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Review
. 2019 Jan;156(2):418-430.
doi: 10.1053/j.gastro.2018.08.060. Epub 2018 Sep 27.

Approaches, Progress, and Challenges to Hepatitis C Vaccine Development

Justin R Bailey  1 , Eleanor Barnes  2 , Andrea L Cox  3
Affiliations
Review

Approaches, Progress, and Challenges to Hepatitis C Vaccine Development

Justin R Bailey et al. Gastroenterology. 2019 Jan.

Abstract

Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.

Keywords: HCV; Prophylactic Vaccination; Vaccines; Viral Hepatitis.

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Figures

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Justin R. Bailey
None
Eleanor Barnes
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Andrea L. Cox
Figure 1
Figure 1
Genetic diversities of HCV and human immunodeficiency virus 1 (HIV-1). Phylogenetic trees of reference full-genome HCV (left) and HIV-1 (right) nucleotide sequences downloaded from the Los Alamos National Laboratory sequence database. Trees were inferred using the Neighbor-Joining method, with branch lengths drawn to scale. Genotypes or subtypes are labeled. Trees are on the same scale. The HCV tree is based on 8940 positions, and the HIV-1 tree is based on 8193 positions. Distances were computed using the Tamura-Nei method. Analyses were performed in MEGA7.
Figure 2
Figure 2
bNAb epitopes are conformationally complex and flexible. (A, B) The crystallized structure of a truncated HCV E2 protein, strain H77, PDB 4MWF, from Kong et al, with E2 domains and bNAb binding residues highlighted in Pymol, v1.8.6.2. The E2 front layer is cyan, central beta sheet is red, and the back layer is green. Binding residues of the CD81 binding site-targeting bNAb AR3C (A) or the E1E2 complex-targeting bNAb AR4A (B), identified by alanine scanning mutagenesis and binding assays, are marked with yellow spheres. Amino acid side chains are not shown. *Putative AR4A binding residues not present in the E2 crystal structure are listed next to the structure. Binding residues shown or listed are positions at which mutation to alanine had the greatest effect on AR3C or AR4A binding, but minimal effect on control mAbs. Numbering is relative to the H77 polyprotein sequence. (C) Structures of peptide epitopes crystallized in complex with AS412-targeting bNAbs HC33.1 or HCV1. Fab structures are not shown. HC33.1 binds the peptide in an extended conformation (PDB 4XVJ), whereas HCV1 binds the peptide in a hairpin conformation (PDB 4DGY). Critical binding residues for each bNAb determined by alanine scanning mutagenesis and binding assays are marked with yellow spheres., Amino acid side chains are not shown.
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