Theranostics 2014; 4(5):498-513. doi:10.7150/thno.7457

Research Paper

Protection against Lethal Enterovirus 71 Challenge in Mice by a Recombinant Vaccine Candidate Containing a Broadly Cross-Neutralizing Epitope within the VP2 EF Loop

Longfa Xu1,2*, Delei He1,2*, Zhiqun Li1, Jun Zheng1, Lisheng Yang1, Miao Yu2, Hai Yu1,2, Yixin Chen1,2, Yuqiong Que1,2, James Wai Kuo Shih1,2, Gang Liu2, Jun Zhang1,2, Qinjian Zhao1,2, Tong Cheng1,2✉, Ningshao Xia1,2

1. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen Fujian, 361102, PR China
2. National Institute of Diagnostics and Vaccine Development in infectious diseases, School of Public Health, Xiamen University, Xiamen Fujian, 361102, PR China
* Equally contributing authors

Abstract

Human enterovirus 71 (EV71) is the main causative agent of hand, foot, and mouth disease (HFMD) and is associated with several severe neurological complications in the Asia-Pacific region. Here, we evaluated that while passive transfer of neutralizing monoclonal antibody (nMAb) against the VP2 protein protect against lethal EV71 infection in BALB/c mice. Protective nMAb were mapped to residues 141-155 of VP2 by peptide ELISA. High-resolution structural analysis showed that the epitope is part of the VP2 EF loop, which is the “puff” region that forms the “southern rim” of the canyon. Moreover, a three-dimensional structural characterization for the puff region with prior neutralizing epitopes and receptor-binding sites that can serve to inform vaccine strategies. Interestingly, using hepatitis B virus core protein (HBc) as a carrier, we demonstrated that the cross-neutralizing EV71 antibodies were induced, and the VP2 epitope immunized mice serum also conferred 100% in vivo passive protection. The mechanism of in vivo protection conferred by VP2 nMAb is in part attributed to the in vitro neutralizing titer and ability to bind authentic viral particles. Importantly, the anti-VP2(aa141-155) antibodies could inhibit the binding of human serum to EV71 virions showed that the VP2 epitope is immunodominant. Collectively, our results suggest that a broad-spectrum vaccine strategy targeting the high-affinity epitope of VP2 EF loop may elicits effective immune responses against EV71 infection.

Keywords: Human enterovirus 71, cross-neutralizing linear epitope, VP2 EF loop, therapeutic antibodies, epitope peptide vaccine.

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How to cite this article:
Xu L, He D, Li Z, Zheng J, Yang L, Yu M, Yu H, Chen Y, Que Y, Shih JWK, Liu G, Zhang J, Zhao Q, Cheng T, Xia N. Protection against Lethal Enterovirus 71 Challenge in Mice by a Recombinant Vaccine Candidate Containing a Broadly Cross-Neutralizing Epitope within the VP2 EF Loop. Theranostics 2014; 4(5):498-513. doi:10.7150/thno.7457. Available from http://www.thno.org/v04p0498.htm