Mapping anti-filovirus humoral immune responses in broadly seroreactive individuals

Project Summary/Abstract: Filoviruses encompass a broad group of highly lethal pathogens, including orthoebolaviruses (Ebola (EBOV), Bundibugyo, Sudan, and Taï Forest viruses) and orthomarburgviruses (Marburg (MARV) and Ravn viruses). These viruses cause sporadic disease outbreaks, but which virus will emerge and where cannot be predicted. As such, residents of affected areas, as well as military, aid workers and travelers in Central and West Africa continue to be at risk of infection. Further, currently approved monoclonal antibody (mAb) treatments and vaccines are available only for EBOV. A few known mAbs can cross-react among orthoebolaviruses, but none are yet known to offer broad filovirus neutralization. It is possible that our ability to uncover human mAbs of broad neutralization was limited by the nature of the human samples used for discovery. Prior antibody discovery campaigns to date isolated antibodies from individuals who had been infected once with just one of these viruses (usually EBOV, one with MARV, etc.), and many studies were performed on returning Americans who would not have had more than one filovirus exposure. This proposal, however, utilizes a different cohort. Serology studies in the Democratic Republic of the Congo, where multiple filoviruses are endemic, revealed 23 individuals with extraordinarily broad and strong antibody responses against a broad range of filovirus surface glycoproteins (GP). Some of these individuals have strong reactivity to all of them: all four pathogenic orthoebolaviruses and both orthomarburgviruses. These individuals have lived all or most of their lives in remote villages that have had known outbreaks and have occupations that likely led to multiple filovirus exposures over time. In this project, we will analyze, in detail, the antibody repertoires of these multiply exposed individuals. We will analyze reactivity at the polyclonal and monoclonal levels alike. We expect that mAbs identified in these individuals will have greater breadth and broader filovirus activity than have been discovered before. The results from this study could lead to the discovery of a novel, broad-spectrum filovirus mAb therapeutic, guide the development of more broadly applicable vaccines, and will deepen our understanding of how a lifetime of exposure shapes the humoral immune response to these viruses.