Is a multivalent hand, foot, and mouth disease vaccine feasible?

Human Vaccines and Immunotherapeutics

Volumn 11, Issue 11, 2015, Pages 2688-2704

  Klein, Michel ^a   Chong, Pele ^b,c  

^a VaxioBio Inc   (Canada)

^b NATIONAL HEALTH RESEARCH INSTITUTES   (Taiwan)

^c CHINA MEDICAL UNIVERSITY   (Taiwan)

Author keywords

Bivalent and multivalent vaccines; Coxsackievirus A16; Coxsackieviruses B3 and B5; Echovirus 30; Enterovirus A (EV A); Enterovirus A71; Epidemiology; EV A71 vaccine; Foot and mouth diseases; Hand; Inactivated whole virion vaccines; Monovalent

Indexed keywords

CHITOSAN PDNA VP1 VACCINE; CV A16 VACCINE; EV A71 VACCINE; NEUTRALIZING ANTIBODY; UNCLASSIFIED DRUG; VIRUS VACCINE;

ANTIBODY RESPONSE; ANTIBODY TITER; ANTIGEN SPECIFICITY; CELLULAR IMMUNITY; CROSS PROTECTION; DRUG EFFICACY; DRUG POTENCY; ENTEROVIRUS; ENTEROVIRUS INFECTION; HAND FOOT AND MOUTH DISEASE; HEALTH CARE COST; HUMAN; HUMORAL IMMUNITY; IMMUNOGENICITY; MEMORY T LYMPHOCYTE; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHYLOGENY; REVIEW; VACCINATION; VIRAL TROPISM; VIRUS INACTIVATION; VIRUS ISOLATION; ANIMAL; DRUG DEVELOPMENT; ENTEROVIRUS A; HAND, FOOT AND MOUTH DISEASE; IMMUNIZATION; IMMUNOLOGY; PROCEDURES; TRENDS;

ANIMALS; DRUG DISCOVERY; ENTEROVIRUS; ENTEROVIRUS A, HUMAN; HAND, FOOT AND MOUTH DISEASE; HUMANS; IMMUNIZATION; VIRAL VACCINES;

EID: 84963947307     PISSN: 21645515     EISSN: 2164554X     Source Type: Journal    
DOI: 10.1080/21645515.2015.1049780     Document Type: Review

References (197)

