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

Nat Commun. 2024 Aug 12;15(1):6894. doi: 10.1038/s41467-024-51046-w.

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.

MeSH terms

  • Angiotensin-Converting Enzyme 2* / antagonists & inhibitors
  • Animals
  • Antiviral Agents* / pharmacology
  • COVID-19 Drug Treatment
  • COVID-19* / immunology
  • COVID-19* / prevention & control
  • COVID-19* / virology
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Humans
  • Macaca mulatta
  • Male
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / immunology
  • SARS-CoV-2* / physiology
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism
  • Vero Cells
  • Virus Replication* / drug effects

Substances

  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Antiviral Agents
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2

Supplementary concepts

  • SARS-CoV-2 variants