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

SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-specific therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool in maintaining 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 derived through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 100-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.

Matthew Gagne, Barbara J. Flynn, Christopher Cole Honeycutt, Dillon R. Flebb, Shayne F. Andrew, Samantha J. Provost, Lauren McCormick, Alex Van Ry, Elizabeth McCarthy, John-Paul M. Todd, Sanan Bao, Ling Teng, Shari Marciano, Yinon Rudich, Chunlin Li, Shilpi Jain, Bashra Wali, Laurent Pessaint, Alan Dodson, Anthony Cook, Mark G. Lewis, Hanne Andersen, Jiří Zahrādník, Mehul S. Suthar, Martha C. Nason, Kathryn E. Foulds, Peter D. Kwong, Mario Roederer, Gideon Schreiber, Robert A. Seder, Daniel C. Douek