Progress on the research and development of human enterovirus 71 (EV71) vaccines

Abstract

Enterovirus 71 (EV71) infections, which can cause severe complications, have become one of the serious public health issues in the Western Pacific region and China. To date, a number of pharmaceutical companies and institutes have initiated the research and development of EV71 vaccines as a countermeasure. As is the case with innovative vaccine development, there are several critical bottlenecks in EV71 vaccine development that must be overcome before the clinical trials, including the selection of vaccine strain, standardization of the procedure for quantifying neutralizing antibody (NTAb) and antigen, establishment and application of a reference standard and biological standards, development of animal models for the evaluation of protective efficacy, and identification of the target patient population. To tackle these technical obstacles, researchers in Mainland of China have conducted a series of studies concerning the screening of vaccine strains and the establishment of criteria, biological standards and detection methods, thereby advancing EV71 vaccine development. This review summarizes recent worldwide progress on the quality control and evaluation of EV71 vaccines.

Keywords

enterovirus 71 (EV71) / hand, foot, and mouth disease (HFMD) / vaccine

References

[1] XuJ, QianY, WangS, SerranoJM, LiW, HuangZ, LuS. EV71: an emerging infectious disease vaccine target in the Far East? Vaccine2010; 28(20):3516–3521

[2] LeeMS, ChangLY. Development of enterovirus 71 vaccines. Expert Rev Vaccines2010; 9(2): 149–156

[3] BibleJM, PantelidisP, ChanPK, TongCY. Genetic evolution of enterovirus 71: epidemiological and pathological implications. Rev Med Virol2007; 17(6): 371–379

[4] SchmidtNJ, LennetteEH, HoHH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis1974; 129(3): 304–309

[5] McMinnPC, StratovI, NagarajanL, DavisS. Neurological manifestations of enterovirus 71 infection in children during a hand, foot and mouth disease outbreak in Western Australia. Clin Infect Dis2001; 32: 236–242

[6] ChumakovM, VoroshilovaM, ShindarovL, LavrovaI, GrachevaL, KorolevaG, VasilenkoS, BrodvarovaI, NikolovaM, GyurovaS, GachevaM, MitovG, NinovN, TsylkaE, RobinsonI, FrolovaM, BashkirtsevV, MartiyanovaL, RodinV. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol1979; 60(3–4): 329–340

[7] NagyG, TakátsyS, KukánE, MihályI, DömökI. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol1982; 71(3): 217–227

[8] MizutaK, AbikoC, MurataT, MatsuzakiY, ItagakiT, SanjohK, SakamotoM, HongoS, MurayamaS, HayasakaK. Frequent importation of enterovirus 71 from surrounding countries into the local community of Yamagata, Japan, between 1998 and 2003. J Clin Microbiol2005; 43(12): 6171–6175

[9] MaE, LamT, ChanKC, WongC, ChuangSK. Changing epidemiology of hand, foot, and mouth disease in Hong Kong, 2001–2009. Jpn J Infect Dis2010; 63(6): 422–426

[10] HoM, ChenER, HsuKH, TwuSJ, ChenKT, TsaiSF, WangJR, ShihSR. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999; 341(13): 929–935

[11] SarmaN, SarkarA, MukherjeeA, GhoshA, DharS, MalakarR. Epidemic of hand, foot and mouth disease in West Bengal, India in August, 2007: a multicentric study. Indian J Dermatol2009; 54(1): 26–30

[12] KimKH. Enterovirus 71 infection: An experience in Korea, 2009. Korean J Pediatr2010; 53(5): 616–622

[13] ChanLG, ParasharUD, LyeMS, OngFG, ZakiSR, AlexanderJP, HoKK, HanLL, PallanschMA, SuleimanAB, JegathesanM, AndersonLJ; Outbreak Study Group. Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. Clin Infect Dis2000; 31(3): 678–683

[14] TanX, HuangX, ZhuS, ChenH, YuQ, WangH, HuoX, ZhouJ, WuY, YanD, ZhangY, WangD, CuiA, AnH, XuW. The persistent circulation of enterovirus 71 in People’s Republic of China: causing emerging nationwide epidemics since 2008. PLoS ONE2011; 6(9): e25662

[15] TuPV, ThaoNT, PereraD, HuuTK, TienNT, ThuongTC, HowOM, CardosaMJ, McMinnPC. Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005. Emerg Infect Dis2007; 13(11): 1733–1741

