Characterisation of antigenic MHC Class I-restricted T cell epitopes in the glycoprotein of Ebolavirus
Powlson J., Wright D., Zeltina A., Giza M., Nielsen M., Rampling T., Venkatrakaman N., Ewer KJ., Bowden TA., Hill AVS.
Ebolavirus is a pathogen capable of causing highly lethal haemorrhagic fever in humans. The envelope-displayed viral glycoprotein is the primary target of humoral immunity induced by both natural exposure and vaccination. The epitopes targeted by B cells have been thoroughly characterised by functional and structural analyses of the glycoprotein, GP, yet there is a paucity of information regarding the cellular immune response to Ebolavirus. To date, no T cell epitopes in the glycoprotein have been characterised in detail in humans. A recent Phase I clinical trial of a heterologous prime-boost vaccination regime with viral vectors encoding filovirus antigens elicited strong humoral and T cell responses in vaccinees. Using samples from this trial, the most frequently recognised peptide pools were studied in more detail to identify the minimal epitopes recognised by antigen-specific T cells and associated HLA-restrictions. Using IFNγ ELISPOT and flow cytometry, we characterised nine highly immunogenic T cell epitopes located on both the GP1 and GP2 subunits of the Ebolavirus GP. Epitope mapping revealed the location of these epitopes as presented on the mature virion. HLA-typing on all participants, combined with in silico epitope analysis, determined the likely MHC class I restriction elements. Thirteen HLA-A and -B alleles were predicted to present the identified epitopes, suggesting promiscuous recognition and induction of a broad immune response. The glycoprotein of Ebolavirus is highly immunogenic, inducing both CD4+ and CD8+ T cell responses and we have shown here for the first time that these responses are associated with multiple HLA types. Delivery of this antigen using a heterologous prime-boost approach with ChAd3 and MVA is likely to be highly immunogenic in genetically diverse human populations, due to the induction of responses against multiple immunodominant epitopes.