EV71灭活疫苗适龄接种儿童CVA6血清中和抗体变化分析Analysis of change of serum neutralizing antibody against CVA6 induced by inactivated enterovirus 71 vaccine in children at appropriate ages
曾洁媛;殷琼洲;王雷;李家洪;张莹;王丽春;李琦涵;杭连菊;车艳春;
摘要(Abstract):
目的观察肠道病毒71型(entervirus type 71,EV71)灭活疫苗(人二倍体细胞)适龄接种儿童柯萨奇病毒A组6型(Coxsackievirus A6,CVA6)血清中和抗体变化情况。方法收集EV71灭活疫苗接种儿童的免疫前及免疫后血清,采用微量中和试验检测抗EV71和CVA6中和抗体滴度。结果无手足口病(hand,foot and mouth disease,HFMD)疾病史及EV71灭活疫苗接种史的6~71月龄儿童的血清抗EV71及抗CVA6中和抗体阳性率分别为27.93%和33.91%,共同阳性率为15.32%;两种抗体阳性率总体呈随月龄增加而逐渐升高的趋势(EV71:χ2=4.436,P <0.001;CVA6:χ2=4.436,P <0.001;CVA6:χ2=2.083,P=0.037)。完成EV71灭活疫苗2剂免疫后,抗EV71及抗CVA6中和抗体共同阳性率由15.32%升至32.74%,4个年龄组的抗体共同阳性率也分别由0.00%、8.33%、8.33%和31.11%上升至23.81%、28.00%、13.04%和50.00%;抗EV71中和抗体阳性率(27.93%vs. 98.23%;χ2=2.083,P=0.037)。完成EV71灭活疫苗2剂免疫后,抗EV71及抗CVA6中和抗体共同阳性率由15.32%升至32.74%,4个年龄组的抗体共同阳性率也分别由0.00%、8.33%、8.33%和31.11%上升至23.81%、28.00%、13.04%和50.00%;抗EV71中和抗体阳性率(27.93%vs. 98.23%;χ2=119.257,P <0.001)和几何平均滴度(geometric mean titer,GMT)(7.01 vs. 46.52;χ2=119.257,P <0.001)和几何平均滴度(geometric mean titer,GMT)(7.01 vs. 46.52;χ2=78.730,P <0.001)均较免疫前明显上升;而抗CVA6中和抗体阳性率在免疫前后均为33.91%(χ2=78.730,P <0.001)均较免疫前明显上升;而抗CVA6中和抗体阳性率在免疫前后均为33.91%(χ2=0.000,P> 0.05),GMT在免疫前后差异也无统计学意义(3.09 vs. 4.10;χ2=0.000,P> 0.05),GMT在免疫前后差异也无统计学意义(3.09 vs. 4.10;χ2=0.883,P=0.348)。结论 EV71灭活疫苗适龄接种人群EV71及CVA6的隐性感染率和共同隐性感染率较高。接种EV71灭活疫苗对适龄儿童的抗CVA6中和抗体水平无影响,表明EV71和CVA6之间无中和交叉反应。
关键词(KeyWords): 肠道病毒71型;灭活疫苗;柯萨奇病毒A组6型;中和抗体;隐性感染
基金项目(Foundation): 云南省重大科技专项计划(2017ZF020);; 中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-019)
作者(Authors): 曾洁媛;殷琼洲;王雷;李家洪;张莹;王丽春;李琦涵;杭连菊;车艳春;
DOI: 10.13200/j.cnki.cjb.003453
参考文献(References):
- [1]National Health Commission of the People′s Republic of China.Hand,foot and mouth disease diagnosis and treatment guidelines(2010 edition)[J].Int J Respir,2010,30(24):1473-1475.(in Chinese)中华人民共和国卫生部.手足口病诊疗指南(2010版)[J].国际呼吸杂志,2010,30(24):1473-1475.
- [2]XING W,LIAO Q,VIBOUD C,et al.Hand,foot,and mouth disease in China,2008-12:an epidemiological study[J].Lancet Infect Dis,2014,14(4):308-318.
- [3]SOLOMON T,LEWTHWAITE P,PERERA D,et al.Virology,epidemiology,pathogenesis,and control of enterovirus 71[J].Lancet Infect Dis,2010,10(11):778-790.
- [4]KELLY F,ILAN Y,HUANG J,et al.Hand,foot,and mouth disease caused by Coxsackievirus A6[J].Emerg Infect Dis,2012,18(10):1702-1704.
- [5]European Centre for Disease Prevention and Control(ECDC).Outbreak of enterovirus A71 with severe neurological symptoms among children in Catalonia,Spain 14 June 2016.Stockholm:ECDC,2016.
- [6]ANTONA D,KOSSOROTOFF M,SCHUFFENECKER I,et al.Severe paediatric conditions linked with EV-A71 and EV-D68,France,May to October 2016[J].Eurosurveillance,2016,21(46):30402.
- [7]TIAN H,ZHANG Y,SHI Y,et al.Epidemiological and aetiological characteristics of hand,foot,and mouth disease in Shijiazhuang City,Hebei province,China,2009-2012[J].Plo S One,2017,12(5):e0176604.
- [8]HAN J F,XU S,ZHANG Y,et al.Hand,foot,and mouth disease outbreak caused by coxsackievirus A6,China,2013[J].J Infect,2014,69(3):303-305.
- [9]LU J,ZENG H,ZHENG H,et al.Hand,foot and mouth disease in Guangdong,China,in 2013:new trends in the continuing epidemic[J].Clin Microbiol Infect,2014,20 (7):O442-O445.
