Epidemiology of hand, foot, and mouth disease outbreaks before and during availability of EV-A71 vaccine in China's mainland: analysis of outbreak surveillance data from 2011 to 2023

Abstract

Background: Hand, foot, and mouth disease is a common contagious illness of childhood that causes a heavy disease burden in China's mainland. There are three enterovirus A71 (EV-A71) vaccines licensed and used in China since 2016. Our study describes changes in epidemiological characteristics of HFMD outbreaks following EV-A71 vaccine introduction.

Methods: Using HFMD outbreak data notified to China CDC during 2011-2023, we compared characteristics of HFMD outbreaks before and after EV-A71 vaccine licensure and availability. We determined risk factors associated with outbreak size with a multivariate regression model and explored county-level patterns of outbreak clusters using local indicators of spatial association (Anselin Local Moran's I).

Findings: During 2011-2023, there were 2838 HFMD outbreaks reported with more than ten cases each that were included in our study. There were 53,958 HFMD cases and 17 deaths in the included outbreaks. The median attack rate was 0.07% (IQR = 0.04%-0.13%) and the median outbreak duration was 14 days (IQR = 9-21). Outbreaks began before school seasons started and peaked during weeks 16-25; most (87.95%) occurred in kindergartens, followed by primary or secondary schools (6.69%). Coxsackievirus A16 (CV-A16) caused 54.94% of the HFMD outbreaks, EV-A71 caused 19.77%, CV-A6 caused 8.99%, CV-A10 caused 0.53%, and other enteroviruses caused 15.76%. After EV-A71 vaccine was introduced into the market as a non-National Immunization Program (NIP) vaccine, the proportion of outbreaks caused by EV-A71 declined to 2.93% in the southern provinces and 4.84% in the northern provinces, and CV-A16, CV-A6, CV-A10, and other enteroviruses increased in proportion. Before EV-A71 vaccine availability, high-high clusters occurred in 37 counties of nine provinces, expanding to 117 counties of nine provinces after vaccine introduction, mainly into southern provinces.

Interpretation: After EV-A71 vaccine was introduced to the market in China, fewer HFMD outbreaks were caused by EV-A71 and more were caused by CV-A16, CV-A6, and CV-A10. The changes of spectrum for HFMD and expansion of outbreaks hotspots associated with vaccine introduction calls for multi-enterovirus vaccine development for controlling HFMD outbreaks.

Funding: Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education; Prevention and Control Mechanisms for Major Infectious Diseases in the Cyber-Physical-Social Tri-Space (2023YFC2308702).

Keywords: Enterovirus A 71 vaccine; Epidemiology; Hand, foot, and mouth disease; Outbreaks.

Fig. 1

Flow chart for HFMD outbreak data extraction and analysis.

Fig. 2

The number of outbreaks and HFMD cases reported in China's mainland, from 2011 to 2023.

Fig. 3

HFMD outbreak distribution by week. (A) Weekly distribution from 2011 to 2023. (B) Weekly distribution by aggregated data from 2011 to 2023. Redline is northern provinces. Green line is southern provinces. Blue line is total provinces. (C) Weekly distribution by province. Southern and northern provinces are divided by a dashed line.

Fig. 4

The composition of enterovirus serotypes by year. The pre-vaccine time is from 2011 to 2015. The vaccine transition time is between 2016 and 2017. The post-vaccine time is from 2018 to 2023.

Fig. 5

Outbreak geographical distribution and enterovirus type composition by province pre vs. post EV-A71 vaccine availability. The number of outbreaks is shown as pale orange (low) to dark orange (high). The enterovirus spectrum is shown by sector graphs. (A) The study period from 2011 to 2023. (B) The pre-vaccine period is between 2011 and 2015. (C) The vaccine transition time is between 2016 and 2017. (D) The post-vaccine period between 2018 and 2023.

Fig. 6

Local Moran's I cluster maps showing high-high, low-low, low-high, and high-low spatial associations. (A) The study period from 2011 to 2023. (B) The pre-vaccine period between 2011 and 2015. (C) The vaccine transition time is between 2016 and 2017. (D) The post-vaccine period between 2018 and 2023.