Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
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 mou...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41171-3 |
| _version_ | 1797557895357792256 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nathaniel S. Chapman |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:22:45Z |
| format | Article |
| id | doaj.art-b9951ffe5c244d7b912906b85005d70b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:22:45Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-b9951ffe5c244d7b912906b85005d70b2023-11-20T10:18:04ZengNature PortfolioNature Communications2041-17232023-09-0114111510.1038/s41467-023-41171-3Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low dosesNathaniel S. Chapman0Ruben J. G. Hulswit1Jonna L. B. Westover2Robert Stass3Guido C. Paesen4Elad Binshtein5Joseph X. Reidy6Taylor B. Engdahl7Laura S. Handal8Alejandra Flores9Brian B. Gowen10Thomas A. Bowden11James E. Crowe12Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical CenterDivision of Structural Biology, Wellcome Centre for Human Genetics, University of OxfordDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDivision of Structural Biology, Wellcome Centre for Human Genetics, University of OxfordDivision of Structural Biology, Wellcome Centre for Human Genetics, University of OxfordThe Vanderbilt Vaccine Center, Vanderbilt University Medical CenterThe Vanderbilt Vaccine Center, Vanderbilt University Medical CenterDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical CenterThe Vanderbilt Vaccine Center, Vanderbilt University Medical CenterDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical CenterDepartment of Animal, Dairy and Veterinary Sciences, Utah State UniversityDivision of Structural Biology, Wellcome Centre for Human Genetics, University of OxfordDepartment of Pathology, Microbiology, and Immunology, Vanderbilt University Medical CenterAbstract 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.https://doi.org/10.1038/s41467-023-41171-3 |
| spellingShingle | 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 Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses Nature Communications |
| title | Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses |
| title_full | Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses |
| title_fullStr | Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses |
| title_full_unstemmed | Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses |
| title_short | Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses |
| title_sort | multifunctional human monoclonal antibody combination mediates protection against rift valley fever virus at low doses |
| url | https://doi.org/10.1038/s41467-023-41171-3 |
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