Healthy vaccinee effect did not bias COVID-19 vaccine effectiveness estimates

Health status influences COVID-19 vaccine uptake, with vaccinated individuals generally being healthier than unvaccinated ones. This difference may impact vaccine effectiveness estimates. This study investigated the magnitude of this healthy vaccinee effect on effectiveness estimates. Three national, matched, retrospective cohort studies were conducted on Qatar’s population from February 5, 2020-May 14, 2024, to estimate effectiveness of primary-series and booster vaccinations and of natural infection against infection and severe, critical, or fatal COVID-19. The studies explored three matching scenarios by coexisting conditions, reflecting varying levels of health-status imbalance between vaccinated and unvaccinated individuals. Each matched cohort included >810,000 individuals in the primary-series analysis, >330,000 in the booster analysis, and >730,000 in the natural-infection analysis. Effectiveness was derived from adjusted hazard ratios estimated using Cox regression models. Here we show that vaccine effectiveness against infection and severe, critical, or fatal COVID-19 remained consistent across matching strategies, despite differences in non-COVID-19 mortality. For example, primary-series effectiveness against severe COVID-19 was 96.3% (95% CI: 94.5–97.5) when matching by exact coexisting conditions, 94.2% (95% CI: 92.5–95.6) when matching by number of coexisting conditions, and 94.0% (95% CI: 92.3–95.3) with no matching by coexisting conditions. Similar results were observed in subgroup analyses by follow-up duration and among clinically vulnerable individuals. Comparable findings applied to natural infection’s effectiveness against reinfection and severe COVID-19. Health status differences between vaccinated and unvaccinated individuals did not introduce measurable bias in real-world vaccine effectiveness estimates. Findings highlight the importance of using specific outcomes in vaccine effectiveness studies.