A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions

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We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcriptional regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (Δ3678). The Δ3678 virus replicates about 7,500-fold lower than wild-type SARS-CoV-2 on primary human airway cultures, b...

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Autores principales: Liu, Yang, Zhang, Xianwen, Liu, Jianying, Xia, Hongjie, Zou, Jing, Muruato, Antonio E., Periasamy, Sivakumar, Plante, Jessica A., Bopp, Nathen E., Kurhade, Chaitanya, Bukreyev, Alexander, Ren, Ping, Wang, Tian, Menachery, Vineet D., Plante, Kenneth S., Xie, Xuping, Weaver, Scott C., Shi, Pei-Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863145/
https://www.ncbi.nlm.nih.gov/pubmed/35194609
http://dx.doi.org/10.1101/2022.02.14.480460
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author Liu, Yang
Zhang, Xianwen
Liu, Jianying
Xia, Hongjie
Zou, Jing
Muruato, Antonio E.
Periasamy, Sivakumar
Plante, Jessica A.
Bopp, Nathen E.
Kurhade, Chaitanya
Bukreyev, Alexander
Ren, Ping
Wang, Tian
Menachery, Vineet D.
Plante, Kenneth S.
Xie, Xuping
Weaver, Scott C.
Shi, Pei-Yong
author_facet Liu, Yang
Zhang, Xianwen
Liu, Jianying
Xia, Hongjie
Zou, Jing
Muruato, Antonio E.
Periasamy, Sivakumar
Plante, Jessica A.
Bopp, Nathen E.
Kurhade, Chaitanya
Bukreyev, Alexander
Ren, Ping
Wang, Tian
Menachery, Vineet D.
Plante, Kenneth S.
Xie, Xuping
Weaver, Scott C.
Shi, Pei-Yong
author_sort Liu, Yang
collection PubMed
description We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcriptional regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (Δ3678). The Δ3678 virus replicates about 7,500-fold lower than wild-type SARS-CoV-2 on primary human airway cultures, but restores its replication on interferon-deficient Vero-E6 cells that are approved for vaccine production. The Δ3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the Δ3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the Δ3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter Δ3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that Δ3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use.
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spelling pubmed-88631452022-02-23 A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions Liu, Yang Zhang, Xianwen Liu, Jianying Xia, Hongjie Zou, Jing Muruato, Antonio E. Periasamy, Sivakumar Plante, Jessica A. Bopp, Nathen E. Kurhade, Chaitanya Bukreyev, Alexander Ren, Ping Wang, Tian Menachery, Vineet D. Plante, Kenneth S. Xie, Xuping Weaver, Scott C. Shi, Pei-Yong bioRxiv Article We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcriptional regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (Δ3678). The Δ3678 virus replicates about 7,500-fold lower than wild-type SARS-CoV-2 on primary human airway cultures, but restores its replication on interferon-deficient Vero-E6 cells that are approved for vaccine production. The Δ3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the Δ3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the Δ3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter Δ3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that Δ3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use. Cold Spring Harbor Laboratory 2022-02-15 /pmc/articles/PMC8863145/ /pubmed/35194609 http://dx.doi.org/10.1101/2022.02.14.480460 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Liu, Yang
Zhang, Xianwen
Liu, Jianying
Xia, Hongjie
Zou, Jing
Muruato, Antonio E.
Periasamy, Sivakumar
Plante, Jessica A.
Bopp, Nathen E.
Kurhade, Chaitanya
Bukreyev, Alexander
Ren, Ping
Wang, Tian
Menachery, Vineet D.
Plante, Kenneth S.
Xie, Xuping
Weaver, Scott C.
Shi, Pei-Yong
A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
title A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
title_full A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
title_fullStr A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
title_full_unstemmed A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
title_short A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions
title_sort live-attenuated sars-cov-2 vaccine candidate with accessory protein deletions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863145/
https://www.ncbi.nlm.nih.gov/pubmed/35194609
http://dx.doi.org/10.1101/2022.02.14.480460
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