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

Nat Commun. 2022 Jul 27;13(1):4337. doi: 10.1038/s41467-022-31930-z.

Authors

Yang Liu^#¹, Xianwen Zhang^#¹, Jianying Liu^#^{2

3}, Hongjie Xia^#¹, Jing Zou¹, Antonio E Muruato^{2

3}, Sivakumar Periasamy^{4

5}, Chaitanya Kurhade¹, Jessica A Plante^{2

3

6}, Nathen E Bopp⁴, Birte Kalveram^{1

2}, Alexander Bukreyev^{2

4

5}, Ping Ren^{3

4}, Tian Wang^{2

4

7}, Vineet D Menachery^{2

3}, Kenneth S Plante^{8

9

10}, Xuping Xie¹¹, Scott C Weaver^{12

13

14

15}, Pei-Yong Shi^{16

17

18

19

20}

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
² Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
³ Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
⁴ Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
⁵ Galveston National Laboratory, Galveston, TX, USA.
⁶ World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
⁷ Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA.
⁸ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA. ksplante@utmb.edu.
⁹ Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. ksplante@utmb.edu.
¹⁰ World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA. ksplante@utmb.edu.
¹¹ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA. xuxie@UTMB.edu.
¹² Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA. sweaver@utmb.edu.
¹³ Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. sweaver@utmb.edu.
¹⁴ World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA. sweaver@utmb.edu.
¹⁵ Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA. sweaver@utmb.edu.
¹⁶ Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁷ Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁸ Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
¹⁹ Sealy Institute for Drug Discovery, University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.
²⁰ Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antiviral Agents
COVID-19 Vaccines*
COVID-19* / prevention & control
Cricetinae
Humans
Interferons
Mice
SARS-CoV-2 / genetics
Vaccines, Attenuated
Virus Replication

Substances

Antiviral Agents
COVID-19 Vaccines
Vaccines, Attenuated
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding