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Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters.
Liu, Shufeng; Stauft, Charles B; Selvaraj, Prabhuanand; Chandrasekaran, Prabha; D'Agnillo, Felice; Chou, Chao-Kai; Wu, Wells W; Lien, Christopher Z; Meseda, Clement A; Pedro, Cyntia L; Starost, Matthew F; Weir, Jerry P; Wang, Tony T.
  • Liu S; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Stauft CB; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Selvaraj P; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Chandrasekaran P; Laboratory of Clinical Investigation, National Institutes of Aging, National Institutes of Health, Baltimore, USA.
  • D'Agnillo F; Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Chou CK; Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Wu WW; Facility for Biotechnology Resources, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Lien CZ; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Meseda CA; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Pedro CL; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Starost MF; Division of Veterinary Resources, Diagnostic and Research Services Branch, National Institutes of Health, Rockville Pike, USA.
  • Weir JP; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
  • Wang TT; Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Tony.Wang@fda.hhs.gov.
Nat Commun ; 13(1): 6792, 2022 Nov 10.
Article in English | MEDLINE | ID: covidwho-2117248
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-Nsp1K164A/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-Nsp1K164A/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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2022 Document Type: Article Affiliation country: S41467-022-34571-4

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2022 Document Type: Article Affiliation country: S41467-022-34571-4