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Basic Characteristics of Mutations
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Mutation Site
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K164A |
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Mutation Site Sentence
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The derived virus (WA1-DeltaPRRA-DeltaORF6-8-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. |
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Mutation Level
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Amino acid level |
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Mutation Type
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Nonsynonymous substitution |
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Gene/Protein/Region
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NSP1 |
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Standardized Encoding Gene
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ORF1a
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Genotype/Subtype
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Delta |
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Viral Reference
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-
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Functional Impact and Mechanisms
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Disease
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Cell line
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Immune
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- |
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Target Gene
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-
|
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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- |
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Location
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USA |
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Literature Information
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PMID
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36357440
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Title
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Intranasal delivery of a rationally attenuated SARS-CoV-2 is immunogenic and protective in Syrian hamsters
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Author
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Liu S,Stauft CB,Selvaraj P,Chandrasekaran P,D'Agnillo F,Chou CK,Wu WW,Lien CZ,Meseda CA,Pedro CL,Starost MF,Weir JP,Wang TT
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Journal
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Nature communications
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Journal Info
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2022 Nov 10;13(1):6792
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Abstract
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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-DeltaPRRA-DeltaORF6-8-Nsp1(K164A/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-DeltaPRRA-DeltaORF6-8-Nsp1(K164A/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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Sequence Data
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GSE199922s
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