Ischemic Stroke after Bivalent COVID-19 Vaccination: A Self-Controlled Case Series Study

Introduction The potential association between bivalent COVID-19 vaccination and ischemic stroke remains uncertain, despite several studies conducted thus far. The purpose is to evaluate the risk of ischemic stroke following bivalent COVID-19 vaccination. Methods A self-controlled case series study was conducted among members aged ≥12 years who experienced ischemic stroke between September 1, 2022 and March 31, 2023 in a large California health care system. Ischemic strokes were identified using ICD-10 codes in Emergency Department and inpatient settings. Exposures were Pfizer-BioNTech or Moderna bivalent COVID-19 vaccination. Risk intervals were pre-specified as 1–21 days and 1–42 days after bivalent COVID-19 vaccination; all non-risk-interval person-time served as control interval. We conducted overall and subgroup analyses by age, history of SARS-CoV-2 infection, and co-administration of influenza vaccine. When an elevated risk was detected, we performed chart review of ischemic strokes, and re-evaluated the risk. RESULTS With 4933 cases, we found no increased risk within 21-day risk interval across vaccines and by subgroups. However, an elevated risk emerged within 42-day risk interval among individuals <65 years who received co-administration of Pfizer-BioNTech bivalent vaccine and influenza vaccine on the same day; relative incidence (RI) was 2.14 (95% CI, 1.02–4.49). Among those who also had history of SARS-CoV-2 infection, RI was 3.94 (95% CI, 1.10–14.16). After chart review, RIs were 2.35 (95% CI, 0.98–5.65) and 4.33 (95% CI, 0.98–19.11), respectively. Among individuals <65 years who received Moderna bivalent vaccine and had history of SARS-CoV-2 infection, RI was 2.62 (95% CI, 1.13–6.03) before chart review and 2.24 (95% CI, 0.78–6.47) after chart review. CONCLUSIONS The potential association between bivalent COVID-19 vaccination and ischemic stroke in the 1-42-day analysis warrants further investigation among individuals <65 years with influenza vaccine co-administration and prior SARS-CoV-2 infection. ### Competing Interest Statement LSS reports research support from Moderna for a COVID-19 vaccine effectiveness study and GlaxoSmithKline, Dynavax, and Moderna for unrelated studies. LQ reports research support from Moderna, GlaxoSmithKline, and Dynavax for unrelated studies. KB reports research support from Moderna, Pfizer, GlaxoSmithKline, and Dynavax for unrelated studies. NPK reports research support from Pfizer for COVID-19 vaccine clinical trials, and unrelated research support from Pfizer, GSK, Merck, and Sanofi Pasteur. ### Funding Statement Funding for this study was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01 AI168209. ### 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 study was approved by Kaiser Permanente Southern California Institutional Review Board 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 study are available upon reasonable request to the authors.