Protective effect of enterovirus‑71 (EV71) virus‑like particle vaccine against lethal EV71 infection in a neonatal mouse model

Cao,Lei; Mao,Fengfeng; Pang,Zheng; Yi,Yao; Qiu,Feng; Tian,Ruiguang; Meng,Qingling; Jia,Zhiyuan; Bi,Shengli

doi:10.3892/mmr.2015.3680

Protective effect of enterovirus‑71 (EV71) virus‑like particle vaccine against lethal EV71 infection in a neonatal mouse model

Authors:
- Lei Cao
- Fengfeng Mao
- Zheng Pang
- Yao Yi
- Feng Qiu
- Ruiguang Tian
- Qingling Meng
- Zhiyuan Jia
- Shengli Bi
View Affiliations

Affiliations: Department of Viral Hepatitis, National Institute for Viral Disease Control and Prevention, China Center for Disease Control and Prevention, Beijing 102206, P.R. China, Laboratory Animal Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
Published online on: April 24, 2015 https://doi.org/10.3892/mmr.2015.3680
Pages: 2473-2480
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Enterovirus-71 (EV71) is a viral pathogen that causes severe cases of hand, foot and mouth disease (HFMD) among young children, with significant mortality. Effective vaccines against HFMD are urgently required. Several EV71 virus‑like particle (VLP) vaccine candidates were found to be protective in the neonatal mouse EV71 challenge model. However, to what extent the VLP vaccine protects susceptible organs against EV71 infection in vivo has remained elusive. In the present study, the comprehensive immunogenicity of a potential EV71 vaccine candidate based on VLPs was evaluated in a neonatal mouse model. Despite lower levels of neutralizing antibodies to EV71 in the sera of VLP‑immunized mice compared with those in mice vaccinated with inactivated EV71, the VLP‑based vaccine was shown to be able to induce immunoglobulin (Ig)G and IgA memory‑associated cellular immune responses to EV71. Of note, the EV71 VLP vaccine candidate was capable of inhibiting viral proliferation in cardiac muscle, skeletal muscle, lung and intestine of immunized mice and provided effective protection against the pathological damage caused by viral attack. In particular, the VLP vaccine was able to inhibit the transportation of EV71 from the central nervous system to the muscle tissue and greatly protected muscle tissue from infection, along with recovery from the viral infection. This led to nearly 100% immunoprotective efficacy, enabling neonatal mice delivered by VLP‑immunized female adult mice to survive and grow with good health. The present study provided valuable additional knowledge of the specific protective efficacy of the EV71 VLP vaccine in vivo, which also indicated that it is a promising potential candidate for being developed into an EV71 vaccine.

