Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses

Nathaniel S Chapman, Ruben J G Hulswit, Jonna L B Westover, Robert Stass, Guido C Paesen, Elad Binshtein, Joseph X Reidy, Taylor B Engdahl, Laura S Handal, Alejandra Flores, Brian B Gowen, Thomas A Bowden, James E Crowe

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number5650
Number of pages15
JournalNature Communications
Volume14
Issue number1
Early online date13 Sept 2023
DOIs
Publication statusPublished - Dec 2023
Externally publishedYes

Keywords

  • Disease
  • Encephalitis
  • Immunization
  • Immunogenicity
  • Infection
  • Neutralization
  • Prediction
  • Receptor
  • System
  • Vaccine

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