tetano
Editor, Senior Moderator
Nat Commun
. 2022 Nov 10;13(1):6792.
doi: 10.1038/s41467-022-34571-4.
Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters
Shufeng Liu[SUP] #[/SUP][SUP] 1 [/SUP], Charles B Stauft[SUP] #[/SUP][SUP] 1 [/SUP], Prabhuanand Selvaraj[SUP] #[/SUP][SUP] 1 [/SUP], Prabha Chandrasekaran[SUP] #[/SUP][SUP] 2 [/SUP], Felice D'Agnillo[SUP] #[/SUP][SUP] 3 [/SUP], Chao-Kai Chou[SUP] 4 [/SUP], Wells W Wu[SUP] 4 [/SUP], Christopher Z Lien[SUP] 1 [/SUP], Clement A Meseda[SUP] 1 [/SUP], Cyntia L Pedro[SUP] 1 [/SUP], Matthew F Starost[SUP] 5 [/SUP], Jerry P Weir[SUP] 1 [/SUP], Tony T Wang[SUP] 6 [/SUP]
Affiliations
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[SUP]K164A/H165A[/SUP]) 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[SUP]K164A/H165A[/SUP] 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.
. 2022 Nov 10;13(1):6792.
doi: 10.1038/s41467-022-34571-4.
Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters
Shufeng Liu[SUP] #[/SUP][SUP] 1 [/SUP], Charles B Stauft[SUP] #[/SUP][SUP] 1 [/SUP], Prabhuanand Selvaraj[SUP] #[/SUP][SUP] 1 [/SUP], Prabha Chandrasekaran[SUP] #[/SUP][SUP] 2 [/SUP], Felice D'Agnillo[SUP] #[/SUP][SUP] 3 [/SUP], Chao-Kai Chou[SUP] 4 [/SUP], Wells W Wu[SUP] 4 [/SUP], Christopher Z Lien[SUP] 1 [/SUP], Clement A Meseda[SUP] 1 [/SUP], Cyntia L Pedro[SUP] 1 [/SUP], Matthew F Starost[SUP] 5 [/SUP], Jerry P Weir[SUP] 1 [/SUP], Tony T Wang[SUP] 6 [/SUP]
Affiliations
- PMID: 36357440
- DOI: 10.1038/s41467-022-34571-4
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[SUP]K164A/H165A[/SUP]) 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[SUP]K164A/H165A[/SUP] 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.