黄琼姿,朱瑞,徐龙发,程通

• 1:国家传染病诊断试剂与疫苗工程技术研究中心
• 2:厦门大学公共卫生学院

摘要(Abstract)：

手足口病（Hand,foot and mouth disease,HFMD）是一种由人肠道病毒（Human enterovirus,HEV）感染引起的儿童常见的全球性急性传染病，多发于5岁以下婴幼儿。我国是HFMD的主要流行地区，近年来每年的感染报告病例数居高不下，已经严重影响我国儿童的生命健康。柯萨奇病毒A6型（Coxsackievirus A6,CVA6）和柯萨奇病毒A10型（Coxsackievirus A10,CVA10）是导致HFMD的主要病原体。然而，目前尚未有CVA6和CVA10的预防疫苗或特效治疗药物。为此，本文基于致手足口病CVA6和CVA10，对其疫苗最新研究进展以及疫苗研发中的挑战作一综述，以期为HFMD的科学防控及疫苗研发提供有价值的信息。

关键词(KeyWords)： 手足口病;柯萨奇病毒A6型;柯萨奇病毒A10型;疫苗

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目（课题号：82101918）,题目：柯萨奇病毒A6型广谱抗病毒表位特征及其中和机制研究

作者(Author): 黄琼姿,朱瑞,徐龙发,程通

DOI: 10.13242/j.cnki.bingduxuebao.004332

参考文献(References)：

• [1]吴军.卫生部通报阜阳疫情最新情况[J/OL].中国医药导报，2008(14):4. DOI:10.3969/j. issn. 1673-7210.2008.14.004.
• [2]中国疾病预防控制中心传染病预防控制处. 2020年12月中国甲乙丙类传染病疫情动态概要[J/OL].疾病监测，2021, 36(01):2-3. DOI:10.3784/jbjc.202202280069.
• [3] Tapparel C, Siegrist F, Petty T J, Kaiser L.Picornavirus and enterovirus diversity with associated human diseases[J/OL]. Infect Genet Evol, 2013, 14:282-293. DOI:10.1016/j.meegid.2012.10.016.
• [4] He X, Zhang M, Zhao C, Zheng P, Zhang X, Xu J.From Monovalent to Multivalent Vaccines, the Exploration for Potential Preventive Strategies Against Hand, Foot, and Mouth Disease(HFMD)[J/OL].Virol Sin, 2021, 36(2):167-175. DOI:10.1007/s12250-020-00294-3.
• [5] Osterback R, Vuorinen T, Linna M, Susi P, Hyypia T, Waris M. Coxsackievirus A6 and hand, foot, and mouth disease, Finland[J/OL]. Emerg Infect Dis,2009, 15(9):1485-1488. DOI:10.3201/eid1509.090438.
• [6] Zhao T S, Du J, Sun D P, Zhu Q R, Chen L Y, Ye C,Wang S, Liu Y Q, Cui F, Lu Q B. A review and metaanalysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand-foot-mouth disease in China and global implications[J/OL]. Rev Med Virol,2020, 30(2):e2087. DOI:10.1002/rmv.2087.
• [7] He Y Q, Chen L, Xu W B, Yang H, Wang H Z, Zong W P, Xian H X, Chen H L, Yao X J, Hu Z L, Luo M,Zhang H L, Ma H W, Cheng J Q, Feng Q J, Zhao D J.Emergence, circulation, and spatiotemporal phylogenetic analysis of coxsackievirus a6-and coxsackievirusa10hand-associated, foot, and mouth disease infections from 2008 to 2012 in Shenzhen, China[J/OL]. J Clin Microbiol, 2013, 51(11):3560-3566.DOI:10.1128/JCM.01231-13.
• [8] Li J, Yuan J, Yang F, Wu Z, Hu Y, Xue Y, Zhou B,Jin Q J T J o i. Epidemic characteristics of hand, foot,and mouth disease in southern China, 2013:coxsackievirus A6 has emerged as the predominant causative agent[J/OL]. 2014, 69(3):299-303. DOI:10.1016/j.jinf.2014.04.001.
• [9] Tan X, Li L, Zhang B, Jorba J, Su X, Ji T, Yang D,Lv L, Li J, Xu W. Molecular epidemiology of coxsackievirus A6 associated with outbreaks of hand,foot, and mouth disease in Tianjin, China, in 2013[J/OL]. Arch Virol, 2015, 160(4):1097-1104. DOI:10.1007/s00705-015-2340-3.
• [10]He S Z, Chen M Y, Xu X R, Yan Q, Niu J J, Wu W H, Su X S, Ge S X, Zhang S Y, Xia N S. Epidemics and aetiology of hand, foot and mouth disease in Xiamen, China, from 2008 to 2015[J/OL]. Epidemiol Infect, 2017, 145(9):1865-1874. DOI:10.1017/S0950268817000309.
