Nebulized delivery of a broadly neutralizing SARS-CoV-2 RBD-specific nanobody prevents clinical, virological, and pathological disease in a Syrian hamster model of COVID-19

MAbs. 2022 Jan-Dec;14(1):2047144. doi: 10.1080/19420862.2022.2047144.


There remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and in vitro characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor-binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad in vitro neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an in vivo pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection.Abbreviations: ACE2 - angiotensin converting enzyme 2BSA - buried surface areaCDR - complementary determining regionRBD - receptor binding domainRBM - receptor-binding motifSARS-CoV-2 - severe acute respiratory syndrome coronavirus 2.

Keywords: COVID-19; SARS-CoV-2; nebulized delivery; neutralizing nanobody; single-domain antibody.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Antibodies, Viral / immunology
  • Antibodies, Viral / metabolism*
  • Binding Sites / genetics
  • Broadly Neutralizing Antibodies / immunology
  • Broadly Neutralizing Antibodies / metabolism*
  • COVID-19 / immunology*
  • Cricetinae
  • Disease Models, Animal
  • Humans
  • Lung / pathology*
  • Mesocricetus
  • Nebulizers and Vaporizers
  • Protein Binding
  • SARS-CoV-2 / physiology*
  • Single-Domain Antibodies / immunology
  • Single-Domain Antibodies / metabolism*
  • Spike Glycoprotein, Coronavirus / immunology
  • Viral Load


  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • Single-Domain Antibodies
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2