Impact of EV-A71 Vaccination and Non-Pharmaceutical Interventions on Hand, Foot, and Mouth Disease: A 14-Year Interrupted Time Series Analysis

BACKGROUND: Hand, foot, and mouth disease (HFMD), particularly EV-A71, has caused large-scale epidemics in the Asia-Pacific region, with China alone reporting over 2 million annual cases and causing a substantial morbidity and mortality. While EV-A71 vaccination was introduced in 2016 and COVID-19 non-pharmaceutical interventions (NPIs) were implemented from 2020-2022, comprehensive evidence on their independent and combined effects on HFMD epidemiology remains scarce. We aimed to quantify the impact of vaccination, NPIs, and post-pandemic policy relaxation on HFMD incidence and pathogen distribution. METHODS: We conducted an interrupted time series segmented regression analysis using a 14-year of surveillance dataset (January 2011-December 2024) from Beijing's National Notifiable Disease Reporting System and citywide pathogen surveillance network. The study population included all HFMD cases reported in Beijing. We defined four intervention periods: baseline (pre-vaccination), vaccination introduction (August 2016), stringent NPIs (January 2020), and reopening (January 2023). Primary outcomes were HFMD incidence rates and incidence rate ratios (IRRs). We estimated prevented cases under counterfactual scenarios. RESULTS: Among 324,623 reported HFMD cases across the 14-year study period, interrupted time series regression demonstrated that vaccination was associated with a 33% reduction in incidence (IRR 0.67, 95% CI 0.49-0.91); cumulatively over 8 years (2016-2024), this was estimated to have prevented 23.8% of cases that would have occurred without vaccination. Stringent NPIs were associated with an 84% reduction (IRR = 0.16, 95% CI: 0.06-0.41); cumulatively, during the intervention period (2020-2022), NPIs were estimated to have prevented 82.6% of cases. Following policy relaxation, incidence rebounded 2.53-fold (95% CI 0.64-9.92), although this increase did not reach statistical significance. In absolute terms, monthly mean case counts declined from 3,001 (baseline) to 1,886 following vaccination introduction (37.2% decrease), and further to 299 during stringent NPIs (90.0% decrease from baseline), before surging to 1,503 post-reopening, a fivefold increase from the NPI period. Pathogen surveillance revealed EV-A71 prevalence declined from 30.5% (baseline) to 4.5% (vaccination period), while coxsackievirus A6 emerged as the dominant serotype, from 9.5% (baseline period) to 56.2% (vaccination period). CONCLUSIONS: EV-A71 vaccination and NPIs were each associated with reduced HFMD transmission, but policy relaxation was followed by a substantial resurgence. The observed serotype replacement with non-vaccine-type enteroviruses highlight critical gaps in current prevention strategies. Sustaining HFMD control requires optimizing vaccine design, developing multivalent vaccines, maintaining high coverage, and integrating targeted NPIs during high-transmission seasons.