1. Pallansch M, Oberste MS, Whitton JL. Enteroviruses: polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. In Fields Virology, 6th edn, Fields BN, Knipe DM, Howley PM (eds). Phildelphia, PA: Wolters Kluwer/Lippincott Williams and Wilkins Health, 490-530, 2013.
2. Tapparel C. Siegrist F, Petty TJ, Kaiser L. Picornavirus and enterovirus diversity with associated human diseases. Infect Genet Evol 2013; 14:282-93; PMID:23201849; http://dx.doi.org/10.1016/j.meegid.2012.10.016
3. Kim KS, Hufnagel G, Chapman NM, Tracy S. The group B coxsackieviruses and myocarditis. Rev Med Virol 2001; 11:355-68; PMID:11746998; http://dx.doi.org/10.1002/rmv.326
4. Lee B, Davies HD. Aseptic meningitis. Curr Opin Infect Dis 2007; 20:272-7; PMID:17471037; http://dx.doi.org/10.1097/QCO.0b013e3280ad4672
5. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 2010; 10:778-90; PMID:20961813; http://dx.doi.org/10.1016/S1473-3099(10)70194-8
6. McMinn P. Recent advances in the molecular epidemiology and control of human enterovirus 71 infection. Curr Opin Virol 2012; 2:199-205; PMID:22482716; http://dx.doi.org/10.1016/j.coviro.2012.02.009
7. Yip CCY, Lau SKP, Woo PCY, Yuen KA. Human enterovirus 71 epidemics: what’s next? Emerg Health Threats J 2013; 6:19780; PMID:24119538
8. Mao Q, Wang Y, Yao X, Bian L, Wu X, Xu M, Liang Z. Coxsackievirus A16: epidemiology, diagnosis, and vaccine. Hum Vaccin Immunother 2014; 10:360-7; PMID:24231751; http://dx.doi.org/10.4161/hv.27087
9. Liu SL, Pan H, Liu P, Amer S, Chan TC, Zhan J, Huo X, Liu Y, Teng Z, Wang L, et al. Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014. Rev Med Virol 2015; 25(2):115-28; PMID:25704797; http://dx.doi.org/10.1002/rmv.1827
10. Fonseca MC, Sarmiento L, Resik S, Martínez Y, Hung LH, Morier L, Piñón A, Valdéz O, Kourí V, González G. Coxsackievirus A6 and enterovirus 71 causing hand, foot and mouth disease in Cuba, 2011-2013. Arch Virol 2014; 159:2451-5; PMID:24719197; http://dx.doi.org/10.1007/s00705-014-2071-x
11. Centers for Disease Control and Prevention (CDC). Notes from the field: severe hand, foot and mouth disease associated with coxsackievirus A6 - Alabama, Connecticut, California, and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly Rep 2012; 61:213-4; PMID:22456122
12. Yang F, Zhang T, Hu Y, Wang X, Du J, Li Y, Sun S, Sun X, Li Z, Jin Q. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J 2011; 8:508-11; PMID:22054534; http://dx.doi.org/10.1186/1743-422X-8-508
13. Lu QB, Zhang XA, Wo Y, Xu HM, Li XJ, Wang XJ, Ding SJ, Chen XD, He C, Liu LJ, et al. Circulation of coxsackievirus A10 and A6 in hand, foot and mouth disease in China, 2009-2011. PLoS One 2012; 7(12):e52073; PMID:23272213; http://dx.doi.org/10.1371/journal.pone.0052073
14. Liu W, Wu S, Xiong Y, Li T, Wen Z, Yan M, Qin K, Liu Y, Wu J. Co-circulation and genomic recombination of coxsackievirus A16 and enterovirus 71 during a large outbreak of hand, foot and mouth disease in Central China. PLoS One 2014; 9(4):e96051; PMID:24776922; http://dx.doi.org/10.1371/journal.pone.0096051
15. Hongyan G, Chengile M, Qiaozhi Y, Wenhao H, Juan L, Lin P, Yanli X, Hongshan W, Xingwang L. Hand, foot and mouth disease caused by coxsackievirus A6, Beijing, 2013. Pediatr Infect Dis J 2014; 33:1302-3; PMID:25037037; http://dx.doi.org/10.1097/INF.0000000000000467
16. Han JF, Jiang T, Fan XL, Yang LM, Yu M, Cao RY, Wang JZ, Qin ED, Qin CF. Recombination of human coxsackievirus B5 in hand, foot and mouth disease patients, China. Emerg Infect Dis 2012; 18:351-3; PMID:22305307; http://dx.doi.org/10.3201/eid1802.111524
17. Han JF, Xu S, Zhang Y, Zhu SY, Wu DL, Yang XD, Liu H, Sun BX, Wu XY, Qin CF. Hand, foot and mouth disease outbreak caused by coxsackievirus A6, China 2013. J Infect 2014; 69:303-5; PMID:24704297; http://dx.doi.org/10.1016/j.jinf.2014.03.015
18. Chen JF, Zhang RS, Ou XH, Chen FM, Sun BC. The role of enterovirus 71 and coxsackievirus A strains in a large outbreak of hand, foot and mouth disease in Changsha, China. Int J Infect Dis 2014; 28:17-25; PMID:25236389; http://dx.doi.org/10.1016/j.ijid.2014.07.024
19. Zhang Y, Zhu Z, Yang W, Ren J, Tan X, Wang Y, Mao N, Xu S, Zhu S, Cui A, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand, foot and mouth disease in Fuyang city of China. Virol J 2010; 7:94-102; PMID:20459851; http://dx.doi.org/10.1186/1743-422X-7-94
20. He SJ, Han JF, Ding XX, Wang YD, Qin CF. Characterization of enterovirus 71 and coxsackievirus A16 isolated in hand, foot and mouth disease patients in Guandong, 2010. Int J Infect Dis 2013; 17:e1025-30; PMID:23791223; http://dx.doi.org/10.1016/j.ijid.2013.04.003
21. Lu J, Zeng H, Zheng H, Yi L, Guo X, Liu L, Sun L, Tan X, Li H, Ke C, Lin J. Hand, foot and mouth disease in Guangdong, China, in 2013: new trends in the continuing epidemic. Clin Microbiol Infect 2014; 20: O442-5; PMID:24428125; http://dx.doi.org/10.1111/1469-0691.12468
22. Di B, Zhang Y, Xie H, Li X, Chen C, Ding P, He P, Wang D, Geng J, Luo L, et al. Circulation of coxsackievirus A6 in hand-foot-and-mouth disease in Guangzhou, 2010-2012. Virol J 2014; 11:157-63; PMID:25178398; http://dx.doi.org/10.1186/1743-422X-11-157
23. Han JF, Cao RY, Jiang T, Yu M, Liu W, Tian X, Qin ED, Cao WC, Qin CF. Echovirus 30 in EV71-associated hand, foot and mouth disease outbreak, Guanxi, China. J Clin Virol 2011; 50:348-9; PMID:21306942; http://dx.doi.org/10.1016/j.jcv.2011.01.005
24. Tian H, Zhang Y, Sun Q, Zhu S, Li X, Pan Z, Xu W, Xu B. Prevalence of multiple enteroviruses associated with hand, foot and mouth disease in Shijiazhuang city, Hebei province, China: outbreaks of coxsackieviruses a10 and b3. PLoS One 2014; 9(1):e84233; PMID:24392117; http://dx.doi.org/10.1371/journal.pone.0084233
25. Fan X, Jiang J, Liu Y, Huang X, Wang P, Liu L, Wang J, Chen W, Wu W, Xu B. Detection of human enterovirus 71 and Coxsackievirus A16 in an outbreak of hand, foot and mouth disease in Henan Province, China in 2009. Virus Genes 2013; 46:1-9; PMID:23080402; http://dx.doi.org/10.1007/s11262-012-0814-x
26. Guan HY, Yang MJ, Liu LZ, Wang J, Yang GL, Zhang W, Ma XJ, Wang CR. Pathogenic spectrum of enteroviruses associated with hand, foot and mouth disease by a GeXPTM-based multiplex reverse transcription-PCR assay in Jinan, China, 2009-2012. Bing Du Xue Bao 2014; 30:567-71; PMID:25562968
27. Zhang X, Wang H, Ding S, Wang X, Chen X, Wo Y, Wang L, Huang D, Liu W, Cao W. Prevalence of enteroviruses in children with and without hand, foot and mouth disease in China. BMC Infect Dis 2013; 13:606-13; PMID:24370001; http://dx.doi.org/10.1186/1471-2334-13-606
28. Ni H, Yi B, Yin J, Fang T, He T, Du Y, Wang J, Zhang H, Xie L, Ding Y, et al. Epidemiological and etiological characteristics of hand, foot and mouth disease in Ningbo, China, 2008-2011. J Clin Virol 2012; 54:342-8; PMID:22652041; http://dx.doi.org/10.1016/j.jcv.2012.04.021
29. Du J, Wang X, Hu Y, Li Z, Li Y, Sun S, Yang F, Jin Q. Changing aetiology of hand, foot and mouth disease in Linyi, China, 2009-2011. Clin Microbiol Infect 2014; 20:O47-9; PMID:23910234; http://dx.doi.org/10.1111/1469-0691.12301
