Computational mining of B cell receptor repertoires reveals antigen-specific and convergent responses to Ebola vaccination.

Outbreaks of Ebolaviruses, such as Sudanvirus (SUDV) in Uganda in 2022, demonstrate that species other than the Zaire ebolavirus (EBOV), which is currently the sole virus represented in current licensed vaccines, remain a major threat to global health. There is a pressing need to develop effective pan-species vaccines and novel monoclonal antibody-based therapeutics for Ebolavirus disease. In response to recent outbreaks, the two dose, heterologous Ad26.ZEBOV/MVA-BN-Filo vaccine regimen was developed and was tested in a large phase II clinical trial (EBL2001) as part of the EBOVAC2 consortium. Here, we perform bulk sequencing of the variable heavy chain (VH) of B cell receptors (BCR) in forty participants from the EBL2001 trial in order to characterize the BCR repertoire in response to vaccination with Ad26.ZEBOV/MVA-BN-Filo. We develop a comprehensive database, EBOV-AbDab, of publicly available Ebolavirus-specific antibody sequences. We then use our database to predict the antigen-specific component of the vaccinee repertoires. Our results show striking convergence in VH germline gene usage across participants following the MVA-BN-Filo dose, and provide further evidence of the role of IGHV3-15 and IGHV3-13 antibodies in the B cell response to Ebolavirus glycoprotein. Furthermore, we found that previously described Ebola-specific mAb sequences present in EBOV-AbDab were sufficient to describe at least one of the ten most expanded BCR clonotypes in more than two thirds of our cohort of vaccinees following the boost, providing proof of principle for the utility of computational mining of immune repertoires.

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Copyright © 2024 Richardson, Bibi, McLean, Schimanski, Rijal, Ghraichy, von Niederhäusern, Trück, Clutterbuck, O’Connor, Luhn, Townsend, Peters, Pollard, Deane and Kelly.

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Author AP was a member of WHO’s SAGE until 2022, and he is chair of the UK Department of Health and Social Care’s Joint Committee on Vaccination and Immunisation. KL was a full-time employee of Janssen Pharmaceuticals at the time of the study and reported stock or stock options in Janssen Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest Janssen Vaccines & Prevention B.V., the vaccination study sponsor, was involved in the writing of the manuscript and the decision to publish the results. The Oxford Vaccine Group was contracted by Janssen Pharmaceuticals to help conduct the vaccination study from which data was collected.