Risk of Adverse Events Following Monovalent Third or Booster Dose of COVID-19 mRNA Vaccination in U.S. Adults Ages 18 Years and Older (preprint)

Background: The U.S. FDA authorized the monovalent third primary series or booster doses of COVID-19 mRNA vaccines in August 2021 for persons 18 years and older. Monitoring of outcomes following updated authorizations is critical to evaluate vaccine safety and can provide early detection of rare adverse events (AEs) not identified in pre-licensure trials. Methods We evaluated the risk of 17 AEs following third doses of COVID-19 mRNA vaccines from August 2021 through early 2022 among adults aged 18-64 years in three commercial databases (Optum, Carelon Research, CVS Health) and adults aged >65 years in Medicare Fee-For-Service. We compared observed AE incidence rates to historical (expected) rates prior to the pandemic, estimated incidence rate ratios (IRRs) for the Medicare database and pooled IRR across the three commercial databases. Analyses were also stratified by prior history of COVID-19 diagnosis. Estimates exceeding a pre-defined threshold were considered statistical signals. Results Four AEs met the threshold for statistical signals for BNT162b2 and mRNA-1273 vaccines including Bells Palsy and pulmonary embolism in Medicare, and anaphylaxis and myocarditis/pericarditis in commercial databases. Nine AEs and three AEs signaled among adults with and without prior COVID-19 diagnosis, respectively. Conclusions This early monitoring study identified statistical signals for AEs following third doses of COVID-19 mRNA vaccination. Since this method is intended for screening purposes and generates crude results, results do not establish a causal association between the vaccines and AEs. FDAs public health assessment remains consistent that the benefits of COVID-19 vaccination outweigh the risks of vaccination.

Safety Monitoring of Bivalent COVID-19 mRNA Vaccines Among Recipients 6 months and Older in the United States (preprint)

Importance Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes post-licensure. Objective To evaluate health outcomes following bivalent COVID-19 Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273.222) vaccination among individuals 6 months and older in the United States. Design Monthly monitoring of health outcomes from August 2022 to July 2023 in four administrative claims databases. Descriptive analyses monitored vaccine uptake, outcome counts and coadministration of bivalent COVID-19 and influenza vaccines. Sequential analyses tested for elevated risk of each outcome in a prespecified post-vaccination risk interval, or a period of hypothesized elevation based on clinical guidance, compared to a historical baseline. Participants and Exposures Persons 6 months and older who received a bivalent COVID-19 BNT162b2 or mRNA-1273.222 vaccine during the study period, with continuous enrollment in a medical insurance plan from the start of an outcome-specific clean interval to the COVID-19 vaccination date. Vaccines were identified using product-specific codes from medical coding systems. Health Outcomes Twenty outcomes were monitored in BNT162b2 vaccine recipients 6 months-4 years, and mRNA-1273.222 vaccine recipients 6 months-5 years. Twenty-one outcomes were monitored in BNT162b2 vaccine recipients 5-17 years and mRNA-1273.222 vaccine recipients 6-17 years. Eighteen outcomes were monitored in persons 18 years and older for both mRNA vaccines. Results Overall, 13.9 million individuals 6 months and older received a single bivalent COVID-19 mRNA vaccine. The statistical threshold for a signal was met for two outcomes in one database: anaphylaxis following bivalent BNT162b2 and mRNA-1273.222 vaccines in persons 18-64 years and myocarditis/pericarditis following bivalent BNT162b2 vaccines in individuals 18-35 years. There were no signals identified in young children. Conclusions Results were consistent with prior observations from published studies on COVID-19 vaccine safety. This study supports the safety profile of bivalent COVID-19 mRNA vaccines and the conclusion that the benefits of vaccination outweigh the risks.

Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination (preprint)

Background: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to excipient polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms. Methods: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020 - March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay. Anti-PEG IgG and IgM were measured using two different assays. Laboratorians were blinded to case/control status. Results: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65%) were hospitalized and 7 (35%) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10%) case-patients vs 8 of 30 (27%) controls (p=0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0%) vs 1 of 30 (3%) controls (p>0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats. Conclusion: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.

Safety, reactogenicity, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons: A protocol for a living systematic review and meta-analysis (preprint)

Background Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding safety of these vaccines for the pregnant persons and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, efficacy or effectiveness, reactogenicity, and immunogenicity of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review (LSR) of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide information necessary to help guide vaccine policy decisions.Methods We aim to conduct a LSR based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety (i.e., impacts on obstetric and neonatal outcomes), efficacy or effectiveness of COVID-19 vaccines in pregnant persons. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including pre-specified subgroup and sensitivity analyses, and will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to evaluate the certainty of evidence.Conclusion This will be the first living systematic review (LSR) and meta-analysis assessing the safety, reactogenicity, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons. An online interactive dashboard for data visualization using Microsoft Power BI will be developed to regularly update and disseminate the latest findings (an in-progress version is available at https://safeinpregnancy.org/lsr/). In addition, the findings will be disseminated through publications and presentations.

