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 () and Pei-Yong Shi ()
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Yang Liu: University of Texas Medical Branch
Xianwen Zhang: University of Texas Medical Branch
Jianying Liu: University of Texas Medical Branch
Hongjie Xia: University of Texas Medical Branch
Jing Zou: University of Texas Medical Branch
Antonio E. Muruato: University of Texas Medical Branch
Sivakumar Periasamy: University of Texas Medical Branch
Chaitanya Kurhade: University of Texas Medical Branch
Jessica A. Plante: University of Texas Medical Branch
Nathen E. Bopp: University of Texas Medical Branch
Birte Kalveram: University of Texas Medical Branch
Alexander Bukreyev: University of Texas Medical Branch
Ping Ren: University of Texas Medical Branch
Tian Wang: University of Texas Medical Branch
Vineet D. Menachery: University of Texas Medical Branch
Kenneth S. Plante: University of Texas Medical Branch
Xuping Xie: University of Texas Medical Branch
Scott C. Weaver: University of Texas Medical Branch
Pei-Yong Shi: University of Texas Medical Branch

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31930-z

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