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Seroepidemiology of Human Enterovirus71 and Coxsackievirusa16 in Jiangsu Province, China

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Seroepidemiology of Human Enterovirus71 and Coxsackievirusa16 in Jiangsu Province, China Ji et al. Virology Journal 2012, 9:248 http://www.virologyj.com/content/9/1/248 RESEARCH Open Access Seroepidemiology of human enterovirus71 and coxsackievirusA16 in Jiangsu province, China Hong Ji1, Liang Li1, YanMing Liu2, HengMing Ge3, XuShan Wang4, JianLi Hu1, Bin Wu1, JianGuang Fu1, ZhenYu Zhang3, XiaoQin Chen3, MingLei Zhang3, Qiang Ding4, WenBo Xu2, FenYang Tang1, MingHao Zhou1, Hua Wang1 and FengCai Zhu1* Abstract Background: The major etiology of hand, foot and mouth disease (HFMD) is infection with human enterovirus A (HEV-A). Among subtypes of HEV-A, coxsackievirusA16 (CoxA16) and enterovirus 71 (EV71) are major causes for recurrent HFMD among infants and children in Jiangsu Province, mainland China. Here, we analyzed maternal antibodies between prenatal women and their neonates, to determine age-specific seroprevalence of human EV71 and CoxA16 infections in infants and children aged 0 to 15 years. The results may facilitate the development of immunization against HFMD. Methods: This study used cross-section of 40 pairs of pregnant women and neonates and 800 subjects aged 1 month to 15 years old. Micro-dose cytopathogenic effects measured neutralizing antibodies against EV71 and CoxA16. Chi-square test compared seroprevalence rates between age groups and McNemar test, paired-Samples t-test and independent-samples t-test analyzed differences of geometric mean titers. Results: A strong correlation between titers of neutralizing antibody against EV71 and CoxA16 in prenatal women and neonates was observed (rEV71 = 0.67, rCoxA16 = 0.56, respectively, p < 0.05). Seroprevalence rates of anti-EV71 antibody gradually decreased with age between 0 to 6 months old, remained low between 7 to 11 months (5.0–10.0%), and increased between 1 and 4 years (22.5–87.5%). Age-specific seroprevalence rates of anti-EV71 antibody stabilized in >80% of children between 5 to 15 years of age. However, seroprevalence rates of anti-CoxA16 antibody were very low (0.0–13.0%) between 0 to 6 months of age, gradually increased between 7 months to 4 years (15.0–70.0%), and stabilized at 54.0% (108/200) between 5 to 15 years. Seroprevalence rates against EV71 and CoxA16 were low under 1 year (0.0–10.0%), and showed an age dependent increase with high seroprevalence (52.5–62.5%) between 4 and10 years of age. Conclusions: Concomitant infection of EV71 and CoxA16 was common in Jiangsu Province. Therefore, development of bivalent vaccine against both EV71 and CoxA16 is critical. The optimal schedule for vaccination may be 4 to11 months of age. Keywords: Human enterovirus71, CoxsackievirusA16, Maternally-acquired immunity, Neutralizing antibody, Hand, foot and mouth disease, Seroepidemiology * Correspondence: [email protected] 1Jiangsu Provincial Center for Disease Control and Prevention, No.172, Jiangsu Road, Gulou District, Nanjing, 210009 Jiangsu Province, China Full list of author information is available at the end of the article © 2012 Ji et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ji et al. Virology Journal 2012, 9:248 Page 2 of 8 http://www.virologyj.com/content/9/1/248 Background individuals with positive neutralizing antibodies against Hand, foot and mouth disease (HFMD) is characterized EV71 and 197 with antibodies against CoxA16, 62.3% by brief febrile episodes and characteristic skin rash, (165/264) and 11.2% (22/197) of children aged from with or without oral ulcers in children. Over the last 1 year to 15 years demonstrated higher titers of antibody decades, many outbreaks of HFMD were reported in the against EV71, and the titers of antibodies against Asia Pacific region, especially in areas with dense popu- CoxA16 were equal to or higher than 1:128. lations such as Taiwan, Japan, Malaysia, Singapore, Vietnam, Australia, South Korea, and mainland China. Seroprevalence rates and geometric mean titers of In mainland China, HFMD emerged as an important anti-EV71 and anti-CoxA16 in pairs of blood samples public health problem, and was already classified as a cat- from prenatal women and neonates egory C Notifiable Infectious Disease by the Ministry of The seroprevalence rates of anti-EV71 neutralizing anti- Health in China on 2 May 2008. The outbreak was mainly bodies in prenatal women and their neonates were 80.0% caused by CoxA16 and/or EV71 infection [1-3]. Compared (32/40) and 75.0% (30/40), respectively. There was no sta- to CoxA16, infections with EV71 appeared severe, leading tistically significant difference with regards to seropreva- to more serious complications and fatalities [4]. lence rates of anti-EV71 antibodies