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 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 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

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 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., 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, J, Bopp, NE, Kalveram, B, Bukreyev, A , Ren, P , Wang, T , Menachery, VD , Plante, KS , Xie, X , Weaver, SC & Shi, P-Y 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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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.",

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AU - Muruato, Antonio E.

AU - Periasamy, Sivakumar

AU - Kurhade, Chaitanya

AU - Plante, Jessica

AU - Bopp, Nathen E.

AU - Kalveram, Birte

AU - Bukreyev, Alexander

AU - Ren, Ping

AU - Wang, Tian

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

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