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The transfer and decay of maternal antibodies against enterovirus A71, and dynamics of antibodies due to later natural infections in Chinese infants: a longitudinal, paired mother–neonate cohort study

https://doi.org/10.1016/S1473-3099(20)30480-1Get rights and content

Summary

Background

Since 1997, epidemics of hand, foot, and mouth disease associated with enterovirus A71 (EV-A71) have affected children younger than 5 years in the Asia-Pacific region, including mainland China. EV-A71 vaccines have been licensed for use in children aged 6–71 months in China, but not for infants younger than 6 months. We aimed to assess the dynamics of maternal EV-A71 antibodies to inform choice of potential vaccination strategies to protect infants younger than 6 months, because they have a substantial burden of disease.

Methods

We did a longitudinal cohort study with mother–neonate pairs in local hospitals in southern China during 2013–18. We collected cord blood from neonates and venous blood from mothers at delivery. We followed up and collected blood samples from the children at ages 2, 4, 6, 12, 24, and 36 months and tested for the presence of neutralising antibodies against EV-A71 with virus neutralisation assays. Seropositivity, or protective titre, was defined as a neutralisation antibody titre of 16 or higher. We estimated the seroprevalence, geometric mean titre (GMT), and transfer ratio of maternal antibodies. We used a binomial distribution to derive the 95% CIs of seroprevalence. Seropositivity between mothers and neonates was compared by use of an agreement (κ), while GMTs were compared by use of paired Student's t tests.

Findings

Between Sept 20, 2013, and Oct 14, 2015, 1054 mothers with 1066 neonates were enrolled. The EV-A71 GMT was similar among pairs of neonates (22·7, 95% CI 20·8–24·9) and mothers (22·1, 95% CI 20·2–24·1; p=0·20). The mean transfer ratio of maternal antibodies was 1·03 (95% CI 0·98–1·08). Although 705 (66%) of 1066 neonates acquired protective concentrations of EV-A71 antibodies from mothers, these declined rapidly, with a half-life of 42 days (95% CI 40–44). The time to loss of protective immunity was extended to 5 months in neonates with mothers who had titres of 128 or higher. By age 30 months, 28% of children had become seropositive because of natural infection.

Interpretation

EV-A71 maternal antibodies were efficiently transferred to neonates, but declined quickly to below the protective threshold, particularly among those whose mothers had low antibody titres. Our findings suggest that maternal vaccination could be explored to provide neonatal protection against EV-A71 through maternal antibodies. Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately 30–90% of children that have not had natural EV-A71 infection by that age.

Funding

National Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China.

Introduction

Since 1997, large epidemics of hand, foot, and mouth disease (HFMD) associated with enterovirus A71 (EV-A71) among children younger than 5 years have been reported throughout the Asia-Pacific region, including mainland China.1, 2, 3, 4 The estimated case-severity risk is 1·74% and case-fatality risk is 0·055% in mainland China. Younger age and living in rural areas were associated with greater risk of fatal outcomes.2, 3, 4 In the past 5 years, increased circulation of EV-A71 and outbreaks of HFMD have been described outside of Asia, which poses a growing global public health concern.5, 6, 7

In China, HFMD poses a substantial burden to health, with more than 1 million cases per year, with EV-A71 associated with the most severe and fatal outcomes.3, 4 The case-fatality risk is highest among children younger than 1 year, especially among those younger than 6 months (about 0·17% in children younger than 6 months vs 0·11% in those aged 6–11 months).3 No specific antiviral treatment is available for HFMD. Three licensed inactivated EV-A71 vaccines are available for use in children aged 6–71 months in China.8, 9 Infants younger than 6 months remain susceptible before they receive the first dose of EV-A71 vaccination.

Research in context

Evidence before this study

Enterovirus A71 (EV-A71) is responsible for a substantial disease burden of hand, foot, and mouth disease (HFMD) in young children in the Asia-Pacific region, particularly in mainland China. An increased circulation of EV-A71 was described in European and North American countries, leading to outbreaks of severe neurological illness, which poses a growing global public health concern. A 2015 systematic review showed that 30% of children in China were seronegative against EV-A71 and thus remained susceptible at age 5 years. Available licensed EV-A71 vaccines in China cannot be given to infants younger than 6 months, among whom a substantial burden of severe disease occurs. Necessity and timing of vaccination in early life is highly related with maternal-derived antibody levels and their persistence. We searched PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang up to Feb 10, 2020, using the following search terms: (enterovirus 71 OR EV-A71 OR EV-71 OR EV71) AND (seroepidemiology OR seroepidemiologic OR seroepidemiological OR serosurvey OR seroprevalence OR seroprevalent OR seronegative OR seropositive OR serologic OR serological OR seroincidence OR seroconversion OR seroconvert OR GMT) AND (maternal OR maternally OR mother OR transplacental OR placental OR infant OR newborn OR neonate OR neonatal OR child OR children). Only four cross-sectional studies and one longitudinal cohort study reported the correlation between EV-A71 maternal and neonate antibodies in mother–neonate pairs, with one study presenting the transfer ratio. Of these studies, the cohort study alone characterised the half-life of EV-A71 maternal antibodies, but obtained only two blood specimens from neonates within 6 months of age (ie, the cord blood and venous blood at age 6 months). Another cohort study found that 33% of infants aged 3 months and 7% of infants aged 6 months were positive for EV-A71 antibodies. One study reported the seropositivity and antibody titres in neonates aged 2 and 7 months, but could not estimate the dynamics of maternal antibodies because the blood samples were not collected for neonates at birth. No studies were found that addressed the duration of protection conferred by maternal-transferred antibodies.