between prenatal In humans, the major protective mechanism against women and their neonates (p = 0.688, by McNemar test). EV71 and CoxA16 is cell-mediated immunity [5-8]. The geometric mean titers (GMT) of anti-EV71 antibodies Humoral immunity with neutralizing antibodies is also in prenatal women and their neonates were 18.7 (95%CI: crucial for protection against EV71 and CoxA16 infec- 12.9-27.1) and 20.0 (95%CI: 12.8-31.4), respectively. Again, tion [9-11]. Currently, immunogenicity in maternal there was no statistically significant difference between the serum and the pattern of immune responses against two means (Paired-samples test = 0.408, df = 39; p = HFMD has not been well studied in mainland China. In 0.685). In addition, there was a correlation between anti- addition, only a few studies on HEV71 infection have EV71 antibody titers in neonates and anti-EV7 antibody been conducted in Singapore [12], Germany [13], titers in their mothers (r = 0.67, p < 0.01). Vietnam [14], Taiwan [15], Brazil [16] and Japan [17]. The seroprevalence rates of anti-CoxA16 neutralizing With regards to the distribution of immunogenicity antibodies in these prenatal women and their neonates against infection with CoxA16, further study is required. were 12.5% (5/40) and 10.0% (4/40), respectively. No sta- To provide fundamental data for the establishment of tistically significant difference in seroprevalence rates of an immunization program against infection with EV71 anti-CoxA16 antibodies was observed between these two and CoxA16 in China, local seroepidemiological studies groups (p = 1.000, by McNemar test). Furthermore, the are indispensable. To investigate the seroepidemiology GMTs of anti-CoxA16 antibodies were 4.5 (95%CI: 4.0- of infection with EV71 or CoxA16 in Jiangsu province, 5.1) in prenatal women and 4.6 (95%CI: 4.0-5.3) in their China, we conducted a cross-sectional study. Trans- neonates. There was no statistically significant difference placental antibodies from prenatal women and anti- between these two mean values (Paired-samples test = bodies from their neonates were collected and analyzed 0.298; df = 39; p = 0.767). The titers of anti-CoxA16 anti- to identify the age-specific seroprevalence rate of natural body in neonates correlated with the titers of anti-CoxA16 infections with EV71 and CoxA16 in infants/children antibodies in their mothers (r = 0.56, p <0.01),(Table1). between 0 months and 15 years of age. All serum sam- ples were collected in August 2010 from two towns in Ganyu County and two towns in Donghai County, both Seroprevalence rates and GMTs of anti-EV71/anti-CoxA16 in LianYun Gang City, Jiang Su Province, East China. by age group The seroprevalence rates of anti-EV71 antibodies Results showed a gradual decrease in infants aged 0 to 6 months Titers of neutralizing antibodies to EV71 and CoxA16 by old, ranging from 75.0% to 6.7%. There was a significant age group drop in seroprevalence rates in infants aged 0 to The levels of neutralizing antibodies against EV71 and 6 months old (p = 0.000). The seroprevalence rates were CoxA16 in prenatal women and their neonates were al- relatively low (5.0–10.0%) in infants aged from 7 month most equally distributed. The titers against EV71 and to 9–11 months old. No statistically significant differ- CoxA16 decreased with age in infants aged from 1 to ence in seroprevalence rate was shown in this age group 9 months, while the titers increased with age in children (p = 0.697). The seroprevalence rates showed a gradual aged from 1 to 3 years, and then reached a peak level in rise from 22.5% in children aged 1 year old to 87.5% in children at the age of 4 years. The titer level showed a children aged 4 years old, and thereafter reached a plat- decrease in children aged 5 years, 6 to 10 years and 11 eau in over 80.0% of children older than five years of age to 15 years (Figure 1). In addition, from the 264 (Figure 2A). Ji et al. Virology Journal 2012, 9:248 Page 3 of 8 http://www.virologyj.com/content/9/1/248 EV71 Neutralizing Antibody CoxA 16 Neutralizing Antibody A D 100 prenatal women Neonates 100 1Mo 2Mo prenatal women Neonates 80 3Mo 4Mo 80 1Mo 2Mo 3Mo 4Mo 60 60 40 40 20 20 0 0 8 16 32 64 128 256 512 1024 8 16 32 64 128 256 512 1024 Titer Titer B 100 E 100 5Mo 6Mo 5Mo 6Mo 80 80 7Mo 8Mo 7Mo 8Mo 9-11Mo 1Yr 60 9-11Mo 1Yr 60 40 40 Participants (%) 20 Participants (%)20 Participants (%) 0 0 8 16 32 64 128 256 512 1024 8 16 32 64 128 256 512 1024 Titer Titer C 2Yr 3Yr F 2Yr 3Yr 100 4Yr 5Yr 100 4Yr 5Yr 6-10Yr 11-15Yr 80 80 6-10Yr 11-15Yr 60 60 40 40 Participants (%)20 Participants (%) 20 Participants (%) 0 0 8 16 32 64 128 256 512 1024 8 16 32 64 128 256 512 1024 Titer Titer Figure 1 Reverse cumulative distribution curves of neutralizing antibody titers in seropositive individuals by age group.
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