Objective: To estimate the potential causal impact of Enterovirus A71 (EV71) vaccination program on the reduction of EV71-infected hand, foot, and mouth disease (HFMD) in Zhejiang Province. Methods: We utilized the longitudinal surveillance dataset of HFMD and EV71 vaccination in Zhejiang Province during 2010–2019. We estimated vaccine efficacy using a Bayesian structured time series (BSTS) model, and employed a negative control outcome (NCO) model to detect unmeasured confounding and reveal potential causal association. Results: We estimated that 20,132 EV71 cases (95% CI: 16,733, 23,532) were prevented by vaccination program during 2017–2019, corresponding to a reduction of 29% (95% CI: 24%, 34%). The effectiveness of vaccination increased annually, with reductions of 11% (95% CI: 6%, 16%) in 2017 and 66% (95% CI: 61%, 71%) in 2019. Children under 5 years old obtained greater benefits compared to those over 5 years. Cities with higher vaccination coverage experienced a sharper EV71 reduction compared to those with lower coverage. The NCO model detected no confounding factors in the association between vaccination and EV71 cases reduction. Conclusions: This study suggested a potential causal effect of the EV71 vaccination, highlighting the importance of achieving higher vaccine coverage to control the HFMD.
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