HUMAN ANTIBODIES TO RIFT VALLEY FEVER VIRUS AND CRIMEAN CONGO HEMORRHAGIC FEVER VIRUS

Abstract

Rift Valley fever virus (RVFV) and Crimean Congo Hemorrhagic fever virus (CCHFV) are two lethal viruses that impact human health. Little is known about the human antibody response to either virus. In this work, I show that RVFV Gn domain A targeting antibodies and a novel class of fusion inhibitory antibodies potently neutralized RVFV. The fusion inhibitory antibodies did not bind either monomeric surface glycoproteins alone but instead recognized the co-expression of Gc and Gn. A representative antibody from each class provided protection at low doses in lethal mouse models of infection. RVFV Gn antibodies blocked attachment, but the process by which these antibodies function is poorly understood. I observed that RVFV Gn antibodies do not block the LRP1 and Gn interaction by direct epitope competition, and bivalent full-length IgG1 was needed to achieve maximal neutralization capacity of this representative antibody. A representative antibody from each class neutralized RVFV in diverse cell lines. I reasoned to combine these antibodies to make the first dual-mechanism combination of antibodies against RVFV. My collaborators showed this combination was protective at low doses in a lethal mouse model of infection. Protective CCHFV antibodies have been difficult to identify. Through isolation of a panel of antibodies from a survivor of CCHFV infection, I identified a non-neutralizing antibody to CCHFV that offered partial protection against lethal challenge of CCHFV in a mouse model of infection using the Turkish strain of CCHFV, as done by my collaborators in ABSL-4 conditions. This work identified some protective features of the humoral immune response and may inform rational vaccine design efforts against these pathogens.