30. Hu YF, Yang F, Du J, Zhang T, Xue Y, Jin Q. Coxsackie B5 associated with neurological hand, foot and mouth disease, China. J Infect 2012; 65:189-91; PMID:22484273; http://dx.doi.org/10.1016/j.jinf.2012.03.021
31. Zhang T, Du J, Xue Y, Su H, Yang F, Jin Q. Epidemics and frequent recombination within species in outbreaks of human enteroviruses B-associated hand, foot and mouth disease in Shangdong China in 2010 and 2011. PLoS One 2013; 8(6):e67157; PMID:23840610; http://dx.doi.org/10.1371/journal.pone.0067157
32. Han JF, Zhang Y, Hou PQ, Zhu SY, Wu XY, Zhao H, Yu M, Qin CF. Human enterovirus co-infection in severe HFMD patients in China. J Clin Virol 2014; 61:621-2; PMID:25449173; http://dx.doi.org/10.1016/j.jcv.2014.09.005
33. Yan XF, Gao S, Xia JF, Ye R, Yu H, Long JE. Epidemic characteristic of hand, foot and mouth disease in Shanghai from 2009 to 2010: Enterovirus 71 subgenotype C4 as the primary causative agent and a high incidence of mixed infections with coxsackievirus A16. Scand J Infect Dis 2012; 44:297-305; PMID:22176514; http://dx.doi.org/10.3109/00365548.2011.634433
34. Zeng M, Li YF, Wang XH, Lu GP, Shen HG, Yu H, Zhu QR. Epidemiology of hand, foot and mouth disease in children in Shanghai 2007-2010. Epidemiol Infect 2012; 140:1122-30; PMID:21878145; http://dx.doi.org/10.1017/S0950268811001622
35. Xu M, Su L, Cao L, Zhong H, Dong N, Xu J. Enterovirus genotypes causing hand, foot and mouth disease in Shanghai, China: a molecular epidemiological analysis. BMC Infect Dis 2013; 13:489-97; PMID:24148902; http://dx.doi.org/10.1186/1471-2334-13-489
36. He YQ, Chen L, Xu WB, Yang H, Wang HZ, Zong WP, Xian HX, Chen HL, Yao XJ, Hu ZL, et al. Emergence, circulation and spatiotemporal phylogenetic analysis of coxsackievirus a6- and coxsackievirus a10-associated hand, foot and mouth disease infections from 2010 to 2012 in Shenzhen, China. J Clin Microbiol 2013; 51:3560-6; PMID:23966496; http://dx.doi.org/10.1128/JCM.01231-13
37. Li JL, Yuan J, Yang F, Wu ZQ, Hu YF, Xue Y, Zhou BP, Jin Q. Epidemic characteristics of hand, foot and mouth disease in southern China, 2013: coxsackievirus A6 has emerged as the predominant causative agent. J. Infect 2014; 69:299-303; PMID:24731881; http://dx.doi.org/10.1016/j.jinf.2014.04.001
38. 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. Arch Virol 2015; 160:1097-104; PMID:25680566; http://dx.doi.org/10.1007/s00705-015-2340-3
39. Chen L, Mou X, Zhang Q, Li Y, Lin J, Liu F, Yuan L, Tang Y, Xiang C. Detection of human enterovirus 71 and coxsackievirus A16 in children with hand, foot and mouth disease in China. Mol Med Rep 2012; 5:1001-4; PMID:22218731
40. Gopalkrishna V, Patil PR, Patil GP, Chitambar SD. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol 2012; 61:420-5; PMID:22052995; http://dx.doi.org/10.1099/jmm.0.036400-0
41. Kar BR, Dwibedi B, Kar SK. An outbreak of hand, foot and mouth in Bhubaneswar, Odisha. Indian Pediatr 2013; 50:139-42; PMID:22728634; http://dx.doi.org/10.1007/s13312-013-0033-0
42. Lee MS, Tseng FC, Wang JR, Chi CY, Chong P, Su IJ. Challenges to licensure of enterovirus 71 vaccines. PLoS Negl Trop Dis 2012; 6(8):e1737; PMID:22953003; http://dx.doi.org/10.1371/journal.pntd.0001737
43. Iwai M, Masaki A, Hasegawa S, Obara M, Horimoto E, Nakamura K, Tanaka Y, Endo K, Tanaka K, Ueda J, et al. Genetic changes of coxsackievirus A16 and enterovirus 71 isolated from hand, foot and mouth disease patients in Toyama, Japan between 1981 and 2007. Jpn J Infect Dis 2009; 62:254-9; PMID:19628900
44. Sano T, Saito T, Kondo M, Watanabe S, Onoue Y, Konnai M, Sato Y, Orihara N. Enterovirus detection status of patients with herpangina and hand, foot and mouth disease in epidemic season 2007, Kanagawa Prefecture, Japan. Jpn J Infect Dis 2008; 61:162-3; PMID:18362414
45. Miyamoto A, Hirata R, Ishimoto K, Hisatomi M, Wasada R, Akita Y, Ishihara T, Fujimoto T, Eshima N, Hatano Y, et al. An outbreak of hand-foot-andmouth disease mimicking chicken pox, with a frequent association of onychomadesis in Japan in 2009: a new phenotype caused by coxsackievirus A6. Eur J Dermatol 2014; 24:103-4; PMID:24334231
46. Fujimoto T, Iizuka S, Enomoto M, Abe K, Yamashita K, Hanaoka N, Okabe N, Yoshida H, Yasui Y, Kobayashi M, et al. Hand, foot and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis 2012; 18:337-9; PMID:22304983; http://dx.doi.org/10.3201/eid1802.111147
47. Park SH, Lee BH, Baek KA, Cheon D, Yeo S, Park J, Soh J, Cheon H, Yoon K, Choi Y. Enteroviruses isolated from herpangina and hand, foot and mouth disease in Korean children. Virol J 2012; 9:205-10; PMID:22985487; http://dx.doi.org/10.1186/1743-422X-9-205
48. Chua KB, Kasri AR. Hand, foot and mouth disease due to enterovirus 71 in Malaysia. Virol Sin 2011; 26:221-8; PMID:21847753; http://dx.doi.org/10.1007/s12250-011-3195-8
49. Ang LW, Koh BK, Chan KP, Chua LT, James L, Goh KT. Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007. Ann Acad Med Singapore 2009; 38:106-12; PMID:19271036
50. Wu Y, Yeo A, Phoon MC, Tan EL, Poh CL, Quak SH, Chow VT. The largest outbreak of hand, foot and mouth disease in Singapore in 2008: the role of enterovirus71 and coxsackievirus A strains. Int J Infect Dis 2010; 14:e1076-81; PMID:20952237; http://dx.doi.org/10.1016/j.ijid.2010.07.006
51. Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY. Epidemiologic features of hand-foot-mouth disease and hyperangina caused by enterovirus 71 in Taiwan, 1998-2005. Pediatrics 2007; 120:e245-52
52. Lo SH, Huang YC, Huang CG, Tsao KC, Li WC, Hsieh YC, Chiu CH, Lin TY. Clinical and epidemiologic features of coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect 2011; 44:252-7; PMID:21524960; http://dx.doi.org/10.1016/j.jmii.2011.01.031
53. Hsu CH, Lu CY, Shao PL, Lee PI, Kao CL, Chung MY, Chang LY, Huang LM. Epidemiologic and clinical features of non-polio enteroviral infections in northern Taiwan in 2008. J Microbiol Immunol Infect 2011; 44:265-73; PMID:21524954; http://dx.doi.org/10.1016/j.jmii.2011.01.029
54. Lee MH, Huang LM, Wong WW, Wu TZ, Chiu TF, Chang LY. Molecular diagnosis and clinical presentations of enteroviral infections in Taipei during the 2008 epidemic. J Microbiol Immunol Infect 2011; 44:178-83; PMID:21524611; http://dx.doi.org/10.1016/j.jmii.2011.01.018
55. Huang WC, Huang LM, Lu CY, Cheng AL, Chang LY. Atypical hand-foot-mouth disease in children: a hospital-based prospective cohort study. Virol J 2013; 10:209-17; PMID:23800163; http://dx.doi.org/10.1186/1743-422X-10-209
56. Puenpa J, Chieochansin T, Linsuwanon P, Korkong S, Thongkomplew S, Vichaiwattana P, Theamboonlers A, Poovorawan Y. et al. Hand, foot and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis 2013; 19:641-3; PMID:23631943; http://dx.doi.org/10.3201/eid1904.121666
57. Puenpa J, Mauleekoonphairoj J, Linsuwanon P, Suwannakarn K, Chieochansin T, Korkong S, Theamboonlers A, Poovorawan Y. Prevalence and characterization of enterovirus infections among pediatric patients with hand foot mouth disease, herpangina and influenza like illness in Thailand, 2012. PLoS One 2014; 9(6):e98888; PMID:24887237; http://dx.doi.org/10.1371/journal.pone.0098888
