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

• Published in: Nature communications Vol. 15; no. 1; pp. 6894 - 13
• Main Authors: Gagne, Matthew, Flynn, Barbara J., Honeycutt, Christopher Cole, Flebbe, Dillon R., Andrew, Shayne F., Provost, Samantha J., McCormick, Lauren, Van Ry, Alex, McCarthy, Elizabeth, Todd, John-Paul M., Bao, Saran, Teng, I-Ting, Marciano, Shir, Rudich, Yinon, Li, Chunlin, Jain, Shilpi, Wali, Bushra, Pessaint, Laurent, Dodson, Alan, Cook, Anthony, Lewis, Mark G., Andersen, Hanne, Zahradník, Jiří, Suthar, Mehul S., Nason, Martha C., Foulds, Kathryn E., Kwong, Peter D., Roederer, Mario, Schreiber, Gideon, Seder, Robert A., Douek, Daniel C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 38/88; 631/154; 631/250/24; 631/250/255/2514; 631/250/347; 631/326/596/4130; 64; ACE2; Affinity; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - antagonists & inhibitors; Animal models; Animals; Antiviral agents; Antiviral Agents - pharmacology; Antiviral drugs; Binding; Chlorocebus aethiops; COVID-19; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 - virology; COVID-19 Drug Treatment; Disease Models, Animal; Drug efficacy; Effectiveness; Evolution; Humanities and Social Sciences; Humans; Immunity; Inhalation; Lymphocytes B; Macaca mulatta; Male; multidisciplinary; Pharmacology; Protein folding; Proteins; Replication; Respiration; SARS-CoV-2 - drug effects; SARS-CoV-2 - immunology; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Vaccines; Vero Cells; Viral diseases; Virus Replication - drug effects; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51046-w

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. SARS-CoV-2 evolution poses a risk to vaccine and antiviral drug efficacy. Here, Gagne et al. report the development of a variant-agnostic protein, RBD-62, with enhanced ACE2 binding obtained through in vitro evolution and show that RBD-62 inhalation protects nonhuman primates against SARS-CoV-2 Delta challenge.