Population-level relative effectiveness of the COVID-19 vaccines and the contribution of naturally acquired immunity

Background: Immune protection against SARS-CoV-2 can be induced by natural infection or vaccination or both. The interaction between vaccine-induced immunity and naturally acquired immunity at the population level has been understudied. Methods: We used regression models to evaluate whether the impact of COVID-19 vaccines differed across states with different levels of naturally acquired immunity from March 2021 to April 2022 in the United States. Analysis was conducted for three evaluation periods separately (Alpha, Delta, and Omicron waves). As a proxy of the proportion of the population with naturally acquired immunity, we used either the reported seroprevalence or the estimated proportion of the population ever infected in each state. Results: COVID-19 mortality decreased as the coverage of [≥]1 dose increased among people [≥]65 years of age, and this effect did not vary by seroprevalence or the proportion of the total population ever infected. Seroprevalence and the proportion ever infected were not associated with COVID-19 mortality, after controlling for vaccine coverage. These findings were consistent in all evaluation periods. Conclusions: COVID-19 vaccination was associated with a sustained reduction in mortality at the state level during the Alpha, Delta, and Omicron periods. The effect did not vary by naturally acquired immunity.