[16] ChuaKB, KasriAR. Hand foot and mouth disease due to enterovirus 71 in Malaysia. Virol Sin2011; 26(4): 221–228

[17] WangSM, HoTS, LinHC, LeiHY, WangJR, LiuCC. Reemerging of enterovirus 71 in Taiwan: the age impact on disease severity. Eur J Clin Microbiol Infect Dis2012; 31(6): 1219–1224

[18] AbuBakarS, SamIC, YusofJ, LimMK, MisbahS, HooiPS, MatRahimN. Enterovirus 71 outbreak, Brunei. Emerg Infect Dis2009; 15(1): 79–82

[19] National notifiable diseases announced by Ministry of Health of the People’s Republic of China. http://www.moh.gov.cn/publicfiles//business/htmlfiles/wsb/pyqxx/list.htm (Accessed on March 22, 2012)

[20] DongC, LiuL, ZhaoH, WangJ, LiaoY, ZhangX, NaR, LiangY, WangL, LiQ. Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys. Vaccine2011; 29(37): 6269–6275

[21] ChangJY, ChangCP, TsaiHH, LeeCD, LianWC, Ih JenSu, SaiIH, LiuCC, ChouAH, LuYJ, ChenCY, LeePH, ChiangJR, ChongPC. Selection and characterization of vaccine strain for Enterovirus 71 vaccine development. Vaccine2012; 30(4): 703–711

[22] FooDG, AlonsoS, PhoonMC, RamachandranNP, ChowVT, PohCL. Identification of neutralizing linear epitopes from the VP1 capsid protein of Enterovirus 71 using synthetic peptides. Virus Res2007; 125(1): 61–68

[23] AritaM, NagataN, IwataN, AmiY, SuzakiY, MizutaK, IwasakiT, SataT, WakitaT, ShimizuH. An attenuated strain of enterovirus 71 belonging to genotype a showed a broad spectrum of antigenicity with attenuated neurovirulence in cynomolgus monkeys. J Virol2007; 81(17): 9386–9395

[24] OngKC, DeviS, CardosaMJ, WongKT. Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease. J Virol2010; 84(1): 661–665

[25] LiuCC, GuoMS, LinFH, HsiaoKN, ChangKH, ChouAH, WangYC, ChenYC, YangCS, ChongPC. Purification and characterization of enterovirus 71 viral particles produced from vero cells grown in a serum-free microcarrier bioreactor system. PLoS ONE2011; 6(5): e20005

[26] WangX, PengW, RenJ, HuZ, XuJ, LouZ, LiX, YinW, ShenX, PortaC, WalterTS, EvansG, AxfordD, OwenR, RowlandsDJ, WangJ, StuartDI, FryEE, RaoZ. A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol2012; 19(4): 424–429

[27] PlevkaP, PereraR, CardosaJ, KuhnRJ, RossmannMG. Crystal structure of human enterovirus 71. Science2012; 336(6086): 1274

[28] ChungYC, HuangJH, LaiCW, ShengHC, ShihSR, HoMS, HuYC. Expression, purification and characterization of enterovirus-71 virus-like particles. World J Gastroenterol2006; 12(6): 921–927

[29] TungWS, BakarSA, SekawiZ, RosliR. DNA vaccine constructs against enterovirus 71 elicit immune response in mice. Genet Vaccines Ther2007; 5(1): 6

[30] ChungYC, HoMS, WuJC, ChenWJ, HuangJH, ChouST, HuYC. Immunization with virus-like particles of enterovirus 71 elicits potent immune responses and protects mice against lethal challenge. Vaccine2008; 26(15): 1855–1862

[31] ChungCY, ChenCY, LinSY, ChungYC, ChiuHY, ChiWK, LinYL, ChiangBL, ChenWJ, HuYC. Enterovirus 71 virus-like particle vaccine: improved production conditions for enhanced yield. Vaccine2010; 28(43): 6951–6957

[32] LinYL, YuCI, HuYC, TsaiTJ, KuoYC, ChiWK, LinAN, ChiangBL. Enterovirus type 71 neutralizing antibodies in the serum of macaque monkeys immunized with EV71 virus-like particles. Vaccine2012; 30(7): 1305–1312

[33] AritaM, ShimizuH, NagataN, AmiY, SuzakiY, SataT, IwasakiT, MiyamuraT. Temperature-sensitive mutants of enterovirus 71 show attenuation in cynomolgus monkeys. J Gen Virol2005; 86(Pt 5): 1391–1401

