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Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

Jessica A. Plante, Yang Liu, Jianying Liu, Hongjie Xia, Bryan A. Johnson, Kumari G. Lokugamage, Xianwen Zhang, Antonio E. Muruato, Jing Zou, Camila R. Fontes-Garfias, Divya Mirchandani, Dionna Scharton, John P. Bilello, Zhiqiang Ku, Zhiqiang An, Birte Kalveram, Alexander N. Freiberg, Vineet D. Menachery, Xuping Xie, Kenneth S. Plante, Scott C. Weaver, Pei-Yong Shi
doi: https://doi.org/10.1101/2020.09.01.278689
Jessica A. Plante
1World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Yang Liu
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Jianying Liu
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Hongjie Xia
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Bryan A. Johnson
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
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Kumari G. Lokugamage
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Xianwen Zhang
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Antonio E. Muruato
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Jing Zou
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Camila R. Fontes-Garfias
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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Divya Mirchandani
1World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Dionna Scharton
1World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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John P. Bilello
5Gilead Sciences, Inc., Foster City, CA, USA
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Zhiqiang Ku
6Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, USA
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Zhiqiang An
6Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, USA
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Birte Kalveram
7Department of Pathology, University of Texas Medical Branch, Galveston TX, USA
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Alexander N. Freiberg
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
7Department of Pathology, University of Texas Medical Branch, Galveston TX, USA
9Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA
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Vineet D. Menachery
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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Xuping Xie
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
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  • For correspondence: xuxie@UTMB.edu ksplante@utmb.edu sweaver@utmb.edu peshi@UTMB.edu
Kenneth S. Plante
1World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
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  • For correspondence: xuxie@UTMB.edu ksplante@utmb.edu sweaver@utmb.edu peshi@UTMB.edu
Scott C. Weaver
1World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston TX, USA
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston TX, USA
3Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston TX, USA
8Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, USA
9Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA
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  • For correspondence: xuxie@UTMB.edu ksplante@utmb.edu sweaver@utmb.edu peshi@UTMB.edu
Pei-Yong Shi
4Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA
8Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, USA
9Center for Biodefense & Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA
11Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA
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  • For correspondence: xuxie@UTMB.edu ksplante@utmb.edu sweaver@utmb.edu peshi@UTMB.edu
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Abstract

A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor-binding domain in an “up” conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development.

Importance Understanding the evolution of SARS-CoV-2 during the COVID-19 pandemic is essential for disease control and prevention. A spike protein mutation D614G emerged and became dominant soon after the pandemic started. By engineering the D614G mutation into an authentic wild-type SARS-CoV-2 strain, we demonstrate the importance of this mutation to (i) enhanced viral replication on human lung epithelial cells and primary human airway tissues, (ii) improved viral fitness in the upper airway of infected hamsters, and (iii) increased susceptibility to neutralization. Together with clinical findings, our work underscores the importance of this mutation in viral spread, vaccine efficacy, and antibody therapy.

Competing Interest Statement

The authors have declared no competing interest.

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Posted September 02, 2020.
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Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility
Jessica A. Plante, Yang Liu, Jianying Liu, Hongjie Xia, Bryan A. Johnson, Kumari G. Lokugamage, Xianwen Zhang, Antonio E. Muruato, Jing Zou, Camila R. Fontes-Garfias, Divya Mirchandani, Dionna Scharton, John P. Bilello, Zhiqiang Ku, Zhiqiang An, Birte Kalveram, Alexander N. Freiberg, Vineet D. Menachery, Xuping Xie, Kenneth S. Plante, Scott C. Weaver, Pei-Yong Shi
bioRxiv 2020.09.01.278689; doi: https://doi.org/10.1101/2020.09.01.278689
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Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility
Jessica A. Plante, Yang Liu, Jianying Liu, Hongjie Xia, Bryan A. Johnson, Kumari G. Lokugamage, Xianwen Zhang, Antonio E. Muruato, Jing Zou, Camila R. Fontes-Garfias, Divya Mirchandani, Dionna Scharton, John P. Bilello, Zhiqiang Ku, Zhiqiang An, Birte Kalveram, Alexander N. Freiberg, Vineet D. Menachery, Xuping Xie, Kenneth S. Plante, Scott C. Weaver, Pei-Yong Shi
bioRxiv 2020.09.01.278689; doi: https://doi.org/10.1101/2020.09.01.278689

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