Added value of this study

In this study, we assessed the transplacental transfer ratio of EV-A71 antibodies, calculated the half-life of maternal-derived EV-A71 antibody titres, and the time to loss of protective immunity in neonates (with a cutoff titre of 16 or higher for protective titres). To our knowledge, this was the largest population-based study of mother–neonate pairs followed up from birth to age 36 months that quantified the transplacental transfer efficiency of EV-A71 antibodies, and measured the dynamics of EV-A71 antibodies in neonates. Our findings show that the mean transplacental transfer ratio was 1·03 (95%CI 0·98–1·08). Although the majority of neonates acquired protective concentrations of EV-A71 antibodies from their mothers, this protection declined rapidly. After the disappearance of maternal antibodies, antibody titres rose because of natural infection, with about a third of children infected by the age of 2·5 years.

Implications of all the available evidence

Our study showed that protective titres of EV-A71 antibodies could be efficiently transferred to neonates from mothers through the placenta. However, maternal antibodies declined rapidly. The findings provide helpful information to guide EV-A71 vaccination programmes and suggest that maternal vaccination could be explored to provide protection to neonates and infants younger than 6 months against EV-A71 through maternal antibodies. Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately 30–90% of children that have not had natural EV-A71 infection by that age.

EV-A71 vaccines are used in the private sector in mainland China. To promote their introduction into the National Immunisation Programme, optimal timing and value of catch-up vaccination should be assessed. Information is needed on the presence and persistence of maternal antibodies and dynamics of antibodies from natural infection in early life. Several cross-sectional studies reported correlation of EV-A71 antibody levels in mother–neonate pairs.10, 11, 12, 13 However, only one longitudinal cohort study presented the half-life (42 days) from blood samples collected at birth and at age 6 months.14 Another study found 33% seropositivity in babies aged 3 months and 7% in those aged 6 months, but had high drop-out rates of 68% at age 3 months and 90% at age 6 months.15 Mao and colleagues16 reported seropositivity and antibody titre in babies aged 2 and 7 months, but could not estimate the dynamics of maternal antibodies because the blood samples were not collected for neonates at birth.

In our study, we quantified antibody concentrations for EV-A71 in paired maternal and cord serum samples from a large cohort of mothers and neonates, assessed the transplacental transfer efficiency of maternal antibodies, and analysed the antibody kinetics from birth to age 3 years, including the decline in maternal antibodies and subsequent increases due to natural infection.

Section snippets

Study design and participants

We established a longitudinal, paired mother–neonate cohort in three townships (Tianzhuang, Jiangnan, and Qingtang) in Anhua county, Hunan Province, southern China from September, 2013, to August, 2018 (appendix 2, p 3). Neonates were eligible for inclusion if they were born after Sept 20, 2013, and their mothers had resided in the study sites in the preceding 3 months or longer. Well trained nurses enrolled mother–neonate pairs in six local hospitals. 89% of pregnant women from these three

Results

Between Sept 20, 2013, and Oct 14, 2015, 3499 pregnant women were approached, 1054 (30%) of whom were enrolled and gave birth to 1066 paired neonates included in the study. For 958 (91%) of 1054 women, blood collection was done on the same day as cord blood collection for paired neonates (appendix 2, p 11). The follow-up rate was over 50% at each visit (figure 1), and 238 (22%) of 1066 neonates completed six follow-ups (full follow-up subgroup). Seven enrolled children were vaccinated against

Discussion

In this large population-based study of mother–neonate pairs followed up from birth to age 36 months, we quantified the transfer efficiency of maternal EV-A71 antibodies, and we measured the dynamics of maternal antibodies and those in neonates due to natural infections. Our study revealed that the average EV-A71 antibody titres and seroprevalence (titres of 16 or higher) were similar in maternal and cord blood, with a mean transfer ratio of maternal antibodies of 1·03 (95% CI 0·98–1·08).

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