The transfer of maternal antibodies and dynamics of maternal and natural infection-induced antibodies against coxsackievirus A16 in Chinese children 0-13 years of age: a longitudinal cohort study

Abstract

Background: A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children.

Methods: Two population-based longitudinal cohorts in southern China were studied during 2013-2018. Participants were enrolled in autumn 2013, including 2475 children aged 1-9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated.

Results: The average maternal antibody transfer ratio was 0.88 (95% CI 0.80-0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9-2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64.

Conclusions: Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0-5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.

Keywords: Antibody kinetics; Coxsackievirus A16 (CVA16); Maternal antibody; Natural infection; Transplacental transfer.

Fig. 1

Recruitment and follow-up rates for the two cohorts. ^#Residual serum samples from 538 participants were available at baseline, while quantities of sera from one participant at 2 months of age were insufficient for the CVA16 neutralization test. ^£Details of the selection are described in the appendix (Additional file 1: Table S1). ^§A subgroup of children (25%, 609/2475) in the paediatric cohort attended semiannual follow-up in addition to the routine annual follow-up

Fig. 2

Anti-CVA16 maternal antibody titre transfer efficacy. A Correlation of anti-CVA16 antibodies between mother and neonates. B The probability for neonatal seropositivity at birth over different maternal antibody levels. The points and vertical bars indicate calculated seropositivity and 95% confidence intervals. Solid lines and shadows indicate predicted average seropositivity and 95% confidence interval bands. C The transfer ratio trend over maternal antibody titre. Two grey dashed lines are presented in panel C. The horizontal grey line indicates that mothers and neonates had the same antibody titre, and another grey dashed line indicates that neonates had the minimum positive maternal antibody titre (8)

Fig. 3

Dynamic pattern of CVA16 neutralization antibody titre and seroprevalence over time. A Observed GMT stratified by age. B Observed seroprevalence stratified by age. The points and vertical bars indicate the mean and 95% confidence interval. *** and * indicate p<0.001 and p<0.05, respectively. C Fitted anti-CVA16 antibody titre dynamics over age by generalized linear mixed model. D Fitted probability of seropositive over age by generalized linear mixed model. The solid line and shadow indicate the fitted mean and 95% confidence band. 1:8 is the positive threshold

Fig. 4

Loss of protective immunity acquired from mothers and the relationship between duration and maternal antibody titre. A The Kaplan–Meier survival curve for the probability of seropositivity in neonates who received maternal antibodies at birth. B Relationship between time to loss of seropositive immunity and maternal antibody titres