known as paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), is an uncommon, but serious, complication described after SARS-CoV-2 infection that is characterized by a generalized hyperinflammatory response. A review of the literature using PubMed identified reports of six persons aged 12–20 years who developed MIS-C following COVID-19 vaccination. Search terms used to identify these reports were: “multisystem inflammatory syndrome in children”, “MIS-C”, “MISC”, “multisystem inflammatory syndrome in adults”, “MIS-A”, “MISA”, “paediatric inflammatory multisystem syndrome”, and “PIMS-TS” each with any COVID-19 vaccine type. There were no exclusion criteria (i.e., all ages and languages). Added value of this study We conducted integrated surveillance for MIS-C after COVID-19 vaccination using two passive surveillance systems, CDC’s MIS-C national surveillance and the Vaccine Adverse Event Reporting System (VAERS), and clinician or health department outreach to CDC, including through Clinical Immunization Safety Assessment (CISA) Project consultations. We investigated reports of potential MIS-C occurring from December 14, 2020, to August 31, 2021, in persons aged 12–20 years any time after receipt of COVID-19 vaccine to identify those that met the CDC MIS-C case definition. Any positive serology test was accepted as meeting the CDC MIS-C case definition, although anti- nucleocapsid antibody is indicative of SARS-CoV-2 infection, while anti-spike protein antibody may be induced either by SARS-CoV-2 infection or by COVID-19 vaccination. We investigated 47 reports and identified 21 persons with MIS-C after receipt of COVID-19 vaccine. Of the 21 persons with MIS-C, median age was 16 years (range 12–20 years), and 13 (62%) were male. Fifteen (71%) had laboratory evidence of past or recent SARS-CoV-2 infection (positive SARS-CoV-2 nucleic acid amplification test [NAAT], viral antigen, or serology test before or during MIS-C illness evaluation), and 5 (33%) of those 15 had illness onset after their second vaccine dose. Six (29%) of 21 persons had no laboratory evidence of past or recent SARS-CoV-2 infection, and five of those six (83%) had onset of MIS-C after the second vaccine dose. Implications of all the available evidence During the first nine months of the COVID-19 vaccination program in the United States, 21 million persons aged 12 to 20 years received ≥1 dose of COVID-19 vaccine as of August 31, 2021. This case series describes MIS-C in 21 persons following vaccine receipt during this time period; the majority of persons reported also had evidence of SARS-CoV-2 infection. The surveillance has limitations, but our findings suggest that MIS-C as identified in this report following COVID-19 vaccination is rare. In evaluating persons with a clinical presentation consistent with MIS-C after COVID-19 vaccination it is important to consider alternative diagnoses, and anti-nucleocapsid antibody testing may be helpful. Continued surveillance for MIS-C illness after COVID-19 vaccination is warranted, especially as pediatric COVID-19 vaccination expands. Providers are encouraged to report potential MIS-C cases after COVID-19 vaccination to VAERS. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by Centers for Disease Control and Prevention Clinical Immunization Safety Assessment (CISA] Project contracts to Vanderbilt University Medical Center and to Cincinnati Childrens Hospital Medical Center. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This activity reviewed by CDC IRB and determined to be a non-research public health surveillance activity. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

This paper presents the first longitudinal study of sex disparities in COVID-19 cases and mortalities across U.S. states, derived from the unique 13-m…