[34] LiYP, LiangZL, GaoQ, HuangLR, MaoQY, WenSQ, LiuY, YinWD, LiRC, WangJZ. Safety and immunogenicity of a novel human Enterovirus 71 (EV71) vaccine: a randomized, placebo-controlled, double-blind, Phase I clinical trial. Vaccine2012; 30(22): 3295–3303

[35] MengFY, LiJX, LiXL, ChuK, ZhangYT, JiH, LiL, LiangZL, ZhuFC. Tolerability and immunogenicity of an inactivated enterovirus 71 vaccine in Chinese healthy adults and children: an open label, phase 1 clinical trial. Hum Vaccin Immunother2012; 8(5): 668–674

[36] WuSC, LiuCC, LianWC. Optimization of microcarrier cell culture process for the inactivated enterovirus type 71 vaccine development. Vaccine2004; 22(29–30): 3858–3864

[37] ChouAH, LiuCC, ChangCP, GuoMS, HsiehSY, YangWH, ChaoHJ, WuCL, HuangJL, LeeMS, HuAY, LinSC, HuangYY, HuMH, ChowYH, ChiangJR, ChangJY, ChongP. Pilot scale production of highly efficacious and stable enterovirus 71 vaccine candidates. PLoS ONE2012; 7(4): e34834

[38] Inviragen Hand, Foot And Mouth Disease Vaccine Generates Immune Responses In 100% of Study Participants. http://www.inviragen.com/press/INV21%20top-line%20Phase%201%20US%20edition.pdf (Accessed on June 22, 2012)

[39] MaoQ, LiN, YuX, YaoX, LiF, LuF, ZhuangH, LiangZ, WangJ. Antigenicity, animal protective effect and genetic characteristics of candidate vaccine strains of enterovirus 71. Arch Virol2012; 157(1): 37–41

[40] LiangZ, MaoQ, GaoQ, LiX, DongC, YuX, YaoX, LiF, YinW, LiQ, ShenX, WangJ. Establishing China’s national standards of antigen content and neutralizing antibody responses for evaluation of enterovirus 71 (EV71) vaccines. Vaccine2011; 29(52): 9668–9674

[41] MaoQY, HeP, YuX, LiN, HaoCS, GaoQ, DongCH, LiangZL, LiFX, ShenXL, WangJZ. Laboratory Evaluation of Method for Determination of Neutralizing Antibody against Human Enterovirus 71. Chin J Biologicals (Zhongguo Sheng Wu Zhi Pin Xue Za Zhi)2010; 23(8): 885–888 (in Chinese)

[42] LiuCC, ChangHW, YangG, ChiangJR, ChowYH, SaiIH, ChangJY, LinSC, SiaC, HsiaoCH, ChouAH, ChongP. Development of a quantitative enzyme linked immunosorbent assay for monitoring the Enterovirus 71 vaccine manufacturing process. J Virol Methods2011; 176(1–2): 60–68

[43] JiaH, CaiF, GaoQ, ZhangJS, JingSR. Development of A Quantitative ELISA Method for EV71 Antigen. Chin J Biologicals (Zhongguo Sheng Wu Zhi Pin Xue Za Zhi)2010; 23(1): 87–90 (in Chinese)

[44] LongRX, XieZP, YangR, LiH, BaiHZ, DongCH, LiuLD, LiQH. Development and Application of BA-ELISA Method for EV71 Antigen. Chin J Biologicals (Zhongguo Sheng Wu Zhi Pin Xue Za Zhi)2009; 22: 1230–1232 (in Chinese)

[45] YuCK, ChenCC, ChenCL, WangJR, LiuCC, YanJJ, SuIJ. Neutralizing antibody provided protection against enterovirus type 71 lethal challenge in neonatal mice. J Biomed Sci2000; 7(6): 523–528

[46] ChenYC, YuCK, WangYF, LiuCC, SuIJ, LeiHY. A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol2004; 85(Pt 1): 69–77

[47] WangYF, ChouCT, LeiHY, LiuCC, WangSM, YanJJ, SuIJ, WangJR, YehTM, ChenSH, YuCK. A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol2004; 78(15): 7916–7924

[48] LiuML, LeeYP, WangYF, LeiHY, LiuCC, WangSM, SuIJ, WangJR, YehTM, ChenSH, YuCK. Type I interferons protect mice against enterovirus 71 infection. J Gen Virol2005; 86(Pt 12): 3263–3269