58. Linsuwanon P, Puenpa J, Huang SW, Wang YF, Mauleekoonphairoj J, Wang JR, Poovorawan Y. Epidemiology and seroepidemiology of human enterovirus 71 among Thai populations. J Biomed Sci 2014; 21:16-28; PMID:24548776; http://dx.doi.org/10.1186/1423-0127-21-16
59. Tu PV, Thao NTT, Perera D, Huu TK, Tien NT, Thuong TC, How OM, Cardosa MJ, McMinn PC. Epidemiologic and virologic investigation of hand, foot and mouth disease, southern Vietnam, 2005. Emerg Infect Dis 2007; 13:1733-41; PMID:18217559; http://dx.doi.org/10.3201/eid1307.060999
60. Thoa le PK, Chiang PS, Khanh TH, Luo ST, Dan TN, Wang YF, Thuong TC, Chung WY, Hung NT, Wang JR, et al. Genetic and antigenic characterization of enterovirus 71 in Ho Chi Minh City, Vietnam, 2011. PLoS One 2013; 8(7):e69895; PMID:23922846; http://dx.doi.org/10.1371/journal.pone.0069895
61. Zander A, Britton PN, Navin T, Horsley E, Tobin S, McAnulty JM. An outbreak of enterovirus 71 in metropolitan Sydney: enhanced surveillance and lessons learnt. Med J Aust 2014; 201:663-6; PMID:25495312; http://dx.doi.org/10.5694/mja14.00014
62. Blomqvist S, Klemola P, Kaijalainen S, Paananen A, Simonen ML, Vuorinen T, Roivainen M. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J ClinVirol 2010; 48:49-54
63. Mirand A, Henquell C, Archimbaud C, Ughetto S, Antona D, Bailly JL, Peigue-Lafeuille H. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 and A10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect 2012; 18:E110-8; PMID:22404077; http://dx.doi.org/10.1111/j.1469-0691.2012.03789.x
64. Kapusinszky B, Szomor KN, Farkas A, Takacs M, Berencsi G. Detection of non-polioviruses in Hungary 2000-2008 and molecular epidemiology of enterovirus 71, coxsackievirus A16 and echovirus 30. Virus Genes 2010; 40:163-73; PMID:20044791; http://dx.doi.org/10.1007/s11262-009-0440-4
65. Bracho MA, Gonzales-Candelas F, Valero A, Cordoba J, Salazar A. Enterovirus co-infections and onychomadesis after hand, foot and mouth disease, Spain, 2008. Emerg Infect Dis 2011; 17:2223-1; PMID:22172227; http://dx.doi.org/10.3201/eid1712.110395
66. Davia JL, Bel PH, Ninet VZ, Bracho MA, Gonzalez-Candelas F, Salazar A, Gobernado M, Bosch IF. Onychomadesis outbreak in Valencia, Spain associated with hand, foot, and mouth disease caused by enteroviruses. Pediatr Dermatol 2011; 28:1-5; PMID:20553401; http://dx.doi.org/10.1111/j.1525-1470.2010.01161.x
67. Cabrerizo M, Tarrago D, Munoz-Almagro C, Del Amo E, Domínguez-Gil M, Eiros JM, López-Miragaya I, Pérez C, Reina J, Otero A, et al. Molecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated hand, foot and mouth disease in Spain. Clin Microbiol Infect 2014; 20:O150-6; PMID:24033818; http://dx.doi.org/10.1111/1469-0691.12361
68. Montes M, Artieda J, Pineiro LD, Gastesi M, Diez-Nieves I, Cilla G. Hand, foot, and mouth disease outbreak and coxsackievirus A6, northern Spain, 2011. Emerg Infect Dis 2013; 19:676-8; PMID:23751014; http://dx.doi.org/10.3201/eid1904.121589
69. Sinclair C, Gaunt E, Simmonds P, Broomfield D, Nwafor N, Wellington L, Templeton K, Willocks L, Schofield O, Harvala H. Atypical hand, foot, and mouth disease associated with coxsackievirus A6 infection, Edinburgh, United Kingdom, January to February 2014. Euro Surveill 2014; 19:20745-51; PMID:24698138
70. World Health Organization. Hand, foot and mouth disease a rising menace in Asia. 13 July 2009. Available at http://www.wpro.who.int/mediacentre/news/2009/2009013/en/
71. Abzug MJ. The enteroviruses: problems in need of treatment. J Infect 2014; 68 Suppl 1:S108-S114; PMID:24119825; http://dx.doi.org/10.1016/j.jinf.2013.09.020
72. Chong P, Liu CC, Chow YH, Chou AH, Klein M. Review of enterovirus 71 vaccines. Clin Infect Dis 2015; 60:797-803; PMID:25352588; http://dx.doi.org/10.1093/cid/ciu852
73. McMinn PC. Enterovirus vaccines for an emerging cause of brain-stem encephalitis. N Engl J Med 2014; 370:792-4; PMID:24571750; http://dx.doi.org/10.1056/NEJMp1400601
74. Wang SM, Ho TS, Lin HC, Lei HY, Wang JR, Liu CC. Reemerging of enterovirus 71 in Taiwan: the age impact on disease severity. Eur J Microbiol Infect Dis 2012; 31:1219-24; PMID:21983920; http://dx.doi.org/10.1007/s10096-011-1432-6
75. Huang MC, Wang SM, Hsu YW, Lin HC, Chi CY, Liu CC. Long-term cognitive and motor deficits after enterovirus 71 brainstem encephalitis in children. Pediatrics 2006; 118:e1785-8; PMID:17116698; http://dx.doi.org/10.1542/peds.2006-1547
76. Yang C, Deng C, Wan J, Zhu L, Leng Q. Neutralizing antibody response in the patients with hand, foot and mouth disease to enterovirus 71 and its clinical implications. Virol J 2011; 8:306-11; PMID:21679417; http://dx.doi.org/10.1186/1743-422X-8-306
77. Wei R, Xu L, Zhang N, Zhu K, Yang J, Yang C, Deng C, Zhu Z, De Groot AS, Altmeyer R, et al. Elevated antigen-specific Th2 type response is associated with the poor prognosis of hand, foot and mouth disease. Virus Res 2013; 177:62-5; PMID:23886670; http://dx.doi.org/10.1016/j.virusres.2013.07.009
78. Li S, Cai C, Feng J, Li X, Wang Y, Yang J, Chen Z. Peripheral T lymphocyte subset imbalances in children with enterovirus 71-induced hand, foot and mouth disease. Virus Res 2014; 180:84-91; PMID:24316007; http://dx.doi.org/10.1016/j.virusres.2013.11.021
79. Huang WC, Huang LM, Kao CL, Lu CY, Shao PL, Cheng AL, Fan TY, Chi H, Chang LY. Seroprevalence of enterovirus 71 and no evidence of crossprotection of enterovirus 71 antibody against the other enteroviruses in kindergarten children in Taipei city. J Microbiol Immunol Infect 2012; 45:96-101; PMID:22154997; http://dx.doi.org/10.1016/j.jmii.2011.09.025
80. Ben-Chetrit E, Wiener-Well Y, Shulman LM, Cohen MJ, Elinav H, Sofer D, Feldman I,Marva E, Wolf DG. Coxsackievirus A6-related hand, foot and mouth disease: skin manifestations in a cluster of adult patients. J Clin Virol 2014; 59:201-3; PMID:24457116; http://dx.doi.org/10.1016/j.jcv.2013.12.012
81. Downing C, Ramirez-Fort MK, Doan HQ, Benoist F, Oberste MS, Khan F, Tyring SK. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol 2014; 60:381-6; PMID:24932735; http://dx.doi.org/10.1016/j.jcv.2014.04.023
82. Aizaki K, Tsuru T, Okumura K, Kondo N. [Three pediatric cases of group A coxsackievirus-associated encephalitis/encephalopathy]. No To Hattatsu 2012; 44:397-400; PMID:23012870
83. 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. Clin Infect Dis 2014; 59:1504-5; PMID:25091307; http://dx.doi.org/10.1093/cid/ciu624
84. Spanakis N, Manolis EN, Tsakris A, Tsiodras S, Panagiotopoulos T, Saroglou G, Legakis NJ. Coxsackievirus B3 sequences in the myocardium of fatal cases in a cluster of acute myocarditis in Greece. J Clin Pathol 2005; 58:357-60; PMID:15790697; http://dx.doi.org/10.1136/jcp.2004.020099
85. Chu PY, Ke GM, Chen YS, Lu PL, Chen HL, Lee MS, Chen BC, Huang TS, Li YC, Chou LC, et al. Molecular epidemiology of Coxsackievirus B3. Infect Genet Evol 2010; 10:777-84; PMID:20398802; http://dx.doi.org/10.1016/j.meegid.2010.04.004
