Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

Matthew Gagne, Barbara J. Flynn, Christopher Cole Honeycutt, Dillon R. Flebbe, Shayne F. Andrew, Samantha J. Provost, Lauren McCormick, Alex Ry, Elizabeth McCarthy, John-Paul M. Todd, Saran Bao, I-Ting Teng, Shir Marciano, Yinon Rudich, Chunlin Li, Shilpi Jain, Bushra Wali, Laurent Pessaint, Alan Dodson, Anthony Cook, Mark G. Lewis, Hanne Andersen, Jiří Zahradník, Mehul S. Suthar, Martha C. Nason, Kathryn E. Foulds, Peter D. Kwong, Mario Roederer, Gideon Schreiber, Robert A. Seder () and Daniel C. Douek ()
Additional contact information
Matthew Gagne: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Barbara J. Flynn: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Christopher Cole Honeycutt: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Dillon R. Flebbe: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Shayne F. Andrew: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Samantha J. Provost: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Lauren McCormick: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Alex Ry: Bioqual Inc.
Elizabeth McCarthy: National Institute of Allergy and Infectious Diseases, National Institutes of Health
John-Paul M. Todd: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Saran Bao: National Institute of Allergy and Infectious Diseases, National Institutes of Health
I-Ting Teng: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Shir Marciano: Weizmann Institute of Science
Yinon Rudich: Weizmann Institute of Science
Chunlin Li: Weizmann Institute of Science
Shilpi Jain: Emory University School of Medicine
Bushra Wali: Emory University School of Medicine
Laurent Pessaint: Bioqual Inc.
Alan Dodson: Bioqual Inc.
Anthony Cook: Bioqual Inc.
Mark G. Lewis: Bioqual Inc.
Hanne Andersen: Bioqual Inc.
Jiří Zahradník: Weizmann Institute of Science
Mehul S. Suthar: Emory University School of Medicine
Martha C. Nason: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Kathryn E. Foulds: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Peter D. Kwong: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Mario Roederer: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Gideon Schreiber: Weizmann Institute of Science
Robert A. Seder: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Daniel C. Douek: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta—the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Date: 2024
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DOI: 10.1038/s41467-024-51046-w

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