Evaluation of Stroke Risk Following COVID-19 mRNA Bivalent Vaccines Among U.S. Adults Aged ≥65 Years

In January 2023, the United States Food and Drug Administration and the Centers for Disease Control and Prevention noted a safety concern for ischemic stroke in adults ≥65 years receiving the BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. This self-controlled case series analysis evaluated stroke risk among Medicare fee-for-service beneficiaries aged ≥65 years receiving: 1) a Pfizer-BioNTech (BNT162b2; WT/OMI BA.4/BA.5) or Moderna (mRNA-1273.222) COVID-19 bivalent vaccine, 2) high-dose/adjuvanted influenza vaccines, and 3) concomitant COVID-19 bivalent vaccines and influenza vaccines, from August 31 to November 6, 2022. The primary analysis did not find elevated stroke risk following COVID-19 bivalent vaccines. In the age subgroup analyses, only the ≥85 year age group had a risk of NHS (Incident Rate Ratio (IRR)=1.36, 95% CI 1.09 – 1.69 [1-21 days]) and NHS/TIA (IRR=1.28, 95% CI 1.08 – 1.52 [1-21 days]) with BNT162b2 Bivalent WT/OMI BA.4/BA.5. Among beneficiaries receiving a concomitant COVID-19 bivalent vaccine and a high-dose/adjuvanted influenza vaccine, an increased risk was observed for NHS (IRR=1.20, 95% CI 1.01 – 1.42 [22-42 days]) with BNT162b2 Bivalent WT/OMI BA.4/BA.5 and for TIA (IRR=1.35, 95% CI 1.06 – 1.74 [1-21 days]) with mRNA-1273.222. Results of the secondary analyses showed a small increased risk of NHS following high-dose or adjuvanted influenza vaccines (IRR=1.09, 95% CI 1.02 – 1.17 [22-42 days]). ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Food and Drug Administration (FDA) as part of the SafeRx Project, a joint initiative of the Centers for Medicare & Medicaid Services and FDA. No third party payments or services were received for the submitted work. ### 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: We conducted this study within the Sentinel Initiative. FDA Amendments Act of 2007 required that FDA develop a national electronic system for monitoring safety of FDA-regulated medical products. FDA built the Sentinel Initiative in response to the congressional requirement. The Office of Human Research Protection (OHRP) determined that the regulations OHRP administers (45 CFR part 46) do not apply to the activities that are included in the FDA's Sentinel Initiative. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.