Poster Presentation 12th Australasian Virology Society Meeting 2024

Imprinting of broadly neutralising anti-HCV antibodies (#180)

Eloise Kershler 1 2 , Arunasingam Abayasingam 2 , David Agapiou 1 , Bethany Horsburgh 2 , Gail Matthews 2 , Greg Dore 2 , Elise Tu 2 , Lisa Maher 2 , Jason Grebely 2 , Nicodemus Tedla 1 , Andrew Lloyd 2 , Rowena Bull 1 2
  1. School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
  2. The Kirby Institute, University of New South Wales, Sydney, NSW, Australia

An effective hepatitis C virus (HCV) vaccine must induce broadly neutralising antibodies (bnAbs) to provide protection against the highly diverse variants of HCV. Unfortunately, there has yet to be a successful HCV vaccine capable of inducing bnAbs across multiple recipients, and it is currently unclear why. A more comprehensive understanding of the impact of the infecting HCV variant on host antibody response may shed new insight. Recent studies have shown certain viral variants of HIV-1 and SARS-CoV2 can induce similar bnAb responses across multiple individuals. If certain HCV variants share this capacity to imprint antibody responses across individuals, identification and characterisation such variants could inform the design and development of an effective HCV vaccine.

Viral sequences from 1,023 HCV infected individuals from four prospective cohorts (HITS-P, HITS-C, SToP-C, and ATAHC) were aligned and a genetic distance matrix was generated to identify 38 transmission clusters of individuals infected by highly similar viruses (>96.5% nucleotide identity). To determine the correlation of antibody responses between members of these transmission clusters, enzyme linked immunosorbent assays (ELISAs) were used to test antibody binding and epitope mapping, and pseudoparticle neutralisation assays were used to test the antibody potency and breadth.

We found that members of the transmission clusters were significantly more likely to have comparable antibody binding magnitude and epitope specificity for five of the seven epitopes tested (Spearman r = 0.3-0.43, P < 0.05). Serum from these clusters also featured potent neutralisation against HCV pseudoparticles known to be neutralisation resistant. These findings demonstrate that different HCV variants feature the capacity to imprint antibody responses across individuals. Application of this knowledge to vaccine design may allow for the identification of immunogens able to consistently induce bnAbs between individuals and the knowledge gained here may be applicable other antigenically diverse viruses including influenza and SARS-CoV-2.