Oral Presentation 12th Australasian Virology Society Meeting 2024

Affinity of Transmitted/Founder virus associates with early emergence of Hepatitis C Virus specific neutralising antibodies (#58)

Arunasingam Abayasingam 1 2 , Money Gupta 3 , Bing-Ru Wu 4 , Clara Young 1 5 , Melanie Walker 1 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. Viral Immunology Systems Program , The Kirby Institute, Sydney, NSW, Australia
  3. Icahn School of Medicine at Mount Sinai, Mount Sinai, New York, USA
  4. School of Medicine , Deakin University, Geelong, VIC, Australia
  5. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

Objectives

A potent prophylactic vaccine against hepatitis C virus (HCV) hinges on eliciting robust neutralising antibody (nAb) responses. Notably, nAb responses in chronic HCV infections exhibit delays compared to those in cleared infections. To develop an effective vaccine, it is essential to gain a comprehensive understanding of the immunogenicity of transmitted/founder (T/F) viruses and host factors leading to either viral clearance or persistence. This knowledge will inform the optimal design of vaccines aimed at eliciting early and effective HCV nAb responses.

Methods

In this study, we isolated a rare subset of HCV transmitted/founder (T/F) envelope variants from acute primary infections from cleared and persistent infections. The immunogenicity of these variants and neutralisation sensitivity were assessed using HCV pseudoparticles (HCVpps) and a panel of well-characterised monoclonal nAbs. Additionally, soluble HCV envelope 2 (E2) proteins were produced to evaluate their ability to engage with epitope-specific nAbs and IgM germ-line antibodies. We also isolated HCV E2-specific B cells from these infections to analyse their B cell repertoire and transcriptomic features.

Results

Our findings indicate that T/Fs from cleared infections are more immunogenic and bind with higher affinity to the broad nAbs (BnAbs). In contrast, T/F variants from chronic progressors, while still binding effectively to autologous germline antibodies, exhibit delayed nAb responses, suggesting that host factors contribute to infection clearance. Additionally, E2-specific B cells in chronic progressors show a delayed response and higher levels of somatic hypermutation.

Conclusions

The natural emergence of BnAbs is a gradual process that requires antigenic stimulation. Consequently, by selecting highly immunogenic T/Fs as vaccine immunogens, it may be possible to generate an early, broad, and sustainable neutralising antibody response. These findings contribute to the ongoing efforts to develop a vaccine that can confer durable protection against HCV infection, thereby addressing a major global health burden.