Surveillance of COVID-19 vaccine safety among elderly persons aged 65 years and older (preprint)

Background: Monitoring safety outcomes following COVID-19 vaccination is critical for understanding vaccine safety especially when used in key populations such as elderly persons age 65 years and older who can benefit greatly from vaccination. We present new findings from a nationally representative early warning system that may expand the safety knowledge base to further public trust and inform decision making on vaccine safety by government agencies, healthcare providers, interested stakeholders, and the public. Methods: We evaluated 14 outcomes of interest following COVID-19 vaccination using the US Centers for Medicare & Medicaid Services (CMS) data covering 30,712,101 elderly persons. The CMS data from December 11, 2020 through Jan 15, 2022 included 17,411,342 COVID-19 vaccinees who received a total of 34,639,937 doses. We conducted weekly sequential testing and generated rate ratios (RR) of observed outcome rates compared to historical (or expected) rates prior to COVID-19 vaccination. Findings: Four outcomes met the threshold for a statistical signal following Pfizer-BioNTech vaccination including pulmonary embolism (PE; RR=1.54), acute myocardial infarction (AMI; RR=1.42), disseminated intravascular coagulation (DIC; RR=1.91), and immune thrombocytopenia (ITP; RR=1.44). After further evaluation, only the RR for PE still met the statistical threshold for a signal; however, the RRs for AMI, DIC, and ITP no longer did. No statistical signals were identified following vaccination with either the Moderna or Janssen vaccines. Interpretation: This early warning system is the first to identify temporal associations for PE, AMI, DIC, and ITP following Pfizer-BioNTech vaccination in the elderly. Because an early warning system does not prove that the vaccines cause these outcomes, more robust epidemiologic studies with adjustment for confounding factors, including age and nursing home residency, are underway to further evaluate these signals. FDA strongly believes the potential benefits of COVID-19 vaccination outweigh the potential risks of COVID-19 infection.

Safety of COVID-19 vaccines, their components or their platforms for pregnant women: A rapid review (preprint)

ABSTRACT Background Pregnant women with COVID-19 are at an increased risk of severe COVID-19 illness as well as adverse pregnancy and birth outcomes. Many countries are vaccinating or considering vaccinating pregnant women with limited available data about the safety of this strategy. Early identification of safety concerns of COVID-19 vaccines, including their components, or their technological platforms is therefore urgently needed. Methods We conducted a rapid systematic review, as the first phase of an ongoing full systematic review, to evaluate the safety of COVID-19 vaccines in pregnant women, including their components, and their technological platforms (whole virus, protein, viral vector or nucleic acid) used in other vaccines, following the Cochrane methods and the PRISMA statement for reporting (PROSPERO-CRD42021234185). We searched literature databases, COVID-19 and pregnancy registries from inception February 2021 without time or language restriction and explored the reference lists of relevant systematic reviews retrieved. We selected studies of any methodological design that included at least 50 pregnant women or pregnant animals exposed to the vaccines that were selected for review by the COVAX MIWG in August 2020 or their components or platforms included in the COVID-19 vaccines, and evaluated adverse events during pregnancy and the neonatal period. Pairs of reviewers independently selected studies through the COVIDENCE web software and performed the data extraction through a previously piloted online extraction form. Discrepancies were resolved by consensus. Results We identified 6768 records, 256 potentially eligible studies were assessed by full-text, and 37 clinical and non-clinical studies (38 reports, involving 2,397,715 pregnant women and 56 pregnant animals) and 12 pregnancy registries were included. Most studies (89%) were conducted in high-income countries. The most frequent study design was cohort studies (n=21), followed by surveillance studies, randomized controlled trials, and registry analyses. Most studies (76%) allowed comparisons between vaccinated and unvaccinated pregnant women (n=25) or animals (n=3) and reported exposures during the three trimesters of pregnancy. The most frequent exposure was to AS03 adjuvant in the context of A/H1N1 pandemic influenza vaccines (n=24), followed by aluminum-based adjuvants (n=11). Aluminum phosphate was used in Respiratory Syncytial Virus Fusion candidate vaccines (n=3) and Tdap vaccines (n=3). Different aluminum-based adjuvants were used in hepatitis vaccines. The replication-deficient simian adenovirus ChAdOx1 was used for a Rift Valley fever vaccine. Only one study reported exposure to messenger RNA (mRNA) COVID-19 vaccines that also used lipid nanoparticles. Except for one preliminary report about A/H1N1 influenza vaccination (adjuvant AS03) - corrected by the authors in a more thorough analysis, all studies concluded that there were no safety concerns. Conclusion This rapid review found no evidence of pregnancy-associated safety concerns of COVID-19 vaccines that were selected for review by the COVAX MIWG or of their components or platforms when used in other vaccines. However, the need for further data on several vaccine platforms and components is warranted given their novelty. Our findings support current WHO guidelines recommending that pregnant women may consider receiving COVID-19 vaccines, particularly if they are at high risk of exposure or have comorbidities that enhance the risk of severe disease.

SARS-CoV-2 Control on a Large Urban College Campus Without Mass Testing (preprint)

Objective. A small percentage of universities and colleges conduct mass SARS-CoV-2 testing. However, universal testing is resource-intensive, strains national testing capacity, and false negative tests can encourage unsafe behaviors. Participants. A large urban university campus. Methods. Virus control centered on three pillars: mitigation, containment, and communication, with testing of symptomatic and a random subset of asymptomatic students. Results. Random surveillance testing demonstrated a prevalence among asymptomatic students of 0.4% throughout the term. There were two surges in cases that were contained by enhanced mitigation and communication combined with targeted testing. Cumulative cases totaled 445 for the term, most resulting from unsafe undergraduate student behavior and among students living off-campus. A case rate of 232/10,000 undergraduates equaled or surpassed several peer institutions that conducted mass testing. Conclusions. An emphasis on behavioral mitigation and communication can control virus transmission on a large urban campus combined with a limited and targeted testing strategy.