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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (1) : 111-121     DOI: 10.1007/s11684-012-0237-z
REVIEW |
Progress on the research and development of human enterovirus 71 (EV71) vaccines
Zhenglun Liang, Qunying Mao, Fan Gao, Junzhi Wang()
National Institutes for Food and Drug Control, Beijing 100050, China
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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     
Corresponding Authors: Wang Junzhi,Email:wangjz@nicpbp.org.cn   
Issue Date: 05 March 2013
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-012-0237-z     OR     http://academic.hep.com.cn/fmd/EN/Y2013/V7/I1/111
Fig.1  Incidence of HFMD (cumulative number, as well as severe and fatal cases) in China (Mainland and Taiwan) from 1998 to 2012. Data Source: http://www.moh.gov.cn/publicfiles//business/htmlfiles/wsb/pyqxx/list.htm; http://www.wpro.who.int/publications/docs/GuidancefortheclinicalmanagementofHFMD.pdf. (Accessed on July 2, 2012)
Fig.1  Incidence of HFMD (cumulative number, as well as severe and fatal cases) in China (Mainland and Taiwan) from 1998 to 2012. Data Source: http://www.moh.gov.cn/publicfiles//business/htmlfiles/wsb/pyqxx/list.htm; http://www.wpro.who.int/publications/docs/GuidancefortheclinicalmanagementofHFMD.pdf. (Accessed on July 2, 2012)
VaccineAntigen (adjuvant)DoseAdministration(number of times)Neutralizing antibodytiterProtectiveefficacyAnimal model (age)Reference
Formalin-inactivatedEV71-075 (B4, alum)107 TCID50i.p. (2)76–173ICR mice (3–4 weeks)[62]
EV71-117 (B4, alum)107 TCID5076–173
Heat-inactivatedB4 (FC)10 μgi.p. (3)64BALB/c mice (6 weeks)[22]
VP1 polypeptideSP55 (FC)50 μg8
VP1 polypeptideSP70 (FC)50 μg32
Heat-inactivatedC2 (FC)10 μgi.p. (2)2 04812/19Immunization:ICR female adult miceChallenge:ICR neonatal mice (1 day)[30]
VLP-baculovirusC2 (FC)10 μg8 19216/18
Formalin-inactivatedB3 (alum)20 μgi.p. (2)>512ICR mice (4–6 weeks)[24]
4 μgs.c. (2)0/8ICR mice (14 days)
Live virusStrain 0875 × 106 TCID50i.p. (2)288BALB/c mice (6 weeks)[63]
Strain 085294
Heat-inactivatedStrain 087 (Al(OH)3)448
Strain 085 (Al(OH)3)384
VLP-baculovirusC2 (FC)10 μgi.p. (2)1 448BALB/c mice (6–8 weeks)[31]
B5 (FC)10 μg5 793
Formalin-inactivatedC2 (MP4, alum)20 μgs.c. (3)256100%Vaccination:BALB/c female adult miceChallenge:BALB/c neonatal mice (1 day)[64]
Formalin-inactivatedC4 (Vac-1, alum)3.125 Ui.p. (2)6 (C4)0/11Vaccination:BALB/c female adult miceChallenge:BALB/c neonatal mice (5 days)[54]
12.5 U50 (C4)10/16
50 U200 (C4)16/16
200 U50 (C4)21/21
800 U128 (C4)18/18
C4 (Vac-2, alum)3.125 Ui.p. (2)6023/25Vaccination:BALB/c female adult miceChallenge:BALB/c neonatal mice (5 days)
12.5 U6416/24
50 U19217/17
200 U19221/21
800 U>256 (C4)25/25
Formalin-inactivatedB4, alum (E particle)0.5 μgi.m. (2)188BALB/c mice (6–8 weeks)[26]
2.5 μg906
B4, alum (F particle)0.5 μg1 604
2.5 μg2 020
Formalin-inactivatedB4 (PBS)1 μgi.m. (2)105BALB/c mice (6–8 weeks)[21]
5 μg214
B4 (AlPO4)1 μg322
2 μg416
5 μg624
B4 (Al(OH)3)1 μg47
2 μg62
Formalin-inactivatedC4 (Al(OH)3)100 Ui.m. (1)7.4Infants(Prevaccination antibody titer:<8)[34]
200 U2.5
400 U6.8
100 Ui.m. (2)28.5
200 U39.9
400 U127.3
100 Ui.m. (3)202.7
200 U296.8
400 U639.5
