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Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization

Qian Wang, Zhiteng Li, Jerren Ho, Yicheng Guo, Andre Yanchen Yeh, Michael Liu, Maple Wang, Jian Yu, View ORCID ProfileZizhang Sheng, Yaoxing Huang, Lihong Liu, David D. Ho
doi: https://doi.org/10.1101/2022.09.05.506628
Qian Wang
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Zhiteng Li
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Jerren Ho
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Yicheng Guo
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Andre Yanchen Yeh
2School of Medicine, National Taiwan University, Taipei 100233, Taiwan
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Michael Liu
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Maple Wang
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Jian Yu
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Zizhang Sheng
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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  • ORCID record for Zizhang Sheng
Yaoxing Huang
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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Lihong Liu
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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  • For correspondence: ll3411@cumc.columbia.edu dh2994@cumc.columbia.edu
David D. Ho
1Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
3Department of Microbiology and Immunology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
4Division of Infectious Diseases, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
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  • For correspondence: ll3411@cumc.columbia.edu dh2994@cumc.columbia.edu
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Abstract

SARS-CoV-2 Omicron subvariants BA.4.6, BA.4.7, and BA.5.9 have recently emerged, and BA.4.6 appears to be expanding even in the presence of BA.5 that is globally dominant. Compared to BA.5, these new subvariants harbor a mutation at R346 residue in the spike glycoprotein, raising concerns for further antibody evasion. We compared the viral receptor binding affinity of the new Omicron subvariants with BA.5 by surface plasmon resonance. We also performed VSV-based pseudovirus neutralization assays to evaluate their antigenic properties using sera from individuals who received three doses of a COVID-19 mRNA vaccine (boosted) and patients with BA.1 or BA.2 breakthrough infection, as well as using a panel of 23 monoclonal antibodies (mAbs). Compared to the BA.5 subvariant, BA.4.6, BA.4.7, and BA.5.9 showed similar binding affinities to hACE2 and exhibited similar resistance profiles to boosted and BA.1 breakthrough sera, but BA.4.6 was slightly but significantly more resistant than BA.5 to BA.2 breakthrough sera. Moreover, BA.4.6, BA.4.7, and BA.5.9 showed heightened resistance over to a class of mAbs due to R346T/S/I mutation. Notably, the authorized combination of tixagevimab and cilgavimab completely lost neutralizing activity against these three subvariants. The loss of activity of tixagevimab and cilgavimab against BA.4.6 leaves us with bebtelovimab as the only therapeutic mAb that has retained potent activity against all circulating forms of SARS-CoV-2. As the virus continues to evolve, our arsenal of authorized mAbs may soon be depleted, thereby jeopardizing the wellbeing of millions of immunocompromised persons who cannot robustly respond to COVID-19 vaccines.

Competing Interest Statement

J.Y., Y.H., L.L., and D.D.H. are inventors on patent applications (WO2021236998) or provisional patent applications (63/271,627) filed by Columbia University for a number of SARS-CoV-2 neutralizing antibodies described in this manuscript. Both sets of applications are under review. D.D.H. is a co-founder of TaiMed Biologics and RenBio, consultant to WuXi Biologics and Brii Biosciences, and board director for Vicarious Surgical.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 06, 2022.
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Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization
Qian Wang, Zhiteng Li, Jerren Ho, Yicheng Guo, Andre Yanchen Yeh, Michael Liu, Maple Wang, Jian Yu, Zizhang Sheng, Yaoxing Huang, Lihong Liu, David D. Ho
bioRxiv 2022.09.05.506628; doi: https://doi.org/10.1101/2022.09.05.506628
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Resistance of SARS-CoV-2 Omicron Subvariant BA.4.6 to Antibody Neutralization
Qian Wang, Zhiteng Li, Jerren Ho, Yicheng Guo, Andre Yanchen Yeh, Michael Liu, Maple Wang, Jian Yu, Zizhang Sheng, Yaoxing Huang, Lihong Liu, David D. Ho
bioRxiv 2022.09.05.506628; doi: https://doi.org/10.1101/2022.09.05.506628

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