Investigating the Antibody Immune Response to Ebola Virus Vaccination in Humans

As the most advanced Ebola virus vaccine candidate, recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) has been used under compassionate use to combat two Ebola virus disease (EVD) outbreaks. Before licensing, more than 350,000 individuals at risk had been administered the vaccination until 2020. Importantly, a detailed molecular analysis of the vaccine-induced humoral immunity was not available. In this thesis, the B cell and antibody immune response is elucidated in an unprecedented depth in a cohort of human volunteers that were enrolled in a phase 1 rVSV-ZEBOV vaccination trial. Sera of all vaccinees and across different vaccination doses showed higher reactivity compared to non-vaccinated individuals. Advanced and comprehensive single B cell sorts and sequence analyses further revealed that all individuals exhibited polyclonal B cell responses with numerous specific B cells. Albeit the response was diverse, it was highly reproducible and amongst vaccinees, convergent B cell responses were observed with B cell clones that shared sequence characteristics to a remarkable degree. Moreover, in all vaccinated subjects, convergent antibodies were identified that combined heavy chains with IGHV3-15 with lambda light chains comprising IGLV1-40, arguing for an eminent yet previously unnoticed role of this group of antibodies in the defense against Ebola viruses. Detailed epitope mapping showed that vaccination induced B cell responses against all domains of EBOV GP. Moreover, vaccination-induced antibodies had overlapping target epitopes with antibodies isolated from EVD survivors, which was shown by competition for EBOV GP epitopes and electron microscopy structure analyses suggesting that vaccination authentically triggers B cell immunity. Importantly, EBOV GP-specific antibodies also cross-reacted with other Filovirus species, which might indicate positive effects on antibody-mediated immunity against other Filoviruses. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies including antibodies combining the IGHV3–15/IGLV1–40 immunoglobulin gene segments. Some of them exerted EBOV-neutralizing activities comparable or even superior to previously reported monoclonal antibodies such as the survivor-derived mAb114, which has recently been licensed as EVD therapy. These findings provide the first comprehensive analysis of the rVSV-ZEBOV-induced B cell response and will help to evaluate and direct current and future means against EVD and potentially other viral diseases