Evaluation of Febrile Seizure Risk Following Ancestral Monovalent COVID-19 mRNA Vaccination Among U.S. Children Aged 2-5 Years (preprint)

Importance The United States Food and Drug Administration noted a potential safety concern for seizure in children aged 2-5 years receiving the ancestral monovalent COVID-19 mRNA vaccines. Objective To evaluate febrile seizure risk following monovalent COVID-19 mRNA vaccination among children aged 2-5 years. Design, Setting, and Participants The primary analysis evaluated children who had a febrile seizure outcome in the 0-1 days following COVID-19 vaccination. A self-controlled case series analysis was performed in three commercial insurance databases to compare the risk of seizure in the risk interval (0-1 days) to a control interval (8-63 days). Exposure Receipt of dose 1 and/or dose 2 of monovalent COVID-19 mRNA vaccinations. Main Outcomes and Measures The primary outcome was febrile seizure (0-1 day risk interval). Analysis A conditional Poisson regression model was used to compare outcome rates in risk and control intervals and estimate incidence rate ratios (IRR) and 95% confidence intervals (CIs). Meta-analyses were used to pool results across databases. Results The primary meta-analysis found a statistically significant increased incidence of febrile seizure, in the 0-1 days following mRNA-1273 vaccination compared to the control interval (IRR: 2.52, 95% CI: 1.35 to 4.69, risk difference (RD)/100,000 doses = 3.22 (95%CI -0.31 to 6.75)). For the BNT162b2 vaccination, the IRR was elevated but not statistically significant (IRR: 1.41, 95%CI: 0.48 to 4.11, RD/100,000 doses = -0.25 (95%CI -2.75 to 2.24). Conclusions and Relevance Among children aged 2-5 years, the analysis showed a small elevated incidence rate ratio of febrile seizures in the 0-1 days following the mRNA-1273 vaccination. Based on the current body of scientific evidence, the safety profile of the monovalent mRNA vaccines remains favorable for use in young children.

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.

Safety of Monovalent BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and NVX-CoV2373 (Novavax) COVID-19 Vaccines in US Children Aged 6 months to 17 years (preprint)

Importance Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials. Objective To conduct near-real-time monitoring of health outcomes following COVID-19 vaccination in the United States (US) pediatric population aged 6 months to 17 years. Design We evaluated 21 pre-specified health outcomes; 15 were sequentially tested through near-real-time surveillance, and 6 were monitored descriptively within a cohort of vaccinated children. We tested for increased rate of each outcome following vaccination compared to a historical comparator cohort. Setting This population-based study was conducted under the US Food and Drug Administration public health surveillance mandate using three commercial claims databases. Participants Children aged 6 months to 17 years were included if they received a monovalent COVID-19 vaccine dose before early 2023 and had continuous enrollment in a medical health insurance plan from the start of an outcome-specific clean window to the COVID-19 vaccination dose. Exposure Exposure was defined as receipt of a monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose. The primary analysis evaluated dose 1 and dose 2 combined, and secondary analyses evaluated each dose separately. Follow-up time was censored at death, disenrollment, end of risk window, end of study period, or a subsequent dose administration. Main Outcomes Twenty-one prespecified health outcomes. Results The study included 4,102,016 enrollees aged 6 months to17 years. Thirteen of 15 outcomes sequentially tested did not meet the threshold for a statistical signal. In the primary analysis, myocarditis or pericarditis signals were detected following BNT162b2 vaccine in children aged 12-17 years old and seizures/convulsions signals were detected following vaccination with BNT162b2 and mRNA-1273 in children aged 2-4/5 years. However, in a post-hoc sensitivity analysis, the seizures/convulsions signal was sensitive to background rates selection and was not observed when 2022 background rates were selected instead of 2020 rates. Conclusions and Relevance Of the two signaled outcomes, the myocarditis or pericarditis signals are consistent with previously published reports. The new signal detected for seizures/convulsions among younger children should be further investigated in a robust epidemiological study with better confounding adjustment.