• [11]Duan X, Zhang C, Wang X, Ren X, Peng H, Tang X,Zhang L, Chen Z, Ye Y, Zheng M, Zhong W, Chen X, Zeng Y, Yuan P, Long L. Molecular epidemiology and clinical features of hand, foot and mouth disease requiring hospitalization after the use of enterovirus A71inactivated vaccine in chengdu, China, 2017-2022:a descriptive study[J/OL]. Emerg Microbes Infect,2022, 11(1):2510-2519. DOI:10.1080/22221751.2022.2125346.
• [12]Itagaki A, Ishihara J, Mochida K, Ito Y, Saito K,Nishino Y, Koike S, Kurimura T. A clustering outbreak of hand, foot, and mouth disease caused by Coxsackie virus A10[J/OL]. Microbiol Immunol, 1983, 27(11):929-935. DOI:10.1111/j.1348-0421.1983.tb00658.x.
• [13]Ji T, Guo Y, Huang W, Shi Y, Xu Y, Tong W, Yao W, Tan Z, Zeng H, Ma J, Zhao H, Han T, Zhang Y,Yan D, Yang Q, Zhu S, Zhang Y, Xu W. The emerging sub-genotype C2 of CoxsackievirusA10Associated with Hand, Foot and Mouth Disease extensively circulating in mainland of China[J/OL]. Sci Rep, 2018, 8(1):13357. DOI:10.1038/s41598-018-31616-x.
• [14]Yang Q, Ding J, Cao J, Huang Q, Hong C, Yang B.Epidemiological and etiological characteristics of hand,foot, and mouth disease in Wuhan, China from 2012 to2013:outbreaks of coxsackieviruses A10[J/OL]. J Med Virol, 2015, 87(6):954-960. DOI:10.1002/jmv.24151.
• [15]Guan H, Wang J, Wang C, Yang M, Liu L, Yang G,Ma X. Etiology of Multiple Non-EV71 and Non-CVA16Enteroviruses Associated with Hand, Foot and Mouth Disease in Jinan, China, 2009-June 2013[J/OL]. PLoS One, 2015, 10(11):e0142733. DOI:10.1371/journal.pone.0142733.
• [16]Liu F, Ren M, Chen S, Nie T, Cui J, Ran L, Li Z,Chang Z. Pathogen Spectrum of Hand, Foot, and Mouth Disease Based on Laboratory SurveillanceChina, 2018[J/OL]. China CDC Wkly, 2020, 2(11):167-171. DOI:10.46234/ccdcw2020.044.
• [17]Wang J, Jiang L, Zhang C, He W, Tan Y, Ning C.The changes in the epidemiology of hand, foot, and mouth disease after the introduction of the EV-A71vaccine[J/OL]. Vaccine, 2021, 39(25):3319-3323.DOI:10.1016/j.vaccine.2021.05.009.
• [18]Song Y, Zhang Y, Ji T, Gu X, Yang Q, Zhu S, Xu W, Xu Y, Shi Y, Huang X, Li Q, Deng H, Wang X,Yan D, Yu W, Wang S, Yu D, Xu W J S r. Persistent circulation of Coxsackievirus A6 of genotype D3 in mainland of China between 2008 and 2015[J/OL].2017, 7(1):5491. DOI:10.1038/s41598-017-05618-0.
• [19]Xie J, Yang X H, Hu S Q, Zhan W L, Zhang C B, Liu H, Zhao H Y, Chai H Y, Chen K Y, Du Q Y, Liu P,Yin A H, Luo M Y. Co-circulation of coxsackieviruses A-6, A-10, and A-16 causes hand, foot, and mouth disease in Guangzhou city, China[J/OL]. BMC Infect Dis, 2020, 20(1):271. DOI:10.1186/s12879-020-04992-x.
• [20]Bian L, Wang Y, Yao X, Mao Q, Xu M, Liang Z.Coxsackievirus A6:a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide[J/OL]. Expert Rev Anti Infect Ther, 2015, 13(9):1061-1071. DOI:10.1586/14787210.2015.1058156.
• [21]Chen J F, Zhang R S, Ou X H, Chen F M, Sun B C.The role of enterovirus 71 and coxsackievirus A strains in a large outbreak of hand, foot, and mouth disease in2012 in Changsha, China[J/OL]. Int J Infect Dis,2014, 28:17-25. DOI:10.1016/j.ijid.2014.07.024.
