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

• DOI: 10.1038/s41467-022-34571-4
• Publication Date: 2022-11-10T13:03:04Z
• Authors: Shufeng Liu; Charles B. Stauft; Prabhuanand Selvaraj; Prabha Chandrasek...; 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
• Keywords: ORFS; Mesocricetus; Proinflammatory cytokine

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 spike protein and open reading frames (ORFs) 6–8, introducing mutations that abolish non-structural 1 (Nsp1)-mediated toxicity. The derived virus (WA1-ΔPRRA-ΔORF6-8-Nsp1 K164A/H165A ) replicates 100- 1000-fold-lower titers than ancestral induces little lung pathology both K18-human ACE2 (hACE2) transgenic mice Syrian hamsters. Immunofluorescence transcriptomic analyses of infected hamsters confirm three-pronged genetic modifications proinflammatory pathways more removal cleavage site alone. Finally, intranasal administration just 100 PFU WA1-ΔPRRA-ΔORF6-8-Nsp1 elicits robust antibody responses protects against SARS-CoV-2-induced weight loss pneumonia. As a proof-of-concept study, we demonstrate but sufficiently may be attainable rational design.