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 language | English |
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Article number | 5650 |
Number of pages | 15 |
Journal | Nature Communications |
Volume | 14 |
Issue number | 1 |
Early online date | 13 Sept 2023 |
DOIs | |
Publication status | Published - Dec 2023 |
Externally published | Yes |
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.
Funders | Funder number |
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National Institutes of Health | HHSN272201700041I, MX-28534 |
Vanderbilt University | |
Wellcome Trust | 203141/Z/16/Z. |
Medical Research Council | MR/S007555/1, MR/V031635/1 |
Keywords
- Disease
- Encephalitis
- Immunization
- Immunogenicity
- Infection
- Neutralization
- Prediction
- Receptor
- System
- Vaccine