Changing epidemiology of hand, foot, and mouth disease in China, 2013−2019: a population-based study

Abstract

Background Hand, foot, and mouth disease (HFMD) is an important public health problem. A monovalent EV-A71 vaccine was launched in China in 2016. Previous studies showed that inactivated monovalent EV-A71 vaccines were highly efficient against HFMD associated with EV-A71 but not against HFMD with other etiologies, leading to a hypothesis that the introduction of EV-A71 vaccines might change the pathogen spectrum and epidemiological trend of HFMD. In this study, we described for the first time the changing epidemiological characteristics of HFMD after the launch of the EV-A71 vaccine.Methods We extracted individual-based epidemiological data on HFMD cases reported to the Chinese Center for Disease Control and Prevention between January 2013 and December 2019. We described the changing epidemiological characteristics of HFMD before and after vaccine launch according to the distribution of diseases characteristics (demographic, temporal, and geographical) and evaluated the potential changes in risk factors of severe patients. All analyses were stratified by the phase before and after vaccine launch, and by enterovirus serotype.Findings During 2013À2019, 15,316,710 probable cases of HFMD were reported. Of these, 787,197 (5¢1%) were laboratory confirmed and 76,982 (0¢5%) were severe. After the launch of the EV-A71 vaccine, the median age of HFMD patients infected with EV-A71 increased from 2¢24 years (IQR:1¢43, 3¢56) to 2¢81 years (IQR:1¢58, 4¢01). The proportion of patients less than 3 years of age decreased while the proportion of patients 3À5 years of age increased. There was a large decrease (60¢7%) in the proportion of severe cases as well as a decline (28¢3%) in HFMD patients infected with EV-A71. After the launch of the EV-A71 vaccine, the severe illness rate and mortality rate of HFMD patients in all age groups has decreased sharply, 62¢20% and 83¢78% respectively. The timing of the HFMD epidemic peak was delayed (1-2 months) . After the launch of EV-A71 vaccine, the risk of becoming a severe case for EV-A71 serotype was decreased, whereas that risk was instead increased for CV-A16 (from 0¢17 (95% CI:0¢16, 0¢18) to 0¢23 (95% CI:0¢21, 0¢25)) and other enterovirus compared to EV-A71 (from 0¢38 (95% CI:0¢37, 0¢39) to 0¢58 (95% CI:0¢56, 0¢61)). The longer the time from onset to diagnosis, the higher was the risk of being a severe case, but the effect size was decreased.Interpretation The introduction of the EV-A71 vaccine has effectively reduced the proportion of severe HFMD cases and mortality, but changes to the dominant serotypes should be closely monitored. Development of multivalent vaccines to avoid an increased case burden due to other enteroviruses is greatly needed.

Epidemiological characteristics of hand, foot, and mouth disease clusters during 2016–2020 in Beijing, China

“…Previous studies have shown that EV‐A71 vaccines were effective against EV‐A71‐associated HFMD 35 . After the launch of the EV‐A71 vaccine, the proportion of the HFMD cases infected by EV‐A71 decreased, and the cumulative incidence of EV‐A71 serotype HFMD showed a significant decrease in its geographical distribution 36 . CV‐A6 was the main pathogen from 2016 to 2020, especially in 2020.…”

“…35 After the launch of the EV-A71 vaccine, the proportion of the HFMD cases infected by EV-A71 decreased, and the cumulative incidence of EV-A71 serotype HFMD showed a significant decrease in its geographical distribution. 36 in 2013 and during 2015-2019 in Beijing. 11 The etiological and phylogenetic analysis of HFMD in southern China showed that the predominant virus was also CV-A6 in 2020.…”

Epidemiology of hand, foot, and mouth disease and the genetic characteristics of Coxsackievirus A16 in Taiyuan, Shanxi, China from 2010 to 2021

“…In recent years, national surveillance of HFMD cases has revealed that the pathogens causing HFMD are constantly changing. After applying the EV-A71 inactivated vaccine marketed in China in 2016, the number of HFMD caused by EV-A71 has decreased rapidly (Hong et al, 2022), whereas the proportion of CVA16 has gradually increased, and the proportion of other EVs in the pathogen spectrum has increased significantly (Chen et al, 2017;He et al, 2018). This indicates that the monovalent EV-A71 inactivated vaccine can prevent 90% of EV-A71-induced HFMD cases, but provides no cross-protection against infection with CVA16 and other EVs (Li et al, 2014;Li et al, 2016;Takahashi et al, 2016), resulting in the consistently high number of CVA16-related HFMD cases.…”

Thermal stabilization of enterovirus A 71 and production of antigenically stabilized empty capsids

“…The most advanced vaccine approach is based upon inactivated virus, and these vaccines have been licensed in PR China, where EVA71 is responsible for periodic outbreaks of HFMD [11][12][13][14][15]. In PR China, the introduction of two-dose vaccination of children aged 6-59 months in December 2015 resulted in an overall reduction in disease and lower rates of serious or fatal infection [16][17][18].…”