A Critical Analysis of All-Cause Deaths during COVID-19 Vaccination in an Italian Province

Abstract

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the "all-cause deaths" outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations.

Keywords: healthy-vaccinee bias; immortal time bias; pandemic vaccine effectiveness; total mortality.