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

Thomas J Esparza; Yaozong Chen; Negin P Martin; Helle Bielefeldt-Ohmann; Richard A Bowen; William D Tolbert; Marzena Pazgier; David L Brody

doi:10.1101/2021.11.10.468147

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

bioRxiv [Preprint]. 2021 Nov 12:2021.11.10.468147. doi: 10.1101/2021.11.10.468147.

Authors

Thomas J Esparza^{1

2

3}, Yaozong Chen⁴, Negin P Martin^{5

6}, Helle Bielefeldt-Ohmann⁷, Richard A Bowen⁸, William D Tolbert⁴, Marzena Pazgier⁴, David L Brody^{1

2

9}

Affiliations

¹ The National Institute of Neurological Disorders and Stroke Intramural Research Program, Laboratory of Functional and Molecular Imaging, Bethesda, MD, USA 20892.
² Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA 20817.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA 20817.
⁴ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA 20814.
⁵ Viral Vector Core, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, NC, USA 27709.
⁶ Neurobiology Laboratory, National Institute of Environmental Health Sciences, NIH/DHHS, Research Triangle Park, NC, USA 27709.
⁷ School of Chemistry & Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, Qld 4072, Australia.
⁸ Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA, 80523.
⁹ Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA 20814.

Abstract

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, including the currently dominant Delta variant. 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.

Publication types

Preprint