Epstein-Barr virus antigen design and characterisation

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The Epstein-Barr virus (EBV) is a human herpesvirus that infects epithelial cells and B lymphocytes; and transforms B cells to remain latent and can spontaneously reactivate. The virus infects over 90% of adults, and in most cases causes no problems or relatively mild symptoms (typically infectious mononucleosis, also known as glandular fever). In a small minority of those who are infected, however, EBV is associated with the development of multiple sclerosis or certain cancers. These diseases are often associated with poor prognoses and often require expensive treatment interventions, posing a significant issue to society. Indeed, data from Cancer Research UK suggests that EBV infection accounts for 200,000 new cases of cancer each year resulting in more than 140,000 deaths yearly. Therefore, there is an urgent need to design an efficacious vaccine that prevents EBV infection with the aim in the long run to reduce the onset of these more severe EBV associated pathologies. To date there is no approved EBV vaccine candidate, in part due to the inability to select an appropriate antigen that elicits robust neutralising antibodies to block infection. Recently there has been increasing support and research towards EBV vaccine development, with Moderna having initiated Phase I trials of their mRNA candidate targeting four key EBV envelope glycoproteins gH, gL, gp42 and gp220. The supervisor's group have taken a different approach in targeting the class III fusogen protein, glycoprotein B (gB), which is crucial for mediating membrane fusion to both epithelial cells and B lymphocytes. However, the gB protein very rapidly switches conformation from a pre-fusion state (natural conformation on the viral membrane) towards a post-fusion structure. A high-resolution structure of the pre-fusion state has not yet been established. Defining the pre-fusion state of gB would largely promote its use as a vaccine antigen.The project will use a library of gB mutants to establish which residues within the protein are involved in the stability of the pre-fusion conformation, and hence to attempt to design a pre-fusion stabilised form of the protein. It is hypothesised that a stabilised pre-fusion gB could elicit stronger immune responses upon immunisation, analogous to the 2P-based vaccines that target SARS-CoV-2. Furthermore, this project could provide further insight into the molecular architecture and dynamics that drive gB fusion and thus EBV infection.