HCV p7 as a novel vaccine-target inducing multifunctional CD4+ and CD8+ T-cells targeting liver cells expressing the viral antigen

Jonathan Filskov,Else Marie Agger,Jens Bukh,Peter Andersen

doi:10.1038/s41598-019-50365-z

Jonathan Filskov, Else Marie Agger + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-50365-z

Copy DOI

Abstract

Despite recent treatment advances for chronic hepatitis C virus (HCV) infection, a vaccine is urgently needed for global control of this important liver pathogen. The lack of robust immunocompetent HCV infection models makes it challenging to identify correlates of protection and test vaccine efficacy. However, vigorous CD4+ and CD8+ T-cell responses are detected in patients that spontaneously resolve acute infection, whereas dysfunctional T-cell responses are a hallmark of chronic infection. The HCV p7 protein, forming ion-channels essential for viral assembly and release, has not previously been pursued as a vaccine antigen. Herein, we demonstrated that HCV p7 derived from genotype 1a and 1b sequences are highly immunogenic in mice when employed as overlapping peptides formulated as nanoparticles with the cross-priming adjuvant, CAF09. This approach induced multifunctional cytokine producing CD4+ and CD8+ T-cells targeting regions of p7 that are subject to immune pressure during HCV infection in chimpanzees and humans. Employing a surrogate in vivo challenge model of liver cells co-expressing HCV-p7 and GFP, we found that vaccinated mice cleared transgene expressing cells. This study affirms the potential of a T-cell inducing nanoparticle vaccine platform to target the liver and introduces HCV p7 as a potential target for HCV vaccine explorations.

Highlights

Despite a remarkable success in the development of curative direct acting antiviral treatments for chronic hepatitis C virus (HCV) infection, an effective prophylactic vaccine is considered the only means to substantially reduce the burden of the global HCV epidemic causing at least 400,000 deaths annually[1,2,3]
Our data show that multifunctional CD4+ and CD8+ T-cell responses could be generated by vaccination with overlapping peptide panels covering HCV p7 sequences formulated in cross-priming, cationic nanoparticles
Several other residues of p7 are subject to mutational escape from T-cells as demonstrated in chimpanzees experimentally infected with HCV15,41,57

Summary

Introduction

Despite a remarkable success in the development of curative direct acting antiviral treatments for chronic hepatitis C virus (HCV) infection, an effective prophylactic vaccine is considered the only means to substantially reduce the burden of the global HCV epidemic causing at least 400,000 deaths annually[1,2,3]. The only HCV vaccine being evaluated in clinical trials is a potent CD4+ and CD8+ T-cell inducing adenoviral vector Chimp/MVA vaccine[29,30] Alternative vaccine approaches such as peptide- and subunit vaccines are relatively easy to manufacture and store, are considered safe due to their simplicity and can readily be tailored to targetand combine specific antigen sequences[31,32]. These do, require co-administration of a suitable adjuvant in order to facilitate cross-presentation of exogenous antigens to MHC class I molecules on antigen presenting cells (APCs), e.g. through Toll-like receptor (TLR) engagement. P7 might represent an interesting target for antiviral therapy and vaccine development

Methods

Results

Conclusion