Identifying HLA-bespoke changes to CD4+ T cell epitopes in influenza A virus derived antigens to drive superior protective and heterotypic immunity

Influenza A virus (IAV) remains a major pathogen affecting nearly all populations globally; most vaccines are directed to the surface haemagglutinin (HA) and need reformulating annually due to viral genetic drift. The lack of cross-protection between subtypes of IAV such as avian influenza, with its pandemic potential, presents a major threat.
CD4+ T helper cell (TH cell) responses are fundamentally important for co-ordinating and driving serological protection and cytotoxic CD8+ T cell responses, and hence play a crucial role in protective immunity to IAV. This project focuses on driving a superior TH cell response to influenza proteins and improving heterosubtypic immunity. TH cells recognise short peptide epitopes presented by HLA class II molecules (pHLA-II). The approach revolves around increasing the inherent immunogenicity of IAV-derived proteins by introducing bespoke changes to defined HLA-II presented epitopes. Previous work has shown a striking increase in clearance of IAV infection, and long-term homo-/heterosubtypic protective immunity from re-infection, after priming mice with HA modified at just a single amino acid in an HLA-DR-1 defined epitope.
This project will develop this approach, firstly by defining the key IAV derived epitopes presented by the five commonest HLA-DR allotypes (allowing coverage of >90% of the population). We will focus on HA from different influenza strains along with highly conserved internal proteins Matrix M1 and nucleoprotein NP, increasing the chance of heterosubtypic protection to future challenges such as avian influenza. Secondly HLA-II-defined epitopes will be empirically altered in the flanking residues adjacent to the binding core of the peptide and tested on cognate TH cells. Those favoured changes leading to increased TH cell activation, will be incorporated into antigens that will be tested in pre-clinical models employing intramuscular RNA vaccines initially and then novel mucosa-administered vaccines such as...