Characterization of an Attenuated SARS-CoV-2 Variant with a Deletion at the S1/S2 Junction of the Spike Protein

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 14

PMID 33986286

Citations 23

Authors

Pui Wang

Siu-Ying Lau

Shaofeng Deng

Pin Chen

Bobo Wing-Yee Mok

Anna Jinxia Zhang

Andrew Chak-Yiu Lee

Kwok-Hung Chan

Rachel Chun-Yee Tam

Haoran Xu

Runhong Zhou

Wenjun Song

Li Liu

Kelvin Kai-Wang To

Jasper Fuk-Woo Chan

Zhiwei Chen

Kwok-Yung Yuen

Honglin Chen

Affiliations

Soon will be listed here.

Abstract

SARS-CoV-2 is of zoonotic origin and contains a PRRA polybasic cleavage motif which is considered critical for efficient infection and transmission in humans. We previously reported on a panel of attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction of the spike protein. Here, we characterize pathogenicity, immunogenicity, and protective ability of a further cell-adapted SARS-CoV-2 variant, Ca-DelMut, in in vitro and in vivo systems. Ca-DelMut replicates more efficiently than wild type or parental virus in Vero E6 cells, but causes no apparent disease in hamsters, despite replicating in respiratory tissues. Unlike wild type virus, Ca-DelMut causes no obvious pathological changes and does not induce elevation of proinflammatory cytokines, but still triggers a strong neutralizing antibody and T cell response in hamsters and mice. Ca-DelMut immunized hamsters challenged with wild type SARS-CoV-2 are fully protected, with little sign of virus replication in the upper or lower respiratory tract, demonstrating sterilizing immunity.

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References

Long Q, Tang X, Shi Q, Li Q, Deng H, Yuan J . Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020; 26(8):1200-1204. DOI: 10.1038/s41591-020-0965-6. View

Andersen K, Rambaut A, Lipkin W, Holmes E, Garry R . The proximal origin of SARS-CoV-2. Nat Med. 2020; 26(4):450-452. PMC: 7095063. DOI: 10.1038/s41591-020-0820-9. View

Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y . Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease 2019. Clin Infect Dis. 2020; 71(8):1937-1942. PMC: 7184354. DOI: 10.1093/cid/ciaa449. View

Hou Y, Okuda K, Edwards C, Martinez D, Asakura T, Dinnon 3rd K . SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell. 2020; 182(2):429-446.e14. PMC: 7250779. DOI: 10.1016/j.cell.2020.05.042. View

Zhang A, Lee A, Chu H, Chan J, Fan Z, Li C . Severe Acute Respiratory Syndrome Coronavirus 2 Infects and Damages the Mature and Immature Olfactory Sensory Neurons of Hamsters. Clin Infect Dis. 2020; 73(2):e503-e512. PMC: 7454453. DOI: 10.1093/cid/ciaa995. View

Lam T, Jia N, Zhang Y, Shum M, Jiang J, Zhu H . Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature. 2020; 583(7815):282-285. DOI: 10.1038/s41586-020-2169-0. View

Mazzoni A, Salvati L, Maggi L, Capone M, Vanni A, Spinicci M . Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J Clin Invest. 2020; 130(9):4694-4703. PMC: 7456250. DOI: 10.1172/JCI138554. View

Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K . Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2020; 21(2):181-192. PMC: 7832443. DOI: 10.1016/S1473-3099(20)30843-4. View

Polack F, Thomas S, Kitchin N, Absalon J, Gurtman A, Lockhart S . Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020; 383(27):2603-2615. PMC: 7745181. DOI: 10.1056/NEJMoa2034577. View

10.

Wu F, Zhao S, Yu B, Chen Y, Wang W, Song Z . A new coronavirus associated with human respiratory disease in China. Nature. 2020; 579(7798):265-269. PMC: 7094943. DOI: 10.1038/s41586-020-2008-3. View

11.

Menachery V, Graham R, Baric R . Jumping species-a mechanism for coronavirus persistence and survival. Curr Opin Virol. 2017; 23:1-7. PMC: 5474123. DOI: 10.1016/j.coviro.2017.01.002. View

12.

Chan J, Yuan S, Kok K, To K, Chu H, Yang J . A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395(10223):514-523. PMC: 7159286. DOI: 10.1016/S0140-6736(20)30154-9. View

13.

Stadler K, Masignani V, Eickmann M, Becker S, Abrignani S, Klenk H . SARS--beginning to understand a new virus. Nat Rev Microbiol. 2004; 1(3):209-18. PMC: 7097337. DOI: 10.1038/nrmicro775. View

14.

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

15.

Xiao K, Zhai J, Feng Y, Zhou N, Zhang X, Zou J . Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Nature. 2020; 583(7815):286-289. DOI: 10.1038/s41586-020-2313-x. View

16.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H . Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395(10224):565-574. PMC: 7159086. DOI: 10.1016/S0140-6736(20)30251-8. View

17.

Chan J, Lau S, To K, Cheng V, Woo P, Yuen K . Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015; 28(2):465-522. PMC: 4402954. DOI: 10.1128/CMR.00102-14. View

18.

de Haan C, Haijema B, Schellen P, Wichgers Schreur P, te Lintelo E, Vennema H . Cleavage of group 1 coronavirus spike proteins: how furin cleavage is traded off against heparan sulfate binding upon cell culture adaptation. J Virol. 2008; 82(12):6078-83. PMC: 2395124. DOI: 10.1128/JVI.00074-08. View

19.

Zhang T, Wu Q, Zhang Z . Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Curr Biol. 2020; 30(8):1578. PMC: 7169893. DOI: 10.1016/j.cub.2020.03.063. View

20.

Kawaoka Y, Webster R . Sequence requirements for cleavage activation of influenza virus hemagglutinin expressed in mammalian cells. Proc Natl Acad Sci U S A. 1988; 85(2):324-8. PMC: 279540. DOI: 10.1073/pnas.85.2.324. View