Evaluation of Potential Adverse Events Following COVID-19 mRNA Vaccination Among Adults Aged 65 Years and Older: A Self-Controlled Study in the U.S. (preprint)

Background Our near-real-time safety monitoring of 16 adverse events (AEs) following COVID-19 mRNA vaccination identified potential elevations in risk for six AEs following primary series and monovalent booster dose administration. The crude association with AEs does not imply causality. Accordingly, we conducted robust evaluations of the potential associations. Methods We conducted self-controlled case series studies of COVID-19 mRNA vaccines (BNT162b2 and mRNA-1273) in U.S. Medicare beneficiaries aged 65 years and older. Adjusted incidence rate ratio (IRRs) and 95% confidence intervals (CIs) were estimated following primary series doses for acute myocardial infarction (AMI), pulmonary embolism (PE), immune thrombocytopenia (ITP), disseminated intravascular coagulation (DIC); and following booster doses for AMI, PE, ITP, Bells Palsy (BP) and Myocarditis/Pericarditis (Myo/Peri). Results Among 3,360,981 individuals who received 6,388,542 primary series doses and 6,156,100 individuals with monovalent booster doses of either BNT162b2 or mRNA-1273, AE counts were: AMI (3,653 primary series, 16,042 booster), inpatient PE (2,470 primary, 5,085 booster), ITP (1,085 primary, 88 booster), DIC (254 primary), BP (3,268 booster), and Myo/Peri (1,295 booster). The IRR for inpatient PE cases following BNT162b2 primary series and booster was 1.19 (95% CI: 1.03 to 1.38) and 0.86 (95% CI: 0.78 to 0.95), respectively; and for mRNA-1273 primary series and booster, 1.15 (95% CI: 0.94 to 1.41) and 0.87 (95% CI: 0.79 to 0.96), respectively. The IRR for BP following BNT162b2 and mRNA-1273 booster was 1.17 (95% CI: 1.06 to 1.29) and 1.16 (95% CI: 1.05 to 1.29), respectively. Conclusion In these two studies of the U.S. elderly we did not find an increased risk for AMI, ITP, DIC, and Myo/Peri; the results were not consistent for PE; and there was a small elevated risk of BP after exposure to COVID-19 mRNA vaccines. These results support the favorable safety profile of COVID-19 mRNA vaccines administered in the elderly.

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.

Results of safety monitoring of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in U.S. children aged 5-17 years (preprint)

Importance: Active monitoring of health outcomes following COVID-19 vaccination offers early detection of rare outcomes that may not be identified in pre-licensure trials. Objective: To conduct near-real time monitoring of health outcomes following BNT162b2 COVID-19 vaccination in the U.S. pediatric population aged 5-17 years. Design: We conducted rapid cycle analysis of 20 pre-specified health outcomes, 13 of which underwent sequential testing and 7 of which were monitored descriptively within a cohort of vaccinated individuals. We tested for increased risk of each health outcome following vaccination compared to a historical baseline, while adjusting for repeated looks at the data as well as claims processing delay. Setting: This is a population-based study in three large commercial claims databases conducted under the U.S. FDA public health surveillance mandate. Participants: The study included over 3 million enrollees aged 5-17 years with BNT162b2 COVID-19 vaccination through mid-2022 in three commercial claims databases. We required continuous enrollment in a medical health insurance plan from the start of an outcome-specific clean window to the COVID-19 vaccination. Exposure: Exposure was defined as receipt of a BNT162b2 COVID-19 vaccine dose. The primary analysis assessed primary series doses together (Dose 1 + Dose 2), and dose-specific secondary analyses were conducted. Follow up time was censored for death, disenrollment, end of risk window, end of study period, or a subsequent vaccine dose. Main Outcome(s) and Measure(s): We monitored 20 pre-specified health outcomes. We performed descriptive monitoring for all outcomes and sequential testing for 13 outcomes. Results: Among 13 health outcomes evaluated by sequential testing, 12 did not meet the threshold for a statistical signal in any of the three databases. In our primary analysis, myocarditis/pericarditis signaled following primary series vaccination with BNT162b2 in ages 12-17 years across all three databases. Conclusions and Relevance: Consistent with published literature, our near-real time monitoring identified a signal for only myocarditis/pericarditis following BNT162b2 COVID-19 vaccination in children aged 12-17 years. This method is intended for early detection of safety signals. Our results are reassuring of the safety of the vaccine, and the potential benefits of vaccination outweigh the risks.