Cohort studies may underestimate rare vaccine adverse events: evidence from stroke incidence following COVID-19 vaccination

Background: The self-controlled case series (SCCS) design is widely used for short-term vaccine safety assessment but allows only indirect estimation of absolute risk differences. This study evaluated whether absolute measures should be estimated exclusively using cohort designs by comparing excess stroke incidence following COVID-19 vaccination in a nationwide cohort with previous estimates from an SCCS analysis. Methods: A nationwide retrospective cohort study was conducted in Qatar between 1 December 2020 and 11 April 2023. Stroke incidence during the 42 days following vaccination was compared between 1,111,939 vaccinated persons and an equal number of individually matched unvaccinated persons. Results: During follow-up, 8 strokes occurred in the vaccinated cohort and 19 in the unvaccinated cohort, corresponding to incidence rates of 0.2 (95% CI, 0.1–0.3) and 0.4 (95% CI, 0.2–0.6) per 100,000 person-weeks, respectively. The adjusted hazard ratio comparing vaccinated with unvaccinated individuals was 0.42 (95% CI, 0.18–0.96). Conclusion: These cohort findings suggesting a spurious protective effect contrast with SCCS results from the same and other populations, which indicate a small increase in post-vaccination stroke risk. This divergence may reflect healthy vaccinee bias in between-person comparisons, challenging the exclusive use of cohort designs for estimating absolute risk differences.