- [10]HONGYAN G,CHENGJIE M,QIAOZHI Y,et al.Hand,foot and mouth disease caused by coxsackievirus a6,beijing,2013[J].Pediatr Infect Dis J,2014,33(12):1302.
- [11]LI J L,YUAN J,YANG F,et al.Epidemic characteristics of hand,foot,and mouth disease in southern China,2013:coxsackievirus A6 has emerged as the predominant causative agent[J].J Infect,2014,69(3):299-303.
- [12]DI B,ZHANG Y,XIE H,et al.Circulation of Coxsackievirus A6 in hand-foot-mouth disease in Guangzhou,2010-2012[J].Virol J,2014,11(1):157.
- [13]MAO Q Y,BIAN L L,WANG Y D.New trends for pathogen spectrum of hand,foot and mouth disease and research of vaccines in China[J].Chin J Biologicals,2015,28(9):979-984.(in Chinese)毛群颖,卞莲莲,王一平.我国手足口病病原谱以及疫苗研究新动态[J].中国生物制品学杂志,2015,28(9):979-984.
- [14]JR H M F,BENNETT N,MODLIN J F.Atypical hand,foot,and mouth disease:a vesiculobullous eruption caused by Coxsackie virus A6[J].Lancet Infect Dis,2014,14(1):83-86.
- [15]CHEN B,YU G Q,RAO D P,et al.A prevalence survey and analysis of risk factors on subclinical infection of the EV71 and Cox A16 in healthy children in nurseries[J].J Trop Med,2013,13(4):496-498.(in Chinese)陈兵,余光清,饶东平,等.托幼机构健康儿童EV71和Cox A16隐性感染的现况调查及危险因素分析[J].热带医学杂志,2013,13(4):496-498.
- [16]CHEN R L,PAN R Y,LAI Z F,et al.The microneutralization assay for the detection of neutralizing antibodies against EV71and CVA16 among healthy population[J].Chin Prev Med,2013(5):362-365.(in Chinese)陈润莉,潘瑞胤,赖植发,等.微量细胞病变法检测健康人群EV71和CVA16中和抗体水平[J].中国预防医学杂志,2013(5):362-365.
- [17]LI Y,JIANG M,ZHANG Y Y,et al.Analysis of EV71 and CVA16 serum specific antibodies in health children from kindergarten in areas of Guangxi province[J].J Trop Dis Parasitol,2017,15(2):99-101.(in Chinese)李燕,蒋敏,张艳艳,等.广西健康幼托儿童EV71和CVA16血清抗体水平分析[J].热带病与寄生虫学,2017,15(2):99-101.
- [18]WANG H Y.Etiological surveillance of HFMD and survey on the enterovirus distribution in healthy person[D].Hefei:Anhui Medical University,2014.(in Chinese)王宏宇.手足口病病原谱监测及肠道病毒在正常人群中的调查研究[D].安徽合肥:安徽医科大学,2014.
- [19]GUO X B,ZHU S L,WANG D Y,et al.Seroepidemiology investigation of HEV71 in healthy children of 1~6 years old in three counties[J].Chin J Vaccin Immun,2009(2):141-144.(in Chinese)郭学斌,祝双利,王东艳,等.2005年中国3个县1~6岁儿童人肠道病毒71型血清流行病学调查[J].中国疫苗和免疫,2009(2):141-144.
- [20]SUN B C,GAO J,CHEN D,et al.Study on the recessive infection of hand,foot and mouth disease(HFMD) virus in children[J].Pract Prev Med,2014,21(8):914-916.(in Chinese)孙宝昌,高娟,陈栋,等.儿童手足口病病毒隐性感染情况研究[J].实用预防医学,2014,21(8):914-916.
- [21]YAN Y B,ZHENG H N,SU C H.Recessive infection status after the outbreak of hand-foot-mouth disease in kindergartens[J].Chin J Sch Health,2016,37(2):250-252.(in Chinese)颜玉炳,郑惠能,苏成豪.幼托机构手足口病暴发疫情后儿童隐性感染情况[J].中国学校卫生,2016,37(2):250-252.
- [22]YUAN W,CHEN X W,LIU Y Q,et al.Subclinical Infection of Hand-foot-mouth disease in healthy kindergarten children and influencing factors[J].J Prev Med Inf,2018,34 (8):1062-1065.(in Chinese)袁伟,程秀伟,刘雅琼,等.健康儿童手足口病隐性感染情况及影响因素分析[J].预防医学情报杂志,2018,34(8):1062-1065.
- [23]LIU L,MO Z,LIANG Z,et al.Immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy Chinese children:a report of further observations[J].BMC Med,2015,13(1):1-10.
- [24]CHOU A H,LIU C C,CHANG J Y,et al.Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody against subgenotypes B1,B4,B5 and C4A in adult volunteers[J].PLo S One,2013,8(11):e79783.
- [25]MAO Q,CHENG T,ZHU F,et al.The cross-neutralizing activity of enterovirus 71 subgenotype c4 vaccines in healthy chinese infants and children[J].PLo S One,2013,8(11):e79599.
- [26]LI R,LIU L,MO Z,et al.An inactivated enterovirus 71 vaccine in healthy children[J].N Engl J Med,2014,370(9):829.
- [27]ZHU F,XU W,XIA J,et al.Efficacy,safety,and immunogenicity of an enterovirus 71 vaccine in China[J].N Engl JMed,2014,370(9):818-828.