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

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.

Hepatitis C Virus Vaccine: Challenges and Prospects

“…Despite the challenges faced in HCV vaccine design, there have been a variety of different vaccine approaches investigated with a small number of these candidates reaching human trials (summarized in Table 1). Currently, DNA and peptide-based vaccine candidates are actively being investigated in murine models [154][155][156][157][158]. One recently reported peptide candidate consisted of overlapping peptides derived from the p7 protein which induced antigen-specific CD4+ T cells and cytotoxic CD8+ T cells capable of targeting p7 expressing hepatocytes in vivo [154].…”

Structure-Based and Rational Design of a Hepatitis C Virus Vaccine

“…Vaccine designs combining the HCV core protein with E1E2 can induce both B cell and T cell responses, as shown by a VLP assembly of four different HCV genotypes [ 145 ] and a chimeric protein with epitopes from all three antigens and NS3 [ 146 ]. Although p7 has not been the focus of vaccine studies until recently, overlapping peptides of the antigen displayed on nanoparticles stimulated significantly higher T cell responses in mice, providing another avenue for vaccine development [ 147 ]. Rational design approaches have also been utilized to stimulate CD8 + T cell responses by accounting for HCV genetic diversity.…”

Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants

“…CAF09 consists of cationic liposomes combined with the immunostimulants monomycolyl glycerol and the TLR3 ligand poly (I:C) [ 171 ]. The CAF09 adjuvant was used by the same laboratory along with a mixture of six overlapping peptides from the HCV p7 protein, a crucial protein for efficient viral assembly and release [ 165 ]. This vaccine induced specific multifunctional cytokine-producing CD4 + and CD8 + T-cells and cleared hepatocytes expressing HCV p7 in different mice models.…”