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

DOI: 10.1038/s41467-023-41171-3 DOI Help

Authors: Nathaniel S. Chapman (Vanderbilt University) , Ruben J.g. Hulswit (Wellcome Centre for Human Genetics, University of Oxford) , Jonna L. B. Westover (Utah State University) , Robert Stass (Wellcome Trust Centre for Human Genetics, University of Oxford) , Guido C. Paesen (Wellcome Centre for Human Genetics, University of Oxford) , Elad Binshtein (Vanderbilt University Medical Center) , Joseph X. Reidy (Vanderbilt University Medical Center) , Taylor B. Engdahl (Vanderbilt University Medical Center) , Laura S. Handal (Vanderbilt University Medical Center) , Alejandra Flores (Vanderbilt University Medical Center) , Brian B. Gowen (Utah State University) , Thomas A. Bowden (Wellcome Centre for Human Genetics, University of Oxford) , James E. Crowe (Vanderbilt University Medical Center)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: September 2023
Diamond Proposal Number(s): 28534

Open Access Open Access

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.

Diamond Keywords: Rift Valley Fever (RVF); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 14/09/2023 09:57

Documents:
s41467-023-41171-3.pdf

Discipline Tags:

Vaccines Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)