[49] OngKC, BadmanathanM, DeviS, LeongKL, CardosaMJ, WongKT. Pathologic characterization of a murine model of human enterovirus 71 encephalomyelitis. J Neuropathol Exp Neurol2008; 67(6): 532–542

[50] NishimuraY, ShimojimaM, TanoY, MiyamuraT, WakitaT, ShimizuH. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med2009; 15(7): 794–797

[51] YamayoshiS, YamashitaY, LiJ, HanagataN, MinowaT, TakemuraT, KoikeS. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med2009; 15(7): 798–801

[52] LiuJ, DongW, QuanX, MaC, QinC, ZhangL. Transgenic expression of human P-selectin glycoprotein ligand-1 is not sufficient for enterovirus 71 infection in mice. Arch Virol2012; 157(3): 539–543

[53] KhongWX, YanB, YeoH, TanEL, LeeJJ, NgJK, ChowVT, AlonsoS. A non-mouse-adapted enterovirus 71 (EV71) strain exhibits neurotropism, causing neurological manifestations in a novel mouse model of EV71 infection. J Virol2012; 86(4): 2121–2131

[54] BekEJ, HussainKM, PhuektesP, KokCC, GaoQ, CaiF, GaoZ, McMinnPC. Formalin-inactivated vaccine provokes cross-protective immunity in a mouse model of human enterovirus 71 infection. Vaccine2011; 29(29–30): 4829–4838

[55] NagataN, ShimizuH, AmiY, TanoY, HarashimaA, SuzakiY, SatoY, MiyamuraT, SataT, IwasakiT. Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71. J Med Virol2002; 67(2): 207–216

[56] LiuL, ZhaoH, ZhangY, WangJ, CheY, DongC, ZhangX, NaR, ShiH, JiangL, WangL, XieZ, CuiP, XiongX, LiaoY, ZhaoS, GaoJ, TangD, LiQ. Neonatal rhesus monkey is a potential animal model for studying pathogenesis of EV71 infection. Virology2011; 412(1): 91–100

[57] ChangLY, KingCC, HsuKH, NingHC, TsaoKC, LiCC, HuangYC, ShihSR, ChiouST, ChenPY, ChangHJ, LinTY. Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan. Pediatrics2002; 109(6): e88

[58] OoiEE, PhoonMC, IshakB, ChanSH. Seroepidemiology of human enterovirus 71, Singapore. Emerg Infect Dis2002; 8(9): 995–997

[59] LuoST, ChiangPS, ChaoAS, LiouGY, LinR, LinTY, LeeMS. Enterovirus 71 maternal antibodies in infants, Taiwan. Emerg Infect Dis2009; 15(4): 581–584

[60] MaoQY, LiaoXY, YuX, LiN, ZhuFC, ZengY, LiangZL, LiFX, WangJZ, LuFM, ZhuangH. Dynamic change of mother-source neutralizing antibodies against enterovirus 71 and coxsackievirus A16 in infants. Chin Med J (Engl)2010; 123(13): 1679–1684

[61] MaoQY, YangZW, YuX, JingP, HeP, HuangWJ, WuXY, WanZJ, LiangZL, LiFX, WangJZ. Epidemic Tendency of Neutralizing Antibody against Enterovirus 71 and Coxsackievirus A 16 in Infants in Rural Area of Kaifeng City, Henan Province, China. Chin J Biologicals (Zhongguo Sheng Wu Zhi Pin Xue Za Zhi)2009; 22(9): 911–913 (in Chinese)

[62] LiuCC, LianWC, ButlerM, WuSC. High immunogenic enterovirus 71 strain and its production using serum-free microcarrier Vero cell culture. Vaccine2007; 25(1): 19–24

[63] LiXL, ZhangZY, WangXX, YangYJ, HaoCS, ZhaoM, HeWW, ZhangC, ShenXL. Identification and immunogenidty of enterovirus 71 isolates. Chin J Microbiol Immunol (Zhonghua Wei Sheng Wu Xue He Mian Yi Xue Za Zhi)2009; 29(10): 944–948 (in Chinese)

[64] ChenCW, LeeYP, WangYF, YuCK. Formaldehyde-inactivated human enterovirus 71 vaccine is compatible for co-immunization with a commercial pentavalent vaccine. Vaccine2011; 29(15): 2772–2776

Acknowledgements

This work was supported by National High Technology Research and Development Program of China (“863”program) (No. 2012AA02A402).

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg