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

Bibliographical note

Publisher Copyright:
© 2023, Springer Nature Limited.

Funding

EM data collections were conducted at the Center for Structural Biology Cryo-EM Facility at Vanderbilt University. This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. We thank Dr. Robert Carnahan and Dr. Seth Zost for helpful discussions. This work was supported by the National Institutes of Health (HHSN272201700041I). We thank the staff of beamline i04-1 at Diamond Light Source (proposal MX-28534) for assistance with data collection. Additionally, we thank Tom Walter and Karl Harlos for help with crystallization and data collection. T.A.B. is supported by Medical Research Council grants MR/V031635/1, and MR/S007555/1. The Wellcome Centre for Human Genetics is supported by Wellcome Trust Core Award Grant Number 203141/Z/16/Z. EM data collections were conducted at the Center for Structural Biology Cryo-EM Facility at Vanderbilt University. This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. We thank Dr. Robert Carnahan and Dr. Seth Zost for helpful discussions. This work was supported by the National Institutes of Health (HHSN272201700041I). We thank the staff of beamline i04-1 at Diamond Light Source (proposal MX-28534) for assistance with data collection. Additionally, we thank Tom Walter and Karl Harlos for help with crystallization and data collection. T.A.B. is supported by Medical Research Council grants MR/V031635/1, and MR/S007555/1. The Wellcome Centre for Human Genetics is supported by Wellcome Trust Core Award Grant Number 203141/Z/16/Z.

FundersFunder number
National Institutes of HealthHHSN272201700041I, MX-28534
Vanderbilt University
Wellcome Trust203141/Z/16/Z.
Medical Research CouncilMR/S007555/1, MR/V031635/1

    Keywords

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

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