Yu Hongjie's research group has made progress in the research field of seroepidemiology of coxsackievirus A16 mother-borne antibody and its natural infection

Recently, Yu Hongjie's research group of Fudan University has made progress in the research field of seroepidemiology of coxsackievirus A16 (CVA16) mother-borne antibodies and their natural infection, and the results are based on "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," published online Nov.
9 in BMC Medicine (link: https://rdcu.
be/cZmfv).

Hand, foot and mouth disease (HFMD) is a common infectious disease in children and is widely endemic in the Asia-Pacific region, especially China
.
HFMD is mainly caused by multiple group A enterovirus serotype infections, such as EV-A71 and CVA16
.
HFMD outbreaks caused by CVA16 accounted for 58.
6%
of the total outbreaks in China from 2011 to 2018.
Although the symptoms of HFMD caused by CVA16 are generally mild, reports of severe disease or death from HFMD caused by CVA16 have gradually increased in the United States, France, Japan, and China, and have received widespread attention
at home and abroad.
However, there are currently no specific antiviral drugs for enteroviruses, and only three EV-A71 monovalent inactivated vaccines are available in
China.
A CVA16-related vaccine is under development
.
Key scientific questions such as who is targeted for CVA16 vaccine, the optimal age for vaccination, and whether children can be indirectly protected by immunized mothers are unclear
.

To this end, Yu Hongjie's research group and Hunan Provincial Center for Disease Control and Prevention carried out a seroepidemiological and follow-up study
of the mother-infant matching cohort and the cohort of children aged 1-9 years in Anhua County, Hunan Province.
The results showed that the levels of CVA16 neutralizing antibody were positively correlated at birth between the mother and the newborn (Figure 1A), and the geometric mean titer (GMT) and serological positivity of the two were similar.
The mean maternal antibody transmission ratio was 0.
88 (95% CI 0.
80-0.
96), i.
e.
, the neonatal cord blood CVA16 neutralizing antibody titer was 0.
88 times
that of the mother.
Although transmission efficiency tends to decrease with increasing maternal antibodies, neonates can effectively obtain neutralizing antibodies (Figure 1C
).
Multivariate analysis showed that neonatal antibody titer values and antibody positivity status were highly correlated
with maternal antibody levels.
For every 2-fold increase in maternal antibody, the level of neonatal antibody increased by 69.
1%; The probability of obtaining a positive antibody was 17.
7-fold.

Figure 1.
Maternal and neonatal CVA16 neutralizing antibody levels
.

A: antibody titer correlation; B: change in neonatal positivity rate; C: Changes in transmission efficiency of mother-borne antibodies
.

Maternal antibodies acquired by newborns decay rapidly with age, and then due to natural infection, both GMT and positivity increase gradually (Figure 2A, B).

Neonatal CVA16 maternal antibodies decay below the positive threshold (8) at 1.
5 months of age and lowest at 6.
8 months of age (Figure 2C).

The neonatal seroprevalence is 42% at birth, with a minimum at 5.
8 months of age, followed by a rapid increase due to natural infection, reaching 60% at age 5 and slowly rising to 80% at age 13 (Figure 2D).

In addition, the neonates were divided into high titer group, medium titer group and negative group according to the maternal antibody titer level, and the results showed that the dynamic changes of antibody levels in the first six months of neonates in different groups were significantly different, and the trend after 1.
5 years was similar
.
The higher the maternal antibody titers, the later the neonatal antibody decay to the positive threshold and the lower to the bottom; Conversely, the lower the maternal antibody titers, especially in the negative group, the earlier the newborn's antibody elevation due to earlier onset of natural infection
.

Figure 2.
Dynamic characterization of CVA16 neutralizing antibody titer and serological positivity rate
.

A: GMT for all age groups; B: seroprevalence by age group; C: CVA16 antibody dynamic changes; D: Dynamic change in CVA16 seroprevalence
rate.

The decay rate of maternal antibodies was significantly higher than that induced by natural infection, with half-lives of 2.
0 months and 13.
9 months
, respectively.
The average duration of maternal antibodies was 2.
8 months, and the duration of protection lasted for 38 days
for each doufold increase.
When maternal antibody titers ≥ 64 and >512, the duration of protection can be extended to June and December
, respectively.

The above results suggest that maternal CVA16 neutralizing antibodies can be efficiently transmitted through the placenta to the fetus, but the antibodies decay
rapidly after birth in newborns.
Between 40% and 95% of children remain susceptible to CVA16 between the ages of 6 months and 5 years and should be included in the population
targeted for CVA16 vaccine.
In order to reduce the incidence of HFMD in children aged 0-5 years, especially in the 1-year-old group, and to avoid potential interference with the effect of mother-borne antibodies, the optimal immunization time
for CVA16 vaccine is between 1.
5 months and 1 year of age.
Future clinical trials
of CVA16-related vaccines in children aged 1.
5 months to 5 years on dose, safety and protective efficacy are warranted.
In addition, considering the immunogenicity and safety of CVA16 vaccine in young infants, the feasibility of vaccinating mothers with CVA16 vaccine during pregnancy or before pregnancy can be explored to provide indirect protection
for newborns through mother-to-mother antibodies.
This study provides detailed basic information for the development of CVA16 vaccine, which is of great scientific significance
for the prevention and control of hand, foot and mouth disease, especially the formulation of CVA16 vaccine immunization strategy.

Jiaxin Zhou, a 2020 doctoral student from the School of Public Health of Fudan University, Yonghong Zhou, a postdoctoral fellow in Fudan University, Liao Qiaohong, a 2017 doctoral student, and Luo Kaiwei, a doctoral student from the Hunan Provincial Center for Disease Control and Prevention, are co-first authors, and Professor Hongjie Yu from the School of Public Health of Fudan University is the corresponding author
.
This research was supported by the National Natural Science Foundation of China (82130093) and the Li Ka-shing Foundation (NO.
LG33
).