Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters

Shufeng Liu; Charles B Stauft; Prabhuanand Selvaraj; Prabha Chandrasekaran; Felice D'Agnillo; Chao-Kai Chou; Wells W Wu; Christopher Z Lien; Clement A Meseda; Cyntia L Pedro; Matthew F Starost; Jerry P Weir; Tony T Wang

doi:10.1038/s41467-022-34571-4

Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters

Nat Commun. 2022 Nov 10;13(1):6792. doi: 10.1038/s41467-022-34571-4.

Authors

Affiliations

¹ Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
² Laboratory of Clinical Investigation, National Institutes of Aging, National Institutes of Health, Baltimore, USA.
³ Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
⁴ Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
⁵ Division of Veterinary Resources, Diagnostic and Research Services Branch, National Institutes of Health, Rockville Pike, USA.
⁶ Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Tony.Wang@fda.hhs.gov.

^# Contributed equally.

Abstract

Few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are in pre-clinical or clinical development. We seek to attenuate SARS-CoV-2 (isolate WA1/2020) by removing the polybasic insert within the spike protein and the open reading frames (ORFs) 6-8, and by introducing mutations that abolish non-structural protein 1 (Nsp1)-mediated toxicity. The derived virus (WA1-ΔPRRA-ΔORF6-8-Nsp1^K164A/H165A) replicates to 100- to 1000-fold-lower titers than the ancestral virus and induces little lung pathology in both K18-human ACE2 (hACE2) transgenic mice and Syrian hamsters. Immunofluorescence and transcriptomic analyses of infected hamsters confirm that three-pronged genetic modifications attenuate the proinflammatory pathways more than the removal of the polybasic cleavage site alone. Finally, intranasal administration of just 100 PFU of the WA1-ΔPRRA-ΔORF6-8-Nsp1^K164A/H165A elicits robust antibody responses in Syrian hamsters and protects against SARS-CoV-2-induced weight loss and pneumonia. As a proof-of-concept study, we demonstrate that live but sufficiently attenuated SARS-CoV-2 vaccines may be attainable by rational design.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Administration, Intranasal
Animals
Antibody Formation
COVID-19 Vaccines
COVID-19* / prevention & control
Cricetinae
Humans
Lung / pathology
Mesocricetus
Mice
Mice, Transgenic
SARS-CoV-2* / genetics
Spike Glycoprotein, Coronavirus / genetics

Substances

COVID-19 Vaccines
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2