Formalin-inactivatedC4 (Al(OH)3)40 EUs.c. (2)500100%Vaccination:BALB/c female adult miceChallenge:BALB/c neonatal mice(2 days)[20]
160 EU800100%
640 EU850100%
Live virusC4104 CCID50s.c. (2)950
Formalin-inactivatedC4 (Al(OH)3)40 EUs.c. (2)300102 copies/100 mg of tissueRhesus monkeys (2–3.5 years)
160 EU600No virus load in anytissue
640 EU600No virus load in anytissue
Live virusC4105 CCID50s.c. (2)800
Formalin-inactivatedB4 (alum)2 μgi.m. (2)233–443Mice[37]
10 μg654Rats
5 μgi.m. (3)13 575–17 093Rabbits
10 μg13 318–19 308
5 μgi.m. (3)3 169Macaques
10 μg5 623–8 912
VLP-baculovirusC2 (Al(OH)3)20 μgi.m. (3)16 384Macaques[32]
100 μg256
Formalin-inactivatedC2 (neu, Al(OH)3)20 μgi.m. (3)256
Tab.1  Literature published from 2007 to 2012 on EV71 vaccine candidates
No.Research unitsStrain genotypeCell matrixProduction techniqueDevelopment progressClinicalTrials.Gov Identifier
1Beijing Vigoo Biological Co., Ltd.C4VeroBioreactor, inactivationPhase III clinical trialNCT01508247
2Sinovac Biotech Co., Ltd. [34]C4VeroCell factory, inactivationPhase III clinical trialNCT01507857
3Institute of Medical Biology, CAMSC4KMB17Roller bottle, inactivationPhase III clinical trialNCT01569581
4National Health Research Institutes, Taiwan, China [37]B4VeroRoller bottle, inactivationPhase I clinical trialNCT01268787
5Invitrogen Pte. Ltd., Singapore [2]–, inactivationPhase I clinical trialNCT01376479
6Adimmune, Taiwan, China [2]VeroBioreactor, inactivationPreclinical phase
7Beijing Luzhu Biopharmaceutical Co., Ltd., etc.C4Vero–, inactivationPreclinical phase
Tab.2  Progress in the development of inactivated EV71 vaccines
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doi: 10.1007/BF01317504 pmid:228639
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doi: 10.1128/JCM.43.12.6171-6175.2005 pmid:16333123
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pmid:21099093
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12 Kim KH. Enterovirus 71 infection: An experience in Korea, 2009. Korean J Pediatr 2010; 53(5): 616–622
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16 Chua KB, Kasri AR. Hand foot and mouth disease due to enterovirus 71 in Malaysia. Virol Sin 2011; 26(4): 221–228
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doi: 10.3201/eid1501.080264 pmid:19116058
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)
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24 Ong KC, Devi S, Cardosa MJ, Wong KT. Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease. J Virol 2010; 84(1): 661–665
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27 Plevka P, Perera R, Cardosa J, Kuhn RJ, Rossmann MG. Crystal structure of human enterovirus 71. Science 2012; 336(6086): 1274
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28 Chung YC, Huang JH, Lai CW, Sheng HC, Shih SR, Ho MS, Hu YC. Expression, purification and characterization of enterovirus-71 virus-like particles. World J Gastroenterol 2006; 12(6): 921–927
pmid:16521221
29 Tung WS, Bakar SA, Sekawi Z, Rosli R. DNA vaccine constructs against enterovirus 71 elicit immune response in mice. Genet Vaccines Ther 2007; 5(1): 6
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32 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(7): 1305–1312
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