• [22]Bian L, Gao F, Mao Q, Sun S, Wu X, Liu S, Yang X, Liang Z J E r o a-i t. Hand, foot, and mouth disease associated with coxsackievirus A10:more serious than it seems[J/OL]. Expert Rev Anti Infect Ther,2019, 17(4):233-242. DOI:10.1080/14787210.2019.1585242.
• [23]Feder H M, Jr., Bennett N, Modlin J F. Atypical hand, foot, and mouth disease:a vesiculobullous eruption caused by Coxsackie virus A6[J/OL]. Lancet Infect Dis, 2014, 14(1):83-86. DOI:10.1016/S1473-3099(13)70264-0.
• [24]Hayman R, Shepherd M, Tarring C, Best E. Outbreak of variant hand-foot-and-mouth disease caused by coxsackievirus A6 in Auckland, New Zealand[J/OL]. J Paediatr Child Health, 2014, 50(10):751-755. DOI:10.1111/jpc.12708.
• [25]Yang F, Yuan J, Wang X, Li J, Du J, Su H, Zhou B,Jin Q. Severe hand, foot, and mouth disease and coxsackievirus A6-Shenzhen, China[J/OL]. Clin Infect Dis, 2014, 59(10):1504-1505. DOI:10.1093/cid/ciu624.
• [26]Broccolo F, Drago F, Ciccarese G, Genoni A,Puggioni A, Rosa G M, Parodi A, Manukyan H,Laassri M, Chumakov K, Toniolo A. Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6:Clinical presentation and phylogenesis of CV-A6 strains[J/OL]. J Clin Virol,2019, 110:1-6. DOI:0.1016/j.jcv.2018.11.003.
• [27]Yang X, Li Y, Zhang C, Zhan W, Xie J, Hu S, Chai H, Liu P, Zhao H, Tang B, Chen K, Yu J, Yin A,Luo M. Clinical features and phylogenetic analysis of severe hand-foot-and-mouth disease caused by Coxsackievirus A6[J/OL]. Infect Genet Evol, 2020,77:104054. DOI:10.1016/j.meegid.2019.104054.
• [28]Chen M, He S, Yan Q, Xu X, Wu W, Ge S, Zhang S, Chen M, Xia N. Severe hand, foot and mouth disease associated with Coxsackievirus A10 infections in Xiamen, China in 2015[J/OL]. J Clin Virol,2017, 93:20-24. DOI:10.1016/j.jcv.2017.05.011.
• [29]Huang Y, Zhou Y, Lu H, Yang H, Feng Q, Dai Y,Chen L, Yu S, Yao X, Zhang H, Jiang M, Wang Y,Han N, Hu G, He Y. Characterization of severe hand,foot, and mouth disease in Shenzhen, China, 2009-2013[J/OL]. J Med Virol, 2015, 87(9):1471-1479. DOI:10.1002/jmv.24200.
• [30]Zhu F C, Meng F Y, Li J X, Li X L, Mao Q Y, Tao H, Zhang Y T, Yao X, Chu K, Chen Q H, Hu Y M,Wu X, Liu P, Zhu L Y, Gao F, Jin H, Chen Y J,Dong Y Y, Liang Y C, Shi N M, Ge H M, Liu L,Chen S G, Ai X, Zhang Z Y, Ji Y G, Luo F J, Chen X Q, Zhang Y, Zhu L W, Liang Z L, Shen X L.Efficacy, safety, and immunology of an inactivated alumadjuvant enterovirus 71 vaccine in children in China:a multicentre, randomised, double-blind, placebocontrolled, phase 3 trial[J/OL]. Lancet, 2013, 381(9882):2024-2032. DOI:10.1016/S0140-6736(13)61049-1.
• [31]Yang L, Mao Q, Li S, Gao F, Zhao H, Liu Y, Wan J, Ye X, Xia N, Cheng T, Liang Z. A neonatal mouse model for the evaluation of antibodies and vaccines against coxsackievirus A6[J/OL]. Antiviral Res, 2016,134:50-57. DOI:10.1016/j.antiviral.2016.08.025.
• [32]Zhang Z, Dong Z, Wei Q, Carr M J, Li J, Ding S,Tong Y, Li D, Shi W. A Neonatal Murine Model of Coxsackievirus A6 Infection for Evaluation of Antiviral and Vaccine Efficacy[J/OL]. J Virol, 2017, 91(9).DOI:10.1128/JVI.02450-16.
• [33]Qian S S, Wei Z N, Jin W P, Wu J, Zhou Y P, Meng S L, Guo J, Wang Z J, Shen S. Efficacy of a coxsackievirus A6 vaccine candidate in an actively immunized mouse model[J/OL]. Emerg Microbes Infect, 2021, 10(1):763-773. DOI:10.1080/22221751.2021.1906755.
• [34]Shen C, Liu Q, Zhou Y, Ku Z, Wang L, Lan K, Ye X, Huang Z. Inactivated coxsackievirus A10experimental vaccines protect mice against lethal viral challenge[J/OL]. Vaccine, 2016, 34(41):5005-5012.DOI:10.1016/j.vaccine.2016.08.033.
• [35]Zhang Z, Dong Z, Li J, Carr M J, Zhuang D, Wang J,Zhang Y, Ding S, Tong Y, Li D, Shi W. Protective Efficacies of Formaldehyde-Inactivated Whole-Virus Vaccine and Antivirals in a Murine Model of Coxsackievirus A10 Infection[J/OL]. J Virol, 2017, 91(13). DOI:10.1128/JVI.00333-17.
• [36]Li S, Zhao H, Yang L, Hou W, Xu L, Wu Y, Wang W, Chen C, Wan J, Ye X, Liang Z, Mao Q, Cheng T, Xia N. A neonatal mouse model of coxsackievirus A10 infection for anti-viral evaluation[J/OL]. Antiviral Res, 2017, 144:247-255. DOI:10.1016/j.antiviral.2017.06.008.
• [37]Gao W, Yue L, Yang T, Shen D, Li H, Song X, Xie T, He X, Xie Z. Proliferation characteristics of coxsackievirus A10 in mice and immune protection ability of experimental inactivated vaccine[J/OL].Biomed Pharmacother, 2021, 143:112212. DOI:10.1016/j.biopha.2021.112212.
• [38]Zhang Z, Dong Z, Wang Q, Carr M, Li J, Liu T, Li D, Shi W. Characterization of an inactivated whole-virus bivalent vaccine that induces balanced protective immunity against coxsackievirus A6 and A10 in mice[J/OL]. Vaccine, 2018, 36(46):7095-7104. DOI:10.1016/j.vaccine.2018.09.069.
• [39]Caine E A, Fuchs J, Das S C, Partidos C D, Osorio J E. Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice[J/OL]. Viruses,2015, 7(11):5919-5932. DOI:10.3390/v7112916.
• [40]Lim H, In H J, Lee J A, Sik Yoo J, Lee S W, Chung G T, Choi Y K, Chung J K, Cho S J, Lee J W. The immunogenicity and protection effect of an inactivated coxsackievirus A6, A10, and A16 vaccine against hand,foot, and mouth disease[J/OL]. Vaccine, 2018, 36(24):3445-3452. DOI:10.1016/j.vaccine.2018.05.005.
• [41]Liu C C, Guo M S, Wu S R, Lin H Y, Yang Y T, Liu W C, Chow Y H, Shieh D B, Wang J R, Chong P.Immunological and biochemical characterizations of coxsackievirus A6 and A10 viral particles[J/OL].Antiviral Res, 2016, 129:58-66. DOI:10.1016/j.antiviral.2016.02.008.
• [42]Hu Y C, Hsu J T, Huang J H, Ho M S, Ho Y C.Formation of enterovirus-like particle aggregates by recombinant baculoviruses co-expressing P1 and 3CD in insect cells[J/OL]. Biotechnol Lett, 2003, 25(12):919-925. DOI:10.1023/a:1024071514438.
• [43]Chung Y C, Ho M S, Wu J C, Chen W J, Huang J H,Chou S T, Hu Y C. Immunization with virus-like particles of enterovirus 71 elicits potent immune responses and protects mice against lethal challenge[J/OL]. Vaccine, 2008, 26(15):1855-1862. DOI:10.1016/j.vaccine.2008.01.058.
• [44]Lin Y L, Yu C I, Hu Y C, Tsai T J, Kuo Y C, Chi W K, Lin A N, Chiang B L. Enterovirus type 71neutralizing antibodies in the serum of macaque monkeys immunized with EV71 virus-like particles[J/OL].Vaccine, 2012, 30(7):1305-1312. DOI:10.1016/j.vaccine.2011.12.081.
