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-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.

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Publication Details

Journal
Nature Communications
Published
2024-08-12
DOI
https://doi.org/10.1038/s41467-024-51046-w
Citations
1
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.39

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

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

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article en
1 citations

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.

Nature CommunicationsVol. 15(1)
National Institutes of Health (US), Emory University (US), Fred Hutch Cancer Center (US), Bioqual (US), National Institute of Allergy and Infectious Diseases (US), Children's Healthcare of Atlanta (US), Emory National Primate Research Center, Weizmann Institute of Science (IL)
U.S. Department of Health and Human Services, Emory University, Children's Healthcare of Atlanta, Weizmann Institute of Science, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 38%
SARS-CoV-2 and COVID-19 Research
0.39
DOIOpen Access PDFOpenAlex
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