A Hepatitis C Virus (HCV) Vaccine Comprising Envelope Glycoproteins gpE1/gpE2 Derived from a Single Isolate Elicits Broad Cross-Genotype Neutralizing Antibodies in Humans

Sergio Abrignani,Takaji Wakita,Sharon E. Frey,Jason Wong,John Lok Man Law,Darren Hockman,Robert B. Belshe,D. Lorne Tyrrell,Chao Chen,Deanna M. Santer,Christopher T. Jones,Charles M. Rice,Jens Bukh,Michael Houghton

doi:10.1371/journal.pone.0059776

Abstract

Although a cure for HCV is on the near horizon, emerging drug cocktails will be expensive, associated with side-effects and resistance making a global vaccine an urgent priority given the estimated high incidence of infection around the world. Due to the highly heterogeneous nature of HCV, an effective HCV vaccine which could elicit broadly cross-neutralizing antibodies has represented a major challenge. In this study, we tested for the presence of cross-neutralizing antibodies in human volunteers who were immunized with recombinant glycoproteins gpE1/gpE2 derived from a single HCV strain (HCV1 of genotype 1a). Cross neutralization was tested in Huh-7.5 human hepatoma cell cultures using infectious recombinant HCV (HCVcc) expressing structural proteins of heterologous HCV strains from all known major genotypes, 1–7. Vaccination induced significant neutralizing antibodies against heterologous HCV genotype 1a virus which represents the most common genotype in North America. Of the 16 vaccinees tested, 3 were selected on the basis of strong 1a virus neutralization for testing of broad cross-neutralizing responses. At least 1 vaccinee was shown to elicit broad cross-neutralization against all HCV genotypes. Although observed in only a minority of vaccinees, our results prove the key concept that a vaccine derived from a single strain of HCV can elicit broad cross-neutralizing antibodies against all known major genotypes of HCV and provide considerable encouragement for the further development of a human vaccine against this common, global pathogen.

Highlights

Hepatitis C Virus (HCV) is a major global health concern infecting 170 million people worldwide [1]
Replication of the HCV RNA genome is mediated by virus-encoded non-structural protein NS5B, an error prone RNA-dependent RNA polymerase, and the low fidelity of the enzyme has contributed to the high mutagenic rate and broad antigenic diversity of the hepacivirus genus creating a major challenge in developing a global vaccine
The neutralization activities of sera from human volunteers vaccinated with a recombinant HCV gpE1/gpE2 vaccine in a phase I clinical trial were evaluated

Summary

Introduction

HCV is a major global health concern infecting 170 million people worldwide [1]. Replication of the HCV RNA genome is mediated by virus-encoded non-structural protein NS5B, an error prone RNA-dependent RNA polymerase, and the low fidelity of the enzyme has contributed to the high mutagenic rate and broad antigenic diversity of the hepacivirus genus creating a major challenge in developing a global vaccine. There are 7 major genotypes of HCV and many hundreds of subtypes distributed globally, with genotype 1a being the most prominent virus in the North America and genotype 1b infecting the most people worldwide [3,4]. A global vaccine will have to be effective against this vast diversity of HCV variants and has represented a major challenge

Methods

Results

Conclusion