Precautionary Health Behaviours as Potential Confounders in COVID-19 Vaccine Effectiveness Studies

<b>Background/Objectives</b>: Precautionary health behaviours (PHBs), such as hand-washing or self-isolation, are non-pharmaceutical interventions used to reduce SARS-CoV-2 transmission. We investigated the potential confounding by PHBs of COVID-19 vaccine effectiveness (VE) estimates in a subset of study participants enrolled in id.DRIVE. <b>Methods</b>: The id.DRIVE COVID-19 VE study (formerly COVIDRIVE) is a European multicentre test-negative case-control study estimating COVID-19 VE against hospitalisation due to laboratory-confirmed SARS-CoV-2 in patients with severe acute respiratory infection. All adults (≥18 y) prospectively enrolled between 16 November 2021 and 16 August 2023 at three sites were invited to complete a PHB survey capturing indicators of PHBs in the 3 months preceding admission. Fisher's exact test with Bonferroni-adjusted threshold was used to measure the level of association between PHB indicators and both COVID-19 vaccine status and SARS-CoV-2 test result. VE estimates were generated with and without adjustment for PHBs. <b>Results</b>: PHBs were modified over time, with higher precautionary attitudes in the first COVID-19 vaccine booster season (2021-2022) compared to the second one (2022-2023). For the first booster season, PHBs were positively associated with exposures (vaccination status) and outcomes (case or control status). Adjusting for PHBs led to a 6 to 9 percentage-point increase in VE estimates. Conversely, no confounding by PHBs was observed in the second booster season. <b>Conclusions</b>: PHBs should be considered a possible confounder of COVID-19 VE studies. Further research is needed to define when PHBs should be integrated into VE models, as the level of confounding may differ according to the study population and the epidemiological context.