Comparison of methodological approaches in COVID-19 vaccine effectiveness estimation using observational data

Background Target trial emulation (TTE) is a framework to systematically address potential biases in causal inference when using observational data. We estimated vaccine effectiveness (VE) of the Omicron XBB.1.5 booster vaccination against SARS-CoV-2 infection between 2 October 2023 and 2 April 2024 using four TTE approaches. Methods A hypothetical target trial was designed where eligible participants would be randomly assigned to receive booster vaccination or not. Four approaches were used to emulate this hypothetical trial using data of an ongoing prospective cohort study in the Netherlands. The first and second approach defined time zero as the start of the booster vaccination rollout and considered vaccination as a time-varying variable. The first approach adjusted for confounders by regression adjustment, while the second used inverse probability weighting. The third and fourth approach used multiple time zeros. In the third approach, all persons who received a booster vaccination on a specific day were matched 1:1 to persons who were not (yet) vaccinated on that day. In the fourth approach, confounders were adjusted for using inverse probability weighting. Results Overall VE was 30% (95%CI:26–34), 28% (24–32), 28% (24–32) and 27% (24–31) in the first, second, third and fourth approach, respectively. VE decreased as time since vaccination increased, but this was somewhat less pronounced in the third approach. Conclusions Estimated VE was similar across the four approaches. The choice of approach should be based on the model assumptions, estimand of interest, and feasibility.