Intranasal Delivery of a Rationally Attenuated SARS-CoV-2 is Immunogenic and Protective in Syrian Hamsters

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Nov 10

PMID 36357440

Authors

Shufeng Liu

Charles B Stauft

Prabhuanand Selvaraj

Prabha Chandrasekaran

Felice DAgnillo

Chao-Kai Chou

Wells W Wu

Christopher Z Lien

Clement A Meseda

Cyntia L Pedro

Matthew F Starost

Jerry P Weir

Tony T Wang

Affiliations

Soon will be listed here.

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) 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 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.

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