Estimates of underlying health biases in SARS-CoV-2 vaccination recipients: a nationwide study in previously-infected adults

Abstract Background Observational studies may over- or under-estimate SARS-CoV-2 vaccine effectiveness (VE) depending on whether healthier (i.e. healthy vaccine effect (HVE)) or more ill individuals are preferentially vaccinated. To evaluate this issue, we compared non-COVID-19, all-cause, cancer and COVID-19 mortality in vaccinated versus unvaccinated individuals. Methods This is a nationwide retrospective observational study in the entire adult population in Austria with previously documented SARS-CoV-2 infection with a follow-up from 2021 to 2023. Cox regression analyses were used to calculate hazard ratios (HRs) according to the number of SARS-CoV-2 vaccinations. We also performed matched analyses, where on each day, newly vaccinated individuals were matched with unvaccinated individuals based on age, sex and nursing home residency. Results Overall, 4,324,485 individuals (median age (IQR): 46 (33-59) years; 52.56% female) were eligible and 2.23 non-COVID-19 deaths occurred per 100,000 person days. Group differences in non-COVID-19 mortality risk were most prominent in the early periods (e.g., in Q4 2021, adjusted HRs (95% CI) in vaccinated versus unvaccinated were 0.69 (0.59 - 0.81), 0.65 (0.58 - 0.74), and 0.56 (0.48 - 0.66) for 1-, 2-, and 3-vaccinations, respectively) and decreased thereafter. Matched analyses for the first two weeks after vaccination showed HRs below 0.5 for vaccinated versus unvaccinated individuals irrespective of vaccination numbers. Similar findings were retrieved for non-COVID-19, all-cause, and cancer deaths. Overall, COVID-19 deaths were significantly reduced in vaccinated individuals. Conclusions HVE for SARS-CoV-2 vaccines was strong early after vaccination and diminished over time. HVE should be considered when estimating VE.