Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 10. Nov., Seite 6792 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Shufeng [VerfasserIn] |
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| Links: |
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| Themen: |
COVID-19 Vaccines |
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| Anmerkungen: |
Date Completed 14.11.2022 Date Revised 26.12.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-34571-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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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| 700 | 1 | |a Selvaraj, Prabhuanand |e verfasserin |4 aut | |
| 700 | 1 | |a Chandrasekaran, Prabha |e verfasserin |4 aut | |
| 700 | 1 | |a D'Agnillo, Felice |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Chao-Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Wells W |e verfasserin |4 aut | |
| 700 | 1 | |a Lien, Christopher Z |e verfasserin |4 aut | |
| 700 | 1 | |a Meseda, Clement A |e verfasserin |4 aut | |
| 700 | 1 | |a Pedro, Cyntia L |e verfasserin |4 aut | |
| 700 | 1 | |a Starost, Matthew F |e verfasserin |4 aut | |
| 700 | 1 | |a Weir, Jerry P |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tony T |e verfasserin |4 aut | |
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