View Figures

View References

1	Chan KP, Goh KT, Chong CY, Teo ES, Lau G and Ling AE: Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 9:78–85. 2003. View Article : Google Scholar : PubMed/NCBI
2	McMinn PC: An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 26:91–107. 2002. View Article : Google Scholar : PubMed/NCBI
3	Brown BA and Pallansch MA: Complete nucleotide sequence of enterovirus 71 is distinct from poliovirus. Virus Res. 39:195–205. 1995. View Article : Google Scholar : PubMed/NCBI
4	Liu CC, Chou AH, Lien SP, Lin HY, Liu SJ, Chang JY, Guo MS, Chow YH, Yang WS, Chang KH, et al: Identification and characterization of a cross-neutralization epitope of enterovirus 71. Vaccine. 29:4362–4372. 2011. View Article : Google Scholar : PubMed/NCBI
5	Qiu J: Enterovirus 71 infection: A new threat to global public health? Lancet Neurol. 7:868–869. 2008. View Article : Google Scholar : PubMed/NCBI
6	Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, Su IJ and Liu CC: Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: Roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis. 188:564–570. 2003. View Article : Google Scholar : PubMed/NCBI
7	Cardosa MJ, Perera D, Brown BA, Cheon D, Chan HM, Chan KP, Cho H and McMinn P: Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: Comparative analysis of the VP1 and VP4 genes. Emerg Infect Dis. 9:461–468. 2003. View Article : Google Scholar : PubMed/NCBI
8	Fujimoto T, Chikahira M, Yoshida S, Ebira H, Hasegawa A, Totsuka A and Nishio O: Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: Detection and molecular epidemiology of enterovirus 71. Microbiol Immunol. 46:621–627. 2002. View Article : Google Scholar : PubMed/NCBI
9	Yi L, Lu J, Kung HF and He ML: The virology and developments toward control of human enterovirus 71. Crit Rev Microbiol. 37:313–327. 2011. View Article : Google Scholar : PubMed/NCBI
10	Chong P, Hsieh SY, Liu CC, Chou AH, Chang JY, Wu SC, Liu SJ, Chow YH, Su IJ and Klein M: Production of EV71 vaccine candidates. Hum Vaccin Immunother. 8:1775–1783. 2012. View Article : Google Scholar : PubMed/NCBI
11	Lin YL, Yu CI, Hu YC, Tsai TJ, Kuo YC, Chi WK, Lin AN and Chiang BL: Enterovirus type 71 neutralizing antibodies in the serum of macaque monkeys immunized with EV71 virus-like particles. Vaccine. 30:1305–1312. 2012. View Article : Google Scholar : PubMed/NCBI
12	Noad R and Roy P: Virus-like particles as immunogens. Trends Microbiol. 11:438–444. 2003. View Article : Google Scholar : PubMed/NCBI
13	Chang LY, Hsiung CA, Lu CY, Lin TY, Huang FY, Lai YH, Chiang YP, Chiang BL, Lee CY and Huang LM: Status of cellular rather than humoral immunity is correlated with clinical outcome of enterovirus 71. Pediatr Res. 60:466–471. 2006. View Article : Google Scholar : PubMed/NCBI
14	Ku Z, Ye X, Huang X, Cai Y, Liu Q, Li Y, Su Z and Huang Z: Neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71 genotype C4 inhibit infection at pre- and post-attachment steps. PLoS One. 8:e576012013. View Article : Google Scholar : PubMed/NCBI
15	Chang LY, Chang IS, Chen WJ, Huang YC, Chen GW, Shih SR, Juang JL, Shih HM, Hsiung CA, Lin TY, et al: HLA-A33 is associated with susceptibility to enterovirus 71 infection. Pediatrics. 122:1271–1276. 2008. View Article : Google Scholar : PubMed/NCBI
16	Khong WX, Foo DG, Trasti SL, Tan EL and Alonso S: Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. J Virol. 85:3067–3076. 2011. View Article : Google Scholar : PubMed/NCBI
17	Zhang Y, Cui W, Liu L, Wang J, Zhao H, Liao Y, Na R, Dong C, Wang L, Xie Z, et al: Pathogenesis study of enterovirus 71 infection in rhesus monkeys. Lab Invest. 91:1337–1350. 2011. View Article : Google Scholar : PubMed/NCBI
18	Ong KC and Devi S: Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease. J Virol. 84:661–665. 2010. View Article : Google Scholar :
19	Hsiung GD: Virus assay, neutralization test and antiviral assay. Hsiung’s Diagnostic Virology. 4th ed. Hsiung GD, Fong CKY and Landry ML: Yale University Press; New Haven: pp. 46–55. 1994
20	Cao L, Yi Y, Song JD, Tian MM, Tian RG, Meng QL, Qiu F, Jia ZY and Bi SL: The assemblage, purification and characterization of EV71 VLPs expressed in baculovirus. Bing Du Xue Bao. 28:201–206. 2012.In Chinese. PubMed/NCBI
21	Jia CS, Liu JN, Li WB, Ma CM, Lin SZ, et al: The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments. Virol J. 7:472010. View Article : Google Scholar : PubMed/NCBI
22	Meng T, Kolpe AB, Kiener TK, Chow VT and Kwang J: Display of VP1 on the surface of baculovirus and its immunogenicity against heterologous human enterovirus 71 strains in mice. PLoS One. 6:e217572011. View Article : Google Scholar : PubMed/NCBI
23	Foo DG, Alonso S, Chow VT and Poh CL: Passive protection against lethal enterovirus 71 infection in newborn mice by neutralizing antibodies elicited by a synthetic peptide. Microbes Infect. 9:1299–1306. 2007. View Article : Google Scholar : PubMed/NCBI
24	Wang X, Peng W, Ren J, Hu Z, Xu J, Lou Z, Li X, Yin W, Shen X, Porta C, et al: A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol. 19:424–429. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wen ZS, Xu YL, Zou XT and Xu ZR: Chitosan nanoparticles act as an adjuvant to promote both Th1 and Th2 immune responses induced by ovalbumin in mice. Mar Drugs. 9:1038–1055. 2011. View Article : Google Scholar : PubMed/NCBI
26	Emeny RT, Wheeler CM, Jansen KU, Hunt WC, Fu TM, Smith JF, MacMullen S, Esser MT and Paliard X: Priming of human papillomavirus type 11-specific humoral and cellular immune responses in college-aged women with a virus-like particle vaccine. J Virol. 76:7832–7842. 2002. View Article : Google Scholar : PubMed/NCBI
27	Quan FS, Huang C, Compans RW and Kang SM: Virus-like particle vaccine induces protective immunity against homologous and heterologous strains of influenza virus. J Virol. 81:3514–3524. 2007. View Article : Google Scholar : PubMed/NCBI
28	Liu L, Zhao H, Zhang Y, Wang J, Che Y, Dong C, Zhang X, Na R, Shi H, Jiang L, et al: Neonatal rhesus monkey is a potential animal model for studying pathogenesis of EV71 infection. Virology. 412:91–100. 2011. View Article : Google Scholar : PubMed/NCBI
29	Wang W, Duo J, Liu J, Ma C, Zhang L, Wei Q and Qin C: A mouse muscle-adapted enterovirus 71 strain with increased virulence in mice. Microbes Infect. 13:862–870. 2011. View Article : Google Scholar : PubMed/NCBI
30	Duo J, Wang W, Tong W, Cong Z, Jiang H, Xu W, et al: Experimental Studies on ICR Mice with EV71 Infection. Chin J Comp Med. 19:41–46. 2009.
31	Xiu JH, Zhu H, Xu YF, Liu JN, Xia XZ and Zhang LF: Necrotizing myositis causes restrictive hypoventilation in a mouse model for human enterovirus 71 infection. Virol J. 10:2152013. View Article : Google Scholar : PubMed/NCBI