A pan‐genotype hepatitis C virus viral vector vaccine generates T cells and neutralizing antibodies in mice

Abstract

Background and Aims A prophylactic vaccine targeting multiple HCV genotypes (gt) is urgently required to meet World Health Organization elimination targets. Neutralizing antibodies (nAbs) and CD4+ and CD8+ T cells are associated with spontaneous clearance of HCV, and each may contribute to protective immunity. However, current vaccine candidates generate either nAbs or T cells targeting genetically variable epitopes and have failed to show efficacy in human trials. We have previously shown that a simian adenovirus vector (ChAdOx1) encoding conserved sequences across gt1‐6 (ChAd‐Gt1‐6), and separately gt‐1a E2 protein with variable regions deleted (E2Δ123HMW), generates pan‐genotypic T cells and nAbs, respectively. We now aim to develop a vaccine to generate both viral‐specific B‐ and T‐cell responses concurrently. Approach and Results We show that vaccinating with ChAd‐Gt1‐6 and E2Δ123HMW sequentially in mice generates T‐cell and antibody (Ab) responses comparable to either vaccine given alone. We encoded E2Δ123 in ChAdOx1 (ChAd‐E2Δ123) and show that this, given with an E2Δ123HMW protein boost, induces greater CD81‐E2 inhibitory and HCV‐pseudoparticle nAb titers compared to the E2Δ123HMW prime boost. We developed bivalent viral vector vaccines (ChAdOx1 and modified vaccinia Ankara [MVA]) encoding both Gt1‐6 and E2Δ123 immunogens (Gt1‐6‐E2Δ123) generating polyfunctional CD4+ and CD8+ T cells and nAb titers in prime/boost strategies. This approach generated nAb responses comparable to monovalent E2Δ123 ChAd/MVA vaccines and superior to three doses of recombinant E2Δ123HMW protein, while also generating high‐magnitude T‐cell responses. Conclusions These data are an important step forward for the development of a pan‐genotype HCV vaccine to elicit T cells and nAbs for future assessment in humans.

TROLLOPE: A novel sequence-based stacked approach for the accelerated discovery of linear T-cell epitopes of hepatitis C virus

“…In this study, we conducted case studies to evaluate the prediction capability of our stacked model TROLLOPE in practical real‐life situations and compared its performance with the top-five base-classifiers. Specifically, we collected six experimentally verified TCE-HCVs from two previous studies [ 84 ]. The criteria for HCV epitopes selection in this case study were as follows: 1) they have to be experimentally verified from published research papers, 2) only short peptides (8–11 amino acid residues) that are CD8+ T-cell specific epitopes will be considered (not B-cell specific or CD4+ T-cell epitopes), and 3) these TCE-HCVs should not be found in both the training and independent test datasets.…”

Recent Advances in Protective Vaccines against Hepatitis Viruses: A Narrative Review

“…This understanding of E1 and E2 structure will significantly help in the discovery of more effective vaccine and may be a novel therapeutic option [ 187 ]. Donnison et al recently attempted a bivalent viral vector vaccine in mice and found that it could induce both pangenotypic viral-specific B- and T-cell responses [ 188 ]. Moreover, Pihl et al described a whole inactivated cell-culture-derived HC vaccine that was capable of inducing potent neutralizing antibodies [ 189 ].…”

Implementation of a controlled human infection model for evaluation of HCV vaccine candidates

“…[45] Recently, these two immunogens have been successfully encoded in a viral vector and assessed in mice, generating pan-genotypic T cells and antibodies. [46] Furthermore, much has been learned about neutralizing epitopes, structures of E2 have been solved, and structures of the E1/E2 heterodimer have recently been reported-together, these insights will provide further insight into how to fix HCV glycoprotein-based immunogens into conformation, exposing their most vulnerable points for neutralization. The expression of HCV envelope immunogens on virus like particles and scaffold nanoparticles is an approach currently being intensively explored, taking advantage of advances in structural and computational techniques alongside the study of neutralizing antibodies in people who spontaneously resolve HCV.…”

“…Moving forward, exciting new approaches are seeking to overcome genetic diversity and the limitations of previous approaches; this includes the use of modified E2 sequences with HVR deleted43,44 and conserved segment T cell immunogens expressed in viral vectors 45. Recently, these two immunogens have been successfully encoded in a viral vector and assessed in mice, generating pan‐genotypic T cells and antibodies 46. Furthermore, much has been learned about neutralizing epitopes, structures of E2 have been solved, and structures of the E1/E2 heterodimer have recently been reported—together, these insights will provide further insight into how to fix HCV glycoprotein‐based immunogens into conformation, exposing their most vulnerable points for neutralization.…”