Bivalent vaccine platform based on Japanese encephalitis virus (JEV) elicits neutralizing antibodies against JEV and hepatitis C virus

Ryohei Saga,Akira Fujimoto,Noriko Nakamura,Ryosuke Suzuki,Hideki Aizaki,Mami Matsuda,Noriyuki Watanabe,Eiji Konishi,Tomohiko Takasaki,Koichi Watashi,Takaji Wakita,Michinori Kohara,Takanobu Kato,Shigeru Tajima,Haruko Takeyama,Makoto Hasegawa

doi:10.1038/srep28688

Abstract

Directly acting antivirals recently have become available for the treatment of hepatitis C virus (HCV) infection, but there is no prophylactic vaccine for HCV. In the present study, we took advantage of the properties of Japanese encephalitis virus (JEV) to develop antigens for use in a HCV vaccine. Notably, the surface-exposed JEV envelope protein is tolerant of inserted foreign epitopes, permitting display of novel antigens. We identified 3 positions that permitted insertion of the HCV E2 neutralization epitope recognized by HCV1 antibody. JEV subviral particles (SVP) containing HCV-neutralization epitope (SVP-E2) were purified from culture supernatant by gel chromatography. Sera from mice immunized with SVP-E2 inhibited infection by JEV and by trans-complemented HCV particles (HCVtcp) derived from multi-genotypic viruses, whereas sera from mice immunized with synthetic E2 peptides did not show any neutralizing activity. Furthermore, sera from mice immunized with SVP-E2 neutralized HCVtcp with N415K escape mutation in E2. As with the SVP-E2 epitope-displaying particles, JEV SVPs with HCV E1 epitope also elicited neutralizing antibodies against HCV. Thus, this novel platform harboring foreign epitopes on the surface of the particle may facilitate the development of a bivalent vaccine against JEV and other pathogens.

Highlights

Acting antivirals recently have become available for the treatment of hepatitis C virus (HCV) infection, but there is no prophylactic vaccine for Hepatitis C virus (HCV)
These results indicated that the subviral particles (SVP)-E2 particles provided immunogenic presentation of the HCV neutralization epitope
virus-like particles (VLPs)-based vaccines are considered highly immunogenic, eliciting high-titer neutralizing antibody responses more efficiently than do individual proteins or peptides. This superior performance reflects the effective recognition of VLP vaccines by B cells, with resulting stimulation of B cell signaling to facilitate the generation of high-titer, specific antibodies[28]

Summary

Introduction

Acting antivirals recently have become available for the treatment of hepatitis C virus (HCV) infection, but there is no prophylactic vaccine for HCV. Neutralizing antibodies were shown to abrogate established HCV infection in vitro and in a human liver chimeric mouse model[7]. HCV E2 amino acid residues 412–423, a domain highly conserved among various genotypes, was shown to constitute a linear epitope that is recognized by broadly neutralizing monoclonal antibodies (mAbs) such as AP33 and HCV112,13. Antibodies recognizing this epitope are rare in natural infections, suggesting that this region is poorly immunogenic[14,15]

Methods

Results

Conclusion