This study describes maternally-derived and age-specific seroprevalence of anti-EV71 and anti-CoxA16 neutralizing antibodies in infants/children aged from neonates to 15 years old. Retrospective seroepidemiology indicated a geographical difference in EV71 and CoxA16 infection
. The results of this study revealed that EV71 infections occurred more frequently than CoxA16 infections in children over 2 years of age in China.
In mice, trans-placental transfer of maternal antibodies following maternal immunization against EV71 protected newborn mice against lethal infection
. In humans, the presence of maternal anti-EV71 antibodies was also demonstrated in neonates, and the seroprevalence rates and antibody titers of both antibodies demonstrated some correlation with those in their mothers
. Our data also suggest a similar correlation with maternal anti-EV71 antibodies. Unfortunately, the data obtained from studies focused on anti-CoxA16 seemed to be very rare. A cohort study in mainland China revealed a pattern of age-related decline of anti-CoxA16 antibody levels, similar to that of anti-EV71 antibody levels
. In addition, the titers and GMTs against EV71 and CoxA16 were almost equally distributed. It has been suggested that if mothers show higher levels of anti-EV71 and/or anti-CoxA16 antibodies, the antibody titers transferred vertically from mothers to their infants are also higher.
Previous reports showed that 23.7% of HFMD patients showed anti-EV71 antibody titers ≥1:128, whereas none of the healthy children showed such titers
. A recent prospective cohort study showed that 29% of EV71 infections were asymptomatic
. To our surprise, our study found that 62.3% of children aged over 1 year old later developed anti-EV71 antibody titers ≥1:128, although none of these children were confirmed with a clinical diagnosis of HFMD at a hospital or health care provider. This implies that clinically silent or almost silent disease is the most common manifestation of EV71 infection in infants and children in China.
Our data shows that only 11.2% of children aged more than 1 year old had anti-CoxA16 antibody titers ≥1:128. This observation reflects the absence of exposure to CoxA16. A lower seroprevalence rate of anti-CoxA16 compared to anti-EV71 antibodies in children aged 2 to 15 years is also supportive of our previous observation.
This study and several seroepidemiological studies in humans have revealed that the seroprevalence rates of anti-EV71 antibodies increased with age
[11, 22, 23]. Our study not only provided data supportive of age-related seroprevalence of EV71 infection, but also suggested a similar age-related seroprevalence of CoxA16 infection. The seroprevalence rates of EV71 and/or CoxA16 were relatively low in children aged 4 to 11 months of age. In 70.2% (337/480) infants aged from neonate to 9 to 11 months of age there were no antibodies against either EV71 or CoxA16; thus, the high incidence of infection in younger age groups is attributable to the lack of protective antibodies
[12, 23–26]. A cross-sectional study in Singapore also indicated that the infection was mostly acquired in pre-school years, with an annual infection rate of 12%
. In our study, most children aged 2 to 5 years old received pre-school education in kindergartens, and demonstrated higher seroprevalence rates of EV71 and CoxA16, and this finding was supported by the highest incidence of HFMD in preschool years below 5 years of age
. Hence, strengthening health improvement measures in kindergartens is required to effectively control infection. Furthermore, the GMTs and neutralizing titers reached peak levels in children aged 4 years old, and thereafter gradually declined with age, but were still relatively high, indicating reinfection with the same strain was rare and that neutralizing antibody titers were higher at early stages of natural infection. This is consistent with previous studies
[8, 13]. Our data also demonstrated that the population immunity against EV71 and CoxA16 was relatively high in children aged 4 to 10 years old (52.5–62.5%), suggesting that EV71 and CoxA16 infections are highly prevalent in this age group.
Based on historical experiences with poliovirus vaccines and several EV71 vaccine candidates that were evaluated in animals
, several phase I clinical trials to test EV71 vaccine candidates were conducted in Singapore
 and mainland China
[31–36]. Some Phase II clinical trials for EV71 vaccine candidates have also been conducted in mainland China
 between 2010–2011. The inactivated whole-virus vaccine candidates may be available for clinical use in the next 5 to 10 years