Hepatitis C virus chronically infects more than 120 million people globally and causes approximately 700,000 deaths each year.

To address the hepatitis C pandemic, the World Health Organization (WHO) introduced the following targets for 2030: an 80% reduction in new infections, a 65% reduction in deaths and diagnosis rates of 90% in HCV-infected people.

Direct acting antivirals (DAAs) can cure HCV infection in over 95% of people receiving them. However, DAAs alone are unlikely to achieve HCV elimination because: 1. DAAs are prohibitively expensive relative to GDP in most countries, restricting their availability, and placing a major impost on healthcare payers. 2. A large number of people have undiagnosed HCV. 3. Improper use of DAAs may cause drug resistance due to HCV’s high mutation rate and high prevalence of pre-existing drug mutations. 4. Even after viral clearance, people remain at risk of contracting HCV if re-exposed, with reinfection rates of 8-12/100 person years.

As a result, a prophylactic vaccine to prevent primary infection and reinfection is urgently needed.

Vaccines for HCV.

Central to the potential success of an HCV vaccine is the ability to confer broad protection against the 7 circulating HCV genotypes (~30% variation at protein level), comprising over 67 subtypes (~20% variation). Recent studies have shown that humans who clear their infection spontaneously generate broadly neutralising antibodies (bNAbs) early in infection, while passive immunisation of animals with human bNAbs can protect them from HCV challenge[5, 6]. The NAb response is predominantly directed towards the viral envelope glycoprotein E2 receptor binding domain (RBD).

However, viral E2 uses multiple immune evasion mechanisms to restrict the generation of bNAbs including glycan shielding, focussed amino acid sequence evolution in hypervariable regions (HVRs) that allosterically suppress the presentation of bNAb epitopes, and immunodominance of epitopes that preferentially generate isolate-specific NAbs that drive immune escape and non-neutralising antibodies.

Importantly, polyfunctional, durable CD4+ and CD8+ T cell responses have been associated with viral control in humans and CD4+ and CD8+ subset depletion results in persistent infection in chimpanzees.

Our approach to HCV vaccine design is based on the rational re-engineering of E2, and CD4+ and CD8+ T cell epitopes informed by structural, biochemical, immunological and functional data.

This project aims to:

1. Identify the best performing D123 vaccine candidate in small animals and define its structure;
2. determine if a T cell prime improves the bNAb response;
3. determine the immunogenicity of the best performing vaccine candidates in humanised mice and the features of human bNAbs generated through vaccination; and
4. confirm that vaccinal antibodies protect against homologous/heterologous HCV challenge in humanised mice.

Our longer term goal is to advance the best performing candidate into a Phase I clinical trial to determine safety and immunogenicity in humans.

Timeline

2022

Results

1. Scott N, Wilson DP, Thompson AJ, Barnes E, El-Sayed M, Benzaken AS, Drummer HE, Hellard ME. 2019. The case for a universal hepatitis C vaccine to achieve hepatitis C elimination. BMC Med 17:175.
2. Gu J, Hardy J, Boo I, Vietheer P, McCaffrey K, Alhammad Y, Chopra A, Gaudieri S, Poumbourios P, Coulibaly F, Drummer HE. 2018. Escape of Hepatitis C Virus from Epitope I Neutralization Increases Sensitivity of Other Neutralization Epitopes. J Virol 92.
3. Vietheer PT, Boo I, Gu J, McCaffrey K, Edwards S, Owczarek C, Hardy MP, Fabri L, Center RJ, Poumbourios P, Drummer HE. 2017. The core domain of hepatitis C virus glycoprotein E2 generates potent cross-neutralizing antibodies in guinea pigs. Hepatology 65:1117-1131.
4. McCaffrey K, Boo I, Owczarek CM, Hardy MP, Perugini MA, Fabri L, Scotney P, Poumbourios P, Drummer HE. 2017. An Optimized Hepatitis C Virus E2 Glycoprotein Core Adopts a Functional Homodimer That Efficiently Blocks Virus Entry. J Virol 91.
5. Grove J, Hu K, Farquhar MJ, Goodall M, Walker L, Jamshad M, Drummer HE, Bill RM, Balfe P, McKeating JA. 2017. A new panel of epitope mapped monoclonal antibodies recognising the prototypical tetraspanin CD81. Wellcome Open Res 2:82.