Assessing the Impact of the Healthy Vaccinee Effect on COVID-19 Vaccine Effectiveness Estimates

Abstract Background Health status influences uptake of COVID-19 vaccination, with vaccinated individuals generally being healthier than their unvaccinated counterparts. However, the extent to which this healthy vaccinee effect biases vaccine effectiveness estimates remains unclear. This study investigated how different levels of the healthy vaccinee effect may impact these estimates. Methods Three national, matched, retrospective cohort studies were conducted on the population of Qatar from February 5, 2020-May 14, 2024, to estimate effectiveness of primary- series and booster vaccinations and of natural infection against infection and reinfection. The studies explored three different scenarios for matching by coexisting conditions, each reflecting a different level of health-status imbalance between vaccinated and unvaccinated individuals. Results Estimated effectiveness of primary-series and booster vaccinations against infection and against severe, critical, or fatal COVID-19 showed consistent values across the different matching strategies, despite varying hazard ratios for non-COVID-19 deaths. For example, primary-series effectiveness against severe, critical, or fatal COVID-19 was 96.3% (95% CI: 94.5-97.5) when matching by exact coexisting condition types, 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 when the analysis was stratified by the duration of follow-up and for the subgroup of individuals clinically vulnerable to severe COVID-19. Analogous results were found for effectiveness of natural infection against reinfection and against severe, critical, or fatal COVID-19 upon reinfection. Conclusion The imbalance in health status between vaccinated and unvaccinated individuals in real-world conditions did not introduce a healthy vaccinee bias into the estimated vaccine effectiveness.