Assessing Healthy Vaccinee Bias in COVID-19 Vaccine Effectiveness Studies: A National Cohort Study in Qatar

Abstract

Background: This study investigated the presence of the healthy vaccinee bias in two COVID-19 vaccine effectiveness studies, involving primary series and booster vaccinations, as well as its temporal patterns and variability across different subpopulations, by examining the association between COVID-19 vaccination and non-COVID-19 mortality in Qatar. Methods: Two matched, retrospective cohort studies assessed the incidence of non-COVID-19 death in national cohorts of individuals with a primary series vaccination versus no vaccination (two-dose analysis), and individuals with three-dose (booster) vaccination versus primary series vaccination (three-dose analysis), from January 5, 2021, to April 9, 2024. Results: The adjusted hazard ratio (aHR) for non-COVID-19 death was 0.76 (95% CI: 0.64-0.90) in the two-dose analysis and 0.85 (95% CI: 0.67-1.07) in the three-dose analysis. In the first six months of follow-up in the two-dose analysis, the aHR was 0.35 (95% CI: 0.27-0.46); however, the combined analysis of all subsequent periods showed an aHR of 1.52 (95% CI: 1.19-1.94). In the first six months of follow-up in the three-dose analysis, the aHR was 0.31 (95% CI: 0.20-0.50); however, the combined analysis of all subsequent periods showed an aHR of 1.37 (95% CI: 1.02-1.85). The overall effectiveness of the primary series and third-dose vaccinations against severe, critical, or fatal COVID-19 was 95.9% (95% CI: 94.0-97.1) and 34.1% (95% CI: -46.4-76.7), respectively. Subgroup analyses showed that the healthy vaccinee bias is pronounced among those aged 50 years and older and among those more clinically vulnerable to severe COVID-19. Conclusion: A strong healthy vaccinee bias was observed in the first six months following vaccination. This bias may have stemmed from a lower likelihood of vaccination among seriously ill, end-of-life individuals, and less mobile elderly populations. Despite this bias, vaccination provided strong protection against severe COVID-19.