Role of MHC-II epitope modification in enhancing the immunogenicity of Influenza A vaccines

Geary, James 2025. Role of MHC-II epitope modification in enhancing the immunogenicity of Influenza A vaccines. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background – Influenza A viruses (IAV) are endemic respiratory pathogens responsible for significant morbidity and mortality in humans. Vaccination is crucial for generating protective immunity; however, this immunity is often strain-specific, highlighting the need for ‘universal vaccines’ that provide broad, cross-protective immunity. CD4+ T cells are pivotal in the adaptive immune response, aiding the effector functions of CD8+ T cells and B cells, whilst also enacting their own effector functions. Additionally, T cell epitopes from the internal antigens of IAV are highly conserved across strains, making them prime targets for improving vaccine design. Enhancement of CD4+ T cell responses can be achieved through modification of the peptide flanking regions (PFR) of HLA-II epitopes. Introducing basic amino acids, such as arginine (R), into position (P)11 has been shown to increase TCR/pMHC-II affinity and T cell activation, without altering epitope specificity. Hypothesis/Results – This study aimed to test the hypothesis that PFR modification of HLA-DR1 restricted IAV epitopes would enhance CD4+ T cell responses and by doing so, lead to improved protective immunity against IAV infection. To test this, PFR modified antigens were integrated into recombinant influenza A viruses or vaccine vectors, namely self amplifying messenger RNA constructs and recombinant adenoviruses (RAd). The focus was on two HLA-DR1 restricted epitopes: PKY-HA320- 335 from hemagglutinin (HA) and GLI-M1129-143 from matrix 1 (M1). Modifying these epitopes at P11 with arginine (P11R) resulted in improved CD4+ T cell activation and superior CD8+ T cell responses. Enhanced control of IAV infection was also observed with the PFR modified RAd-M1 vaccine. Mucosal immunisation with RAd-M1 generated both systemic and mucosal immunity, with PFR modification also inducing greater populations of influenza-specific memory populations in the lungs. Conclusions – These studies reveal that PFR modification significantly enhances antigen-specific CD4+ and CD8+ T cell responses in an HLA-specific manner. This enhancement was observed across various antigens and vaccine delivery methods. Additionally, the improved immunogenicity of PFR modified RAd-M1 vaccines was shown to offer better protection against IAV infection. These findings suggest a promising advancement for future IAV vaccine design.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	21 October 2025
Last Modified:	21 Oct 2025 13:05
URI:	https://orca.cardiff.ac.uk/id/eprint/181798

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