86. Lee CJ, Huang YC, Yang S, Tsao KC, Chen CJ, Hsieh YC, Chiu CH, Lin TY. Clinical features of coxsackievirus A4, B3 and B4 infections in infants. PLoS One 2014; 9(2):e87391; PMID:24504149; http://dx.doi.org/10.1371/journal.pone.0087391
87. Kim HJ, Kang B, Hwang S, Hong J, Kim K, Cheon DS. Epidemics of viral meningitis cause by echovirus 6 and 30 in Korea in 2008. Virol J 2012; 9:38-44; PMID:22336050; http://dx.doi.org/10.1186/1743-422X-9-38
88. Hober D, Sauter P. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nat Rev Endocrinol 2010; 6:279-89; PMID:20351698; http://dx.doi.org/; http://dx.doi.org/10.1038/nrendo.2010.27
89. Wu PC, Huang LM, Kao CL, Fan TY, Cheng AL, Chang LY. An outbreak of coxsackievirus A16 infection: comparison with other enteroviruses in a preschool in Taipei. J Microbiol Immunol Infect 2010; 43:271-7; PMID:20688286; http://dx.doi.org/10.1016/S1684-1182(10)60043-6
90. Miyazawa I, Azegami Y, Kasuo S, Yoshida T, Kobayashi M, Shiraishi T. Prevalence of enterovirus from patients with herpangina and hand, foot and mouth disease in Nagano Prefecture, Japan, 2007. Jpn J Infect Dis 2008; 61:747-8
91. Yamashita T, Ito M, Tanigushi A, Sakae K. Prevalence of coxsackievirus A5, A6 and A10 in patients with herpangina in Aichi Prefecture, 2005. Jpn J Infect Dis 2005; 58:390-1; PMID:16377876
92. Plevka P, Perera R, Cardosa J, Kuhn RJ, Rossmann MG. Crystal structure of human enterovirus 71. Science 2012; 336:1274-7; PMID:22383808; http://dx.doi.org/10.1126/science.1218713
93. Lyu K, Wang GC, He YL, Han JF, Ye Q, Qin CF, Chen R. Crystal structure of enterovirus 71 (EV71) recombinant virus particles provide insights into vaccine design. J Biol Chem 2015; 290:3198-208; PMID:25492868; http://dx.doi.org/10.1074/jbc.M114.624536
94. Yoder JD, Cifuente JO, Pan J, Bergelson JM, Hafenstein S. The crystal structure of a coxsackievirus B3-RD variant and a refined 9-angstrom cryo-electron microscopy reconstruction of the virus complexed with decay-accelerating factor (DAF) provide a new footprint of DAF on the virus surface. J Virol 2012; 86:12571-81; PMID:22973031; http://dx.doi.org/10.1128/JVI.01592-12
95. Huang PN, Shih SR. Update on enterovirus 71 infection. Curr Opin Virol 2014; 5:98-104; PMID:24727707; http://dx.doi.org/10.1016/j.coviro.2014.03.007
96. Liu CC, Guo MS, Lin FH, Hsiao KN, Chang KH, Chou AH, Wang YC, Chen YC, Yang CS, Chong PC. Purification and characterization of enterovirus 71 particles produced from vero cells grown in serumfree microcarrier bioreactor system. PLoS One 2011; 6(5):e20005; PMID:21603631; http://dx.doi.org/10.1371/journal.pone.0020005
97. Lin JY, Shih SR. Cell and tissue tropism of enterovirus 71 and other enteroviruses infections. J Biomed Sci 2014; 21:18-23; PMID:24602216; http://dx.doi.org/10.1186/1423-0127-21-18
98. Muehlenbachs A, Bhatnagar J, Zaki SR. Tissue tropism, pathology and pathogenesis of enterovirus infection. J Pathol 2015; 235:217-28; PMID:25211036; http://dx.doi.org/10.1002/path.4438
99. Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 2009; 15:794-7; PMID:19543284; http://dx.doi.org/10.1038/nm.1961
100. Yamayoshi A, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, Koike S. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 2009; 15:798-801; PMID:19543282; http://dx.doi.org/10.1038/nm.1992
101. Yamayoshi A, Ohka S, Fujii K, Koike S. Functional comparison of SCARB2 and PSGL1 as receptors for enterovirus 71. J Virol 2013; 87:3335-47; PMID:23302872; http://dx.doi.org/10.1128/JVI.02070-12
102. Yang SL, Chou YT, Wu CN, Ho MS. Annexin II binds to capsid protein VP1 of enterovirus 71 and enhances viral infectivity. J Virol 2011; 85:11809-20; PMID:21900167; http://dx.doi.org/10.1128/JVI.00297-11
103. Tan CW, Poh CL, Sam IC, Chan YF. Enterovirus 71 uses cell surface heparin sulfate glycoaminoglycan as an attachment receptor. J Virol 2013; 87:611-20; PMID:23097443; http://dx.doi.org/10.1128/JVI.02226-12
104. Su PY, Liu YT, Chang HY, Huang SW, Wang YF, Yu CK, Wang JR, Chang CF. Cell surface sialylation affects binding of enterovirus 71 to rhabdomyosarcoma and neuroblastoma cells. BMC Microbiol 2012; 12:162-73; PMID:22853823; http://dx.doi.org/10.1186/1471-2180-12-162
105. Ren XX, Ma L, Liu QW, Li C, Huang Z, Wu L, Xiong SD, Wang JH, Wang HB. The molecule of DC-SIGN captures enterovirus 71 and confers dendritic cell-mediated viral trans-infection. Virol J 2014; 11:47-55; PMID:24620896; http://dx.doi.org/10.1186/1743-422X-11-47
106. Milstone AM, Petrella J, Sanchez MD, Mahmud M, Whitbeck JC, Bergelson JM. Interaction with coxsackievirus and adenovirus receptor, but not with decay-accelerating factor (DAF), induces A-particle formation in a DAF-binding coxsackievirus B3 isolate. J Virol 2005; 79:655-60; PMID:15596863; http://dx.doi.org/10.1128/JVI.79.1.655-660.2005
107. Orthopoulos G, Triantafilou K, Triantafilou M. Coxsackie B viruses use multiple receptors to infect human cardiac cells. J Med Virol 2004; 74:291-9; PMID:15332279; http://dx.doi.org/10.1002/jmv.20184
108. Tsueng G, Tabor-Godwin JM, Gopal A, Ruller CM, Deline S, An N, Frausto RF, Milner R, Crocker SJ, Whitton JL, et al. Coxsackievirus preferentially replicates and induces cytopathic effect in undifferentiated neural progenitor cells. J Virol 2011; 85:5718-32; PMID:21471247; http://dx.doi.org/10.1128/JVI.02261-10
109. Ylipaasto P, Eskelinen M, Salmela K, Hovi T, Roivainen M. Vitronectin receptors, alpha v integrins, are recognized by several non-RGD-containing echoviruses in a continuous laboratory cell line and also in primary human Langerhans’ islets and endothelial cells. J Gen Virol 2010; 91:155-65; PMID:19776235; http://dx.doi.org/10.1099/vir.0.012450-0
110. Lee JW, Yeo SG, Kang BH, Lee HK, Kim JW, Lee SH, Kim KS, Cheon DS. Echovirus 30 induced neuronal cell death through TRIO-RhoA signaling activation. PLoS One 2012; 7(5):e36656; PMID:22586486; http://dx.doi.org/10.1371/journal.pone.0036656
111. Sickles GM, Mutterer M, Feorino P, Plager H. Recently classified types of Coxsackie virus, group A: behavior in tissue culture. Proc Soc Exp Biol Med 1955; 90:529-31; PMID:13273503; http://dx.doi.org/10.3181/00379727-90-22088
112. Robinson CR, Doane FW, Rhodes AJ. Report of an outbreak of febrile illness with pharyngeal lesions and exanthem: Toronto, summer 1957; isolation of group A Coxsackie virus. Can Med Ass J 1958; 79:615-21; PMID:13585281
113. Alsop J, Flewett TH, Foster JR. “Hand-foot-andmouth” disease in Birmingham in 1959. Br Med J 1960; 2:1708-11; PMID:13682692; http://dx.doi.org/10.1136/bmj.2.5214.1708
114. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 1974; 129:304-9; PMID:4361245; http://dx.doi.org/10.1093/infdis/129.3.304
115. Seiff A. Cambodia unravels cause of mystery illness. Lancet 2012; 380:206; PMID:22826834; http://dx.doi.org/10.1016/S0140-6736(12)61200-8
116. Yang F, Ren L, Xiong Z, Li J, Xiao Y, Zhao R, He Y, Bu G, Zhou S, Wang J, et al. Enterovirus 71 outbreaks in the People’s Republic of China in 2008. J Clin Microbiol 2009; 47:2351-2; PMID:19439545; http://dx.doi.org/10.1128/JCM.00563-09
117. Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, Chang Z, Liu F, Fang VJ, Zheng Y, et al. Hand, foot and mouth disease in China, 2008-12: an epidemiology study. Lancet Infect Dis 2014; 14:308-318; PMID:24485991; http://dx.doi.org/10.1016/S1473-3099(13)70342-6
118. Li Z, Yu J, Liu L, Wei Z, Ehrlich ES, Liu G, Li J, Liu X, Wang H, Yu XF, et al. Coxsackievirus A16 infection induces neural cell and non-neural cells apoptosis in vitro. PLoS One 2014; 9(10):e111174; PMID:25350381; http://dx.doi.org/10.1371/journal.pone.0111174
119. Bessaud M, Razafindratsimandresy R, Nougairede A, Joffret ML, Deshpande JM, Dubot-Peres A, Heraud JM, de Lamballerie X, Delpeyroux F, Bailly JL. et al. Molecular comparison and evolutionary analyses of VP1 nucleotide sequences of new African human enterovirus 71 isolates reveal a wide genetic diversity. PLoS One 2014; 9(3):e90624; PMID:24598878; http://dx.doi.org/10.1371/journal.pone.0090624
120. Mizuta K, Aoki Y, Matoba Y, Yahagi K, Itagaki T, Katsushima F, Katsushima Y, Ito S, Hongo S, Matsuzaki Y. Molecular epidemiology of enterovirus 71 strains isolated from children in Yamagata, Japan, between 1990 and 2013. J Med Microbiol 2014; 63:1356-62; PMID:25053796; http://dx.doi.org/10.1099/jmm.0.079699-0
121. Chia MY, Chiang PS, Chung WY, Luo ST, Lee MS. Epidemiology of enterovirus 71 infections in Taiwan. Pediatr Neonatolo 2014; 55:243-9; PMID:24120535; http://dx.doi.org/10.1016/j.pedneo.2013.07.007
122. Zong W, He Y, Yu S, Yang H, Xian H, Liao Y, Hu G. Molecular phylogeny of Coxsackievirus A16 in Shenzhen, China, from 2005 to 2009. J Clin Microbiol 2011; 49:1659-61; PMID:21325543; http://dx.doi.org/10.1128/JCM.00010-11
123. Yang E, Zhao H, Zhang Y, Liu J, Liao Y, Wang L, Cui P, Yang L, Liu L, Dong C, et al. A comparative study of the characteristics of two Coxsackie A virus type 16 strains (genotype B). Sci China Life Sci 2012; 55:336-42; PMID:22566090; http://dx.doi.org/10.1007/s11427-012-4313-z
124. Baek KA, Yeo SG, Lee BH, Park K, Song J, Yu J, Rheem I, Kim J, Hwang S, Choi Y, et al. Epidemics of enterovirus infection in Chungnam Korea, 2008-2009. Virol J 2011; 8:297-305; PMID:21668960; http://dx.doi.org/10.1186/1743-422X-8-297
125. Drake JW, Charlesworth B, Charlesworth D, Cow JF. Rates of spontaneous mutations. Genetics 1998; 148:1667-86; PMID:9560386
126. Huang SW, Cheng HL, Hsieh HY, Chang CL, Tsai HP, Kuo PH, Wang SM, Liu CC, Su IJ, Wang JR. Mutations in the non-structural protein region contribute to intra-genotypic evolution of enterovirus 71. J Biomed Sci 2014; 21:33-47; PMID:24766641; http://dx.doi.org/10.1186/1423-0127-21-33
127. Yang F, Du J, Hu Y, Wang X, Xue Y, Dong J, Sun L, Li Z, Li Y, Sun S, et al. Enterovirus coinfection during an outbreak of hand, foot and mouth disease in Shangdong, China. Clin Infect Dis 2011; 53:400-1; PMID:21785005; http://dx.doi.org/10.1093/cid/cir346
128. Zhang T, Du J, Xue Y, Su H, Yang F, Jin Q. Epidemics and frequent recombination within species in outbreaks of human enterovirus B-associated hand, foot and mouth disease in Shangdong China in 2010 and 2011. PLoS One 2013; 8(6):e67157; PMID:23840610; http://dx.doi.org/10.1371/journal.pone.0067157
129. Zhao K, Han X, Wang G, Hu W, Zhang W, Yu XF. Circulating coxsackievirus A16 identified as recombinant type A human enteroviruses, China. Emerg Infect Dis 2011; 17:1537-40; PMID:21801645
130. Chen X, Tan X, Li J, Jin Y, Gong L, Hong M, Shi Y, Zhu S, Zhang B, Zhang S, et al. Molecular epidemiology of coxsackievirus A16: Intratype and prevalent intertype recombination identified. PLoS One 2013; 8(12):e82861; PMID:24340064; http://dx.doi.org/10.1371/journal.pone.0082861
131. Wu Z, Du J, Zhang T, Xue Y, Yang F, Jin Q. Recombinant human coxsackievirus B3 from children with acute myocarditis in China. J Clin Microbiol 2013; 51:3083-6; PMID:23804378; http://dx.doi.org/10.1128/JCM.00270-13
132. Li Z, Lai S, Zhang H, Wang L, Zhou D, Liu J, Lan Y, Ma J, Yu H, Buckeridge DL, et al. Hand, foot and mouth disease in China: evaluating an automated system for detection of outbreaks. Bull World Health Organ 2014; 92:656-63; PMID:25378756; http://dx.doi.org/10.2471/BLT.13.130666
133. Chen J, Fu Y, Ju L, Miao X, Shen Y, He L, Wang W, Jin J, Shao L, Sampath R, Ecker DJ, et al. Detection and identification of viral pathogens in patients with hand, foot and mouth disease by multilocus PCR, reverse-transcription PCR and electrospray ionization mass spectrometry. J Clin Virol 2014; 59:115-9; PMID:24365476; http://dx.doi.org/10.1016/j.jcv.2013.11.007
134. Klein MH. EV71 vaccines: a first step towards multivalent hand, foot and mouth disease vaccines. Expert Rev Vaccines 2015; 14:337-40; PMID:25536888; http://dx.doi.org/10.1586/14760584.2015.993385
135. Chong P, Hsieh SY, Liu CC, Chou AH, Chang JY, Wu SC, Liu SJ, Chow YH, Su IJ, Klein M. Production of EV71 vaccine candidates. Hum Vaccin Immunother 2012; 8:1775-83; PMID:22992566; http://dx.doi.org/10.4161/hv.21739
136. Kung YA, Hung CT, Liu YC, Shih SR. Update on the development of enterovirus 71 vaccines. Expert Opin Biol Ther 2014; 14:1455-64; PMID:24989170; http://dx.doi.org/10.1517/14712598.2014.935330
137. Li YX, Zhao H, Cao RY, Deng YQ, Han JF, Zhu SY, Ma J, Liu L, Qin ED, Qin CF1. Recombinant tandem multi-linear neutralizing epitopes of human enterovirus 71 elicited protective immunity in mice. Virol J 2014; 11:79-87; PMID:24885030; http://dx.doi.org/10.1186/1743-422X-11-79
138. Wang M, Jiang S, Wang Y. Recombinant VP1 protein expressed in Pichia pastoris induces protective immune responses against EV71 in mice. Biochem Biophys Res Commun 2013; 430:387-93; PMID:23159634; http://dx.doi.org/10.1016/j.bbrc.2012.11.035
139. Chou AH, Liu CC, Chang JY, Lien SP, Guo MS, Tasi HP, Hsiao KN, Liu SJ, Sia C, Wu SC, et al. Immunological evaluation and comparison of different EV71 vaccine candidates. Clin Dev Immunol 2012; 2012:831282
140. Premanand B, Kiener TK, Meng T, Tan YR, Jia Q, Chow VT, Kwang J. Induction of protective immune responses against EV71 in mice by baculovirus encoding a novel expression cassette for capsid protein VP1. Antiviral Res 2012; 95:311-5; PMID:22691220; http://dx.doi.org/10.1016/j.antiviral.2012.05.017
141. Kolpe AB, Kiener TK, Grotenbreg GM, Kwang J. Display of enterovirus 71 VP1 on baculovirus as a type II transmembrane protein elicits protective B and T cell responses in immunized mice. Virus Res 2012; 168:64-72; PMID:22728446; http://dx.doi.org/10.1016/j.virusres.2012.06.014
142. Tung WS, Bakar SA, Sekawi Z, Rosli R. DNA vaccine constructs against enterovirus 71 elicit immune responses in mice. Genet Vaccines 2007; 5:6-18; PMID:17445254; http://dx.doi.org/10.1186/1479-0556-5-6
143. Tian X, Su X, Li X, Li H, Li T, Zhou Z, Zhong T, Zhou R. Protection against enterovirus 71 with neutralizing epitope incorporation within adenovirus type 3 hexon. PLoS One 2012; 7(7):e41381; PMID:22848478; http://dx.doi.org/10.1371/journal.pone.0041381
144. Li HY, Han JF, Qin CF, Chen R. Virus-like particles for enterovirus 71 produced from Saccharomyces cerevisiae potently elicits protective immune responses in mice. Vaccine 2013; 31:3281-7; PMID:23726823; http://dx.doi.org/10.1016/j.vaccine.2013.05.019
