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

Shufeng Liu, Charles B. Stauft, Prabhuanand Selvaraj, Prabha Chandrasekaran, Felice D’Agnillo, Chao-Kai Chou, Wells W. Wu, Christopher Z. Lien, Clement A. Meseda, Cyntia L. Pedro, Matthew F. Starost, Jerry P. Weir and Tony T. Wang ()
Additional contact information
Shufeng Liu: Food and Drug Administration
Charles B. Stauft: Food and Drug Administration
Prabhuanand Selvaraj: Food and Drug Administration
Prabha Chandrasekaran: National Institutes of Health
Felice D’Agnillo: Food and Drug Administration
Chao-Kai Chou: Food and Drug Administration
Wells W. Wu: Food and Drug Administration
Christopher Z. Lien: Food and Drug Administration
Clement A. Meseda: Food and Drug Administration
Cyntia L. Pedro: Food and Drug Administration
Matthew F. Starost: National Institutes of Health
Jerry P. Weir: Food and Drug Administration
Tony T. Wang: Food and Drug Administration

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34571-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34571-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34571-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().