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

Yang Liu; Xianwen Zhang; Jianying Liu; Hongjie Xia; Jing Zou; Antonio E. Muruato; Sivakumar Periasamy; Chaitanya Kurhade; Jessica A. Plante; Nathen E. Bopp; Birte Kalveram; Alexander Bukreyev; Ping Ren; Tian Wang; Vineet D. Menachery; Kenneth S. Plante; Xuping Xie; Scott C. Weaver; Pei Yong Shi

doi:10.1038/s41467-022-31930-z

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

Yang Liu
, Xianwen Zhang
, Jianying Liu
, Hongjie Xia
, Jing Zou
, Antonio E. Muruato
, Sivakumar Periasamy
, Chaitanya Kurhade
, Jessica A. Plante
, Nathen E. Bopp
, Birte Kalveram
, Alexander Bukreyev
, Ping Ren
, Tian Wang
, Vineet D. Menachery
, Kenneth S. Plante
, Xuping Xie
, Scott C. Weaver
, Pei Yong Shi

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcription regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (∆3678). The ∆3678 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 ∆3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the ∆3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the ∆3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter ∆3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that ∆3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use.

Original language	English (US)
Article number	4337
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31930-z
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Liu, Y., Zhang, X., Liu, J., Xia, H., Zou, J., Muruato, A. E., Periasamy, S., Kurhade, C., Plante, J. A., Bopp, N. E., Kalveram, B., Bukreyev, A., Ren, P., Wang, T., Menachery, V. D., Plante, K. S., Xie, X., Weaver, S. C., & Shi, P. Y. (2022). A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions. Nature communications, 13(1), Article 4337. https://doi.org/10.1038/s41467-022-31930-z

Liu, Y, Zhang, X, Liu, J, Xia, H, Zou, J, Muruato, AE, Periasamy, S, Kurhade, C, Plante, JA, Bopp, NE, Kalveram, B, Bukreyev, A , Ren, P , Wang, T, Menachery, VD, Plante, KS , Xie, X , Weaver, SC & Shi, PY 2022, 'A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions', Nature communications, vol. 13, no. 1, 4337. https://doi.org/10.1038/s41467-022-31930-z

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title = "A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions",

abstract = "We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcription regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (∆3678). The ∆3678 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 ∆3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the ∆3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the ∆3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter ∆3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that ∆3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use.",

author = "Yang Liu and Xianwen Zhang and Jianying Liu and Hongjie Xia and Jing Zou and Muruato, \{Antonio E.\} and Sivakumar Periasamy and Chaitanya Kurhade and Plante, \{Jessica A.\} and Bopp, \{Nathen E.\} and Birte Kalveram and Alexander Bukreyev and Ping Ren and Tian Wang and Menachery, \{Vineet D.\} and Plante, \{Kenneth S.\} and Xuping Xie and Weaver, \{Scott C.\} and Shi, \{Pei Yong\}",

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AU - Liu, Yang

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AU - Xia, Hongjie

AU - Zou, Jing

AU - Muruato, Antonio E.

AU - Periasamy, Sivakumar

AU - Kurhade, Chaitanya

AU - Plante, Jessica A.

AU - Bopp, Nathen E.

AU - Kalveram, Birte

AU - Bukreyev, Alexander

AU - Ren, Ping

AU - Wang, Tian

AU - Menachery, Vineet D.

AU - Plante, Kenneth S.

AU - Xie, Xuping

AU - Weaver, Scott C.

AU - Shi, Pei Yong

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N2 - We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcription regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (∆3678). The ∆3678 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 ∆3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the ∆3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the ∆3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter ∆3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that ∆3678 SARS-CoV-2 may serve as a live-attenuated vaccine candidate and a research tool for potential biosafety level-2 use.

AB - We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcription regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (∆3678). The ∆3678 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 ∆3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the ∆3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the ∆3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter ∆3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that ∆3678 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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A live-attenuated SARS-CoV-2 vaccine candidate with accessory protein deletions

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