145. Lin YL, Yu CI, Hu YC, Tsai TJ, Kuo YC, Chi WK, Lin AN, Chiang BL. Enterovirus type 71 neutralizing antibodies in the serum of macaque monkeys immunized with EV71 virus-like particles. Vaccine 2012; 30:1305-12; PMID:22214888; http://dx.doi.org/10.1016/j.vaccine.2011.12.081
146. Chen HF, Chang MH, Chiang BL, Jeng ST. Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71. Vaccine 2006; 24:2944-51; PMID:16448730; http://dx.doi.org/10.1016/j.vaccine.2005.12.047
147. Zhang F, Hao C, Zhang S, Li A, Zhang Q, Wu W, Liu L, Li C, Liang M, Li X, et al. Oral immunization with recombinant enterovirus 71 VP1 formulated with chitosan protects mice against lethal challenge. Virol J 2014; 11:80-8; PMID:24885121; http://dx.doi.org/10.1186/1743-422X-11-80
148. Premanand B, Prabakaran M, Kiener TK, Kwang J. Recombinant baculovirus associated with bilosomes as an oral vaccine candidate against HEV71 infection in mice. PLoS One 2013; 8(2):e55536; PMID:23390538; http://dx.doi.org/10.1371/journal.pone.0055536
149. Chiu CH, Chu C, He CC, Lin TY. Protection of neonatal mice from lethal enterovirus 71 infection by maternal immunization with attenuated Salmonella enterica serovar Typhimurium expressing VP1 of enterovirus 71. Microbes Infect 2006; 8:1671-8; PMID:16815726; http://dx.doi.org/10.1016/j.micinf.2006.01.021
150. Yu Z, Huana Z, Sao C, Huang Y, Zhang F, Ma G, Chen Z, Zeng Z, Qiwen D, Zeng W. Oral immunization of mice using Bifidobacterium longum expressing VP1 protein from enterovirus 71. Arch Virol 2013; 158:1071-7; PMID:23275129; http://dx.doi.org/10.1007/s00705-012-1589-z
151. Arita M, Shimizu H, Nagata N, Ami Y, Suzaki Y, Sata T, Iwasaki T, Miyamura T. Temperature-sensitive mutants of enterovirus 71 show attenuation in cynomolgus monkeys. J Gen Virol 2005; 86:1391-401; PMID:15831951; http://dx.doi.org/10.1099/vir.0.80784-0
152. Meng T, Kwang J. Attenuation of human enterovirus 71 high-replication-fidelity variants in AG129 mice. J Virol 2014; 88:5803-15; PMID:24623423; http://dx.doi.org/10.1128/JVI.00289-14
153. Bek EJ, Hussain KM, Phuektes P, Kok CC, Gao Q, Cai F, Gao Z, McMinn PC. Formalin-inactivated vaccine provokes cross-protective immunity in a mouse model of human enterovirus 71 infection. Vaccine 2011; 29:4829-38; PMID:21550375; http://dx.doi.org/10.1016/j.vaccine.2011.04.070
154. 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. Vaccine 2011; 29:6269-75; PMID:21722686; http://dx.doi.org/10.1016/j.vaccine.2011.06.044
155. Cheng A, Fung CP, Liu CC, Lin YT, Tsai HY, Chang SC, Chou AH, Chang JY, Jiang RH, Hsieh YC, et al. A phase 1, randomized, open-label study to evaluate the safety and immunogenicity of enterovirus 71 vaccine. Vaccine 2013; 31:2471-6; PMID:23541623; http://dx.doi.org/10.1016/j.vaccine.2013.03.015
156. Chou AH, Liu CC, Chang JY, Jiang R, Hsieh YC, Tsao A, Wu CL, Huang JL, Fung CP, Hsieh SM, et al. Formalin-inactivated EV71 vaccine candidate induced crossneutralizing antibody responses against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLoS One 2013; 8 (11):e79783; PMID:24278177; http://dx.doi.org/10.1371/journal.pone.0079783
157. Li JX, Mao QY, Liang ZL, Ji H, Zhu FC. Development of enterovirus 71 vaccines: from the lab bench to phase III clinical trials. Expert Rev Vaccines 2014; 13:609-18; PMID:24621093; http://dx.doi.org/10.1586/14760584.2014.897617
158. Zhu FC, Meng FY, Li JX, Li XL, Mao QY, Tao H, Zhang YT, Yao X, Chu K, Chen QH, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvanted enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2013; 38:2024-32; http://dx.doi.org/10.1016/S0140-6736(13)61049-1
159. Zhu F, Xu W, Xia J, Liang Z, Liu Y, Zhang X, Tan X, Wang L, Mao Q, Wu J, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med 2014; 370:818-28; PMID:24571754; http://dx.doi.org/10.1056/NEJMoa1304923
160. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, Zhang Y, Li Y, Mao Q, Wang J, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med 2014; 370:829-37; PMID:24571755; http://dx.doi.org/10.1056/NEJMoa1303224
161. Mao Q, Cheng T, Zhu F, Li J, Wang Y, Li Y, Gao F, Yang L, Yao X, Shao J, et al. The cross-neutralizing activity of enterovirus 71 subgenotype c4 vaccines in healthy Chinese infants and children. PLoS One 2013; 8(11):e79599; PMID:24260259; http://dx.doi.org/10.1371/journal.pone.0079599
162. Wang J, Qi S, Zhang X, Zhang Y, Liu L, Che Y, He Z, Zhao Y, Lu S, Yu W, et al. Coxsackievirus A16 infection does not interfere with the specific immune response induced by an enterovirus 71 inactivated vaccine in Rhesus monkeys. Vaccine 2014; 32:4436-42; PMID:24958699; http://dx.doi.org/10.1016/j.vaccine.2014.06.062
163. Chen YJ, Meng FY, Mao QY, Chen YJ, Meng FY, Mao Q, Li JX, Wang H, Liang ZL, Zhang YT, et al. Clinical evaluation for batch consistency of an inactivated enterovirus 71 vaccine in a large-scale phase 3 clinical trial. Hum Vaccin Immunother 2014; 10:1366-72; PMID:24633366; http://dx.doi.org/10.4161/hv.28397
164. Shi J, Huang X, Liu Q, Huang Z. Identification of conserved neutralizing linear epitopes within the VP1 protein of coxsackievirus A16. Vaccine 2013; 31:2130-6; PMID:23499595; http://dx.doi.org/10.1016/j.vaccine.2013.02.051
165. Chong P, Guo MS, Lin FH, Hsiao KN, Weng SY, Chou AH, Wang JR, Hsieh SY, Su IJ, Liu CC. Immunological and biochemical characterization of coxsackie virus A16 viral particles. PLoS One 2012; 7 (11):e499973; PMID:23226233; http://dx.doi.org/10.1371/journal.pone.0049973
166. Cai Y, Liu Q, Huang X, Li D, Ku Z, Zhang Y, Huang Z. Active immunization with a Coxsackievirus A16 experimental inactivated vaccine induces neutralizing antibodies and protects mice against lethal infection. Vaccine 2013; 31:2215-21; PMID:23499596; http://dx.doi.org/10.1016/j.vaccine.2013.03.007
167. Yang E, Cheng C, Zhang Y, Wang J, Che Y, Pu J, Dong C, Liu L, He Z, Lu S, et al. Comparative study of the immunogenicity in mice and monkeys of an inactivated CA16 vaccine made from a human diploid cell line. Hum Vaccin Immunother 2014; 10:1266-73; PMID:24583556; http://dx.doi.org/10.4161/hv.28083
168. Li J, Chang J, Liu X, Yang J, Guo H, Wei W, Zhang W, Yu XF. Protection from lethal challenge in a neonatal mouse model by circulating recombinant form coxsackievirus A16 vaccine candidates. J Gen Virol 2014; 95:1083-93; PMID:24496826; http://dx.doi.org/10.1099/vir.0.063560-0
169. Zhao H, Li HY, Han JF, Deng YQ, Li YX, Zhu SY, He YL, Qin ED, Chen R, Qin CF. Virus-like particles produced in Saccharomyces cerevisiae elicit protective immunity against Coxsackievirus A16 in mice. Appl Microbiol Biotechnol 2013; 97:10445-52; PMID:24085395; http://dx.doi.org/10.1007/s00253-013-5257-3
170. Cai Y, Ku Z, Liu Q, Leng Q, Huang Z. A combination vaccine comprising of inactivated enterovirus 71 and coxsackievirus A16 elicits balanced protective immunity against both viruses. Vaccine 2014; 32:2406-12; PMID:24657161; http://dx.doi.org/10.1016/j.vaccine.2014.03.012
