Seroepidemiology of enterovirus A71 infection in prospective cohort studies of children in southern China, 2013-2018

Abstract

Enterovirus A71 (EV-A71)-related hand, foot, and mouth disease (HFMD) imposes a substantial clinical burden in the Asia Pacific region. To inform policy on the introduction of the EV-A71 vaccine into the National Immunization Programme, we investigated the seroepidemiological characteristics of EV-A71 in two prospective cohorts of children in southern China conducted between 2013 and 2018. Our results show that maternal antibody titres declined rapidly in neonates, with over half becoming susceptible to EV-A71 at 1 month of age. Between 6 months and 2 years of age, over 80% of study participants were susceptible, while one third remained susceptible at 5 years old. The highest incidence of EV-A71 infections was observed in children aged 5-6 months. Our findings support EV-A71 vaccination before 6 months for birth cohorts in southern China, potentially with a one-time catch-up vaccination for children 6 months-5 years old. More regionally representative longitudinal seroepidemiological studies are needed to further validate these findings.

Fig. 1. Flowchart of recruitment for all participants aged 1–9 years and the follow-up visit rates (N = 4188).

a Regular follow-up visits between August and November every year (i.e., annual visit) for all enrolled participants during 2014–2016. b The semi-annual visit, i.e., an average of 25% of enrolled participants in each age group were randomly selected to additionally participate in three follow-up visits between February and March during 2014 and 2016.

Fig. 2. The proportion of susceptible populations and new infections of EV-A71 (a cutoff titre of 16) and incidence of EV-A71–related hand, foot, and mouth diseases by age and season.

a Age-specific proportion of susceptible populations for all study participants in Children and Neonate cohort (points represent observed mean proportion; blue curve represents fitted mean proportion, whereas blue shadow represents corresponding 95% CI; the ticks between label 0 and 1 on x-axis represent 1–11 months of age). b Age-specific incidence of EV-A71 infections identified by serology for those study participants with paired sera before and after HFMD epidemics.In the x-axis, “m” represents age in months, “y” represents age in years. Error bar represents corresponding 95% CI. *Age at the first blood draw for the paired sera. c Incidence of EV-A71-associated hand, foot, and mouth diseases in Hunan province by age group. Error bar represents corresponding 95% CI. Note: the sample size of each panel was listed in Supplementary Table 9.

Fig. 3. EV-A71 geometric mean titres (GMT) with age and probability of returning to be susceptible to EV-A71.

a GMT for all study participants in Children and Neonates cohort. Dots and line represent observed and predicted GMT, respectively; error bars and shadow represent 95% CI. b GMT in the seropositive participants, excluding maternal antibody titres. Dots and line represent observed and predicted GMT, respectively; error bars and shadow represent 95% CI. c Kaplan–Meier plot of the probability of loss of immunity in participants who were infected. Note: the sample size of panel a and panel b was listed in Supplementary Table 9.