The impact of underreported infections on vaccine effectiveness estimates derived from retrospective cohort studies

Background: Surveillance data and vaccination registries are widely used to provide real-time vaccine effectiveness (VE) estimates, which can be biased due to underreported (i.e. under-ascertained and under-notified) infections. Here, we investigate how the magnitude and direction of this source of bias in retrospective cohort studies vary under different circumstances, including different levels of underreporting, heterogeneities in underreporting across vaccinated and unvaccinated, and different levels of pathogen circulation. Methods: We developed a stochastic individual-based model simulating the transmission dynamics of a respiratory virus and a large-scale vaccination campaign. Considering a baseline scenario with 22.5% yearly attack rate and 30% reporting ratio, we explored fourteen alternative scenarios, each modifying one or more baseline assumptions. Using synthetic individual-level surveillance data and vaccination registries produced by the model, we estimated the VE against documented infection taking as reference either unvaccinated or recently vaccinated individuals (within 14 days post-administration). Bias was quantified by comparing estimates to the known VE assumed in the model. Results: VE estimates were accurate when assuming homogeneous reporting ratios, even at low levels (10%), and moderate attack rates (<50%). A substantial downward bias in the estimation arose with homogeneous reporting and attack rates exceeding 50%. Mild heterogeneities in reporting ratios between vaccinated and unvaccinated strongly biased VE estimates, downward if cases in vaccinated were more likely to be reported and upward otherwise, particularly when taking as reference unvaccinated individuals. Conclusions: In observational studies, high attack rates or differences in underreporting between vaccinated and unvaccinated may result in biased VE estimates. This study underscores the critical importance of monitoring data quality and understanding biases in observational studies, to more adequately inform public health decisions.