• [45]Shen C, Ku Z, Zhou Y, Li D, Wang L, Lan K, Liu Q, Huang Z. Virus-like particle-based vaccine against coxsackievirus A6 protects mice against lethal infections[J/OL]. Vaccine, 2016, 34(34):4025-4031. DOI:10.1016/j.vaccine.2016.06.028.
• [46]Zhou Y, Shen C, Zhang C, Zhang W, Wang L, Lan K, Liu Q, Huang Z. Yeast-produced recombinant viruslike particles of coxsackievirus A6 elicited protective antibodies in mice[J/OL]. Antiviral Res, 2016, 132:165-169. DOI:10.1016/j.antiviral.2016.06.004.
• [47]Zhou Y, Zhang C, Liu Q, Gong S, Geng L, Huang Z.A virus-like particle vaccine protects mice against coxsackievirus A10 lethal infection[J/OL]. Antiviral Res, 2018, 152:124-130. DOI:10.1016/j.antiviral.2018.02.016.
• [48]Zhang W, Dai W, Zhang C, Zhou Y, Xiong P, Wang S, Ye X, Liu Q, Zhou D, Huang Z. A virus-like particle-based tetravalent vaccine for hand, foot, and mouth disease elicits broad and balanced protective immunity[J/OL]. Emerg Microbes Infect, 2018, 7(1):94. DOI:10.1038/s41426-018-0094-1.
• [49]Nikolaidis M, Mimouli K, Kyriakopoulou Z, Tsimpidis M, Tsakogiannis D, Markoulatos P, Amoutzias G D.Large-scale genomic analysis reveals recurrent patterns of intertypic recombination in human enteroviruses[J/OL]. Virology, 2019, 526:72-80. DOI:10.1016/j.virol.2018.10.006.
• [50]徐莉，郭中平.《中华人民共和国药典》2020年版三部病毒性疫苗制品增修订概况[J/OL].中国新药杂志，2021, 30(22):2024-2028. DOI:10.3969/j.issn.1003-3734.2021.22.002.
• [51]Jacobs J P, Jones C M, Baille J P. Characteristics of a human diploid cell designated MRC-5[J/OL]. Nature,1970, 227(5254):168-170. DOI:10.1038/227168a0.
• [52]Dong C, Liu L, Zhao H, Wang J, Liao Y, Zhang X,Na R, Liang Y, Wang L, Li Q. Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys[J/OL].Vaccine, 2011, 29(37):6269-6275. DOI:10.1016/j.vaccine.2011.06.044.
• [53]何鑫，杨婷，李华，岳磊，宋霞，谢天宏，高微捷，谢忠平.柯萨奇病毒A6临床分离株生物学特性分析[J/OL].中华微生物学和免疫学杂志，2019(04):241-249. DOI:10.3760/cma.j.issn.0254-5101.2019.04.001.
• [54]B?nnelykke K, Sleiman P, Nielsen K, Kreiner-M?ller E, Mercader J M, Belgrave D, den Dekker H T,Husby A, Sevelsted A, Faura-Tellez G, Mortensen L J, Paternoster L, Flaaten R, M?lgaard A, Smart D E,Thomsen P F, Rasmussen M A, Bonàs-Guarch S,Holst C, Nohr E A, Yadav R, March M E, Blicher T,Lackie P M, Jaddoe V W, Simpson A, Holloway J W,Duijts L, Custovic A, Davies D E, Torrents D, Gupta R, Hollegaard M V, Hougaard D M, Hakonarson H,Bisgaard H. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations[J/OL]. Nat Genet,2014, 46(1):51-55. DOI:10.1038/ng.2830.
• [55]Liang Z, Mao Q, Gao Q, Li X, Dong C, Yu X, Yao X, Li F, Yin W, Li Q, Shen X, Wang J. Establishing China′s national standards of antigen content and neutralizing antibody responses for evaluation of enterovirus 71(EV71)vaccines[J/OL]. Vaccine,2011, 29(52):9668-9674. DOI:10.1016/j.vaccine.2011.10.018.
• [56]Wang Y, Gao F, Liang Z, Sun H, Wang J, Mao Q.Establishment of the 1st Chinese national standard for CA6 neutralizing antibody[J/OL]. Hum Vaccin Immunother, 2023:2164140. DOI:10.1080/21645515.2022.2164140.
• [57]Chokephaibulkit K, Perng G C. Challenges for the formulation of a universal vaccine against dengue[J/OL]. Exp Biol Med(Maywood), 2013, 238(5):566-578. DOI:10.1177/1535370212473703.