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

Y. Liu, X. Zhang, J. Liu, H. Xia, J. Zou, A. E. Muruato, S. Periasamy, J. A. Plante, N. E. Bopp, C. Kurhade, A. Bukreyev, P. Ren, T. Wang, V. D. Menachery, K. S. Plante, X. Xie, S. C. Weaver, P.-Y. Shi

PDFDOIPreprint

Abstract

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 ({Delta}3678). The {Delta}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 {Delta}3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models. A single-dose immunization of the {Delta}3678 virus protects hamsters from wild-type virus challenge and transmission. Among the deleted ORFs in the {Delta}3678 virus, ORF3a accounts for the most attenuation through antagonizing STAT1 phosphorylation during type-I interferon signaling. We also developed an mNeonGreen reporter {Delta}3678 virus for high-throughput neutralization and antiviral testing. Altogether, the results suggest that {Delta}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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