171. Lin CW, Liu CC, Lu TC, Liu SJ, Chow YH, Chong P, Huang MH. Immunogenicity studies of bivalent inactivated virions of EV71/CVA16 formulated with submicron emulsion systems. Biomed Res Int 2014; 2014:670506; PMID:25006583
172. Ku Z, Liu Q, Ye X, Cai Y, Wang X, Shi J, Li D, Jin X, An W, Huang Z. A virus-like particle based bivalent vaccine confers dual protection against enterovirus 71 and coxsackievirus A16 infections in mice. Vaccine 2014; 32:4296-303; PMID:24950363; http://dx.doi.org/10.1016/j.vaccine.2014.06.025
173. Zhao H, Li HY, Han JF, Deng YQ, Zhu SY, Li XF, Yang HQ, Li YX, Zhang Y, Qin ED, et al. Novel recombinant chimeric virus-like particle is immunogenic and protective against both enterovirus 71 and coxsackievirus A16 in mice. Sci Rep 2015; 5:7878-85; PMID:25597595; http://dx.doi.org/10.1038/srep07878
174. Sun S, Jiang L, Liang Z, Mao Q, Su W, Zhang H, Li X, Jin J, Xu L, Zhao D, et al. Evaluation of monovalent and bivalent vaccines against lethal Enterovirus 71 and Coxsackievirus A16 infection in newborn mice. Hum Vaccin Immunother 2014; 10:2885-95; PMID:25483672; http://dx.doi.org/10.4161/hv.29823
175. Liu CC, Chow YH, Chong P, Klein M. Prospect and challenges for the development of multivalent vaccines against hand, foot and mouth diseases. Vaccine 2014; 32:6177-82; PMID:25218294; http://dx.doi.org/10.1016/j.vaccine.2014.08.064
176. Kim DS, Nam JH. Characterization of attenuated coxsackievirus B3 strains and prospects of their application as live-attenuated vaccines. Expert Opin Biol Ther 2010; 10:179-90; PMID:20088713; http://dx.doi.org/10.1517/14712590903379502
177. Fohlman J, Pauksen K, Morein B, Bjare U, Ilbäck NG, Friman G. High yield production of an inactivated coxsackie B3 adjuvant vaccines protective effect against experimental myocarditis. Scand J Infect Dis Suppl 1993; 88:103-8; PMID:8390713
178. Jrad-Battikh N, Souli A, Oueslati L, Aouni M, Hober D, Gharbi J, Ben Mhadheb-Gharbi M. Neutralizing activity induced by the attenuated coxsackievirus B3 Sabin3-like strain against CVB3 infection. Curr Microbiol 2014; 68:503-9; PMID:24322405; http://dx.doi.org/10.1007/s00284-013-0498-z
179. Lan J, Gao Z, Xiong H, Chuai X, Jin Y, Li J, Xian X, Liu G, Xie L, Zhang Y, et al. Generation of protective immune responses against coxsackievirus B3 challenge by DNA prime-protein boost vaccination, Vaccine 2011; 29:6894-902; PMID:21803097; http://dx.doi.org/10.1016/j.vaccine.2011.07.049
180. Wang M, Yue Y, Dong C, Li X, Xu W, Xiong S. Mucosal immunization with high-mobility group box 1 in chitosan enhances DNA vaccine-induced protection against coxsackievirus B3-induced myocarditis. Clin Vaccine Immunol 2013; 20:1743-51; PMID:24027262; http://dx.doi.org/10.1128/CVI.00466-13
181. Zhang L, Parham NJ, Zhang F, Aasa-Chapman M, Gould EA, Zhang H. Vaccination with coxsackievirus B3 virus-like particles elicits humoral immune responses and protects mice against myocarditis. Vaccine 2012; 30:2301-08; PMID:22306858; http://dx.doi.org/10.1016/j.vaccine.2012.01.061
182. Koho T, Koivunene MR, Oikarinen S, Kummola L, Mäkinen S, Mähönen AJ, Sioofy-Khojine A, Marjomäki V, Kazmertsuk A, Junttila I, et al. Coxsackievirus B3 VLPs purified by ion exchange chromatography elicit strong immune responses in mice. Antiviral Res 2014; 104:93-101; PMID:24485896; http://dx.doi.org/10.1016/j.antiviral.2014.01.013
183. Wu F, Fan X, Yue Y, Xiong S, Dong C. A vesicular stomatitis virus-based mucosal vaccine promotes dendritic cell maturation and elicits preferable immune response against coxsackievirus B3 induced viral myocarditis. Vaccine 2014; 32:3917-26; PMID:24874923; http://dx.doi.org/10.1016/j.vaccine.2014.05.052
184. Han JF, Cao RY, Deng YQ, Tian X, Jiang T, Qin ED, Qin CF. Antibody-dependent enhancement of infection of enterovirus 71 in vitro and in vivo. Virol J 2011; 8:106-12; PMID:21385398; http://dx.doi.org/10.1186/1743-422X-8-106
185. Wang S, Li J, Liang Z, Xiuling L, Qunying M, Fanyue M, Hua W, Yuntao Z, Fan G, Qinghua C, et al. A booster dose of an inactivated enterovirus vaccine in Chinese young children: a randomized, double-blind, placebo controlled clinical trials. J Infect Dis 2014; 210:1073-82; PMID:24625805; http://dx.doi.org/10.1093/infdis/jiu113
186. Wang YF, Yu CK. Animal models for enterovirus 71 infection: application and limitations. J Biomed Sci 2014; 21:31-41; PMID:24742252; http://dx.doi.org/10.1186/1423-0127-21-31
187. Mao Q, Wang Y, Gao R, Shao J, Yao X, Lang S, Wang C, Mao P, Liang Z, Wang J. A neonatal mouse model of coxsackievirus A16 for vaccine evaluation. J Virol 2012; 86:11967-76; PMID:22951825; http://dx.doi.org/10.1128/JVI.00902-12
188. Lin YW, Yu SI, Shao HY, Lin HY, Liu CC, Hsiao KN, Chitra E, Tsou YL, Chang HW, Sia C, et al. Human SCARB2 transgenic mice as an infectious animal model for enterovirus 71. PLoS One 2013; 8(2): e57591; PMID:23451246; http://dx.doi.org/10.1371/journal.pone.0057591
189. Fujii K, Nagata N, Sato Y, Ong KC, Wong KT, Yamayoshi S, Shimanuki M, Shitara H, Taya C, Koike S. Transgenic mouse model for the study of enterovirus 71 neuropathogenesis. Proc Natl Acad Sci USA 2013; 110:14753-8; PMID:23959904; http://dx.doi.org/10.1073/pnas.1217563110
190. Chang HW, Lin YW, Ho HM, Lin MH, Liu CC, Shao HY, Chong P, Sia C, Chow YH. Protective efficacy of VP1-specific neutralizing antibody associated with a reduction of viral load and pro-inflammatory cytokines in human SCARB2-transgenic mice. PLoS One 2013; 8:269858; PMID:23936115; http://dx.doi.org/10.1371/annotation/e71a42ed-eebf-43c1-b2f5-6ea70e9d8966
191. Luo ST, Chiang PS, Chao AS, Liou GY, Lin R, Lin TY, Lee MS. Enterovirus 71 maternal antibodies in infants, Taiwan. Emerg Infect Dis 2009; 15:581-4; PMID:19331737; http://dx.doi.org/10.3201/1504.081550
192. Chen CW, Lee YP, Wang YF, Yu CK. Formaldehydeinactivated human enterovirus 71 vaccine is compatible for co-immunization with a commercial pentavalent vaccine. Vaccine 2011; 29:2772-6; PMID:21315698; http://dx.doi.org/10.1016/j.vaccine.2011.01.094
193. Mao Q, Wang Y, Shao J, Ying Z, Gao F, Yao X, Li C, Ye Q, Xu M, Li R, et al. The compatibility of inactivated Enterovirus 71 vaccination with Coxsackievirus A16 and Poliovirus immunizations in humans and animals. Hum Vaccin Immunother 2015; PMID:25715318; http://dx.doi.org/10.1080/21645515.2015.1011975
194. Li L, Yin H, An Z, Feng Z. Considerations for developing an immunization strategy with enterovirus 71 vaccine. Vaccine 2015; 33:1107-12; PMID:25444807; http://dx.doi.org/10.1016/j.vaccine.2014.10.081
195. Lee BY, Wateska AR, Bailey RR, Tai JH, Bacon KM, Smith KJ. Forecasting the economic value of an enterovirus 71 EV71 vaccine. Vaccine 2010; 28:7731-6; PMID:20923711; http://dx.doi.org/10.1016/j.vaccine.2010.09.065
196. Liang Z, Wang J. EV71 vaccine, an invaluable gift for children. Clin Transl Immunol 2014; 3:e28; PMID:25505956; http://dx.doi.org/10.1038/cti.2014.24
197. Mirand A, Molet L, Hassel C, Peigue-Lafeuille HC, Rozenberg F, Bailly JL, Henquell CC. Enterovirus A71 subgenotype B5, France, 2013. Emerg Infect Dis 2015; 21:707-9; PMID:25811300; http://dx.doi.org/10.3201/eid2104.141093