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Chapman, Nathaniel S; Hulswit, Ruben J G; Westover, Jonna L B; Stass, Robert; Paesen, Guido C; Binshtein, Elad; Reidy, Joseph X; Engdahl, Taylor B; Handal, Laura S; Flores, Alejandra; Gowen, Brian B; Bowden, Thomas A; Crowe, Jr, James E
Nature communications, 09/2023, Volume: 14, Issue: 1Journal Article
The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.
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