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An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies

Yafei Liu, Wai Tuck Soh, Asa Tada, Akemi Arakawa, Sumiko Matsuoka, Emi E. Nakayama, Songling Li, Chikako Ono, Shiho Torii, Kazuki Kishida, Hui Jin, Wataru Nakai, Noriko Arase, Atsushi Nakagawa, Yasuhiro Shindo, Masako Kohyama, Hironori Nakagami, Keisuke Tomii, Koichiro Ohmura, Shiro Ohshima, Masato Okada, View ORCID ProfileYoshiharu Matsuura, Daron M. Standley, Tatsuo Shioda, View ORCID ProfileHisashi Arase
doi: https://doi.org/10.1101/2020.12.18.423358
Yafei Liu
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Wai Tuck Soh
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Asa Tada
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Akemi Arakawa
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Sumiko Matsuoka
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Emi E. Nakayama
3Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Songling Li
4Dept. Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Chikako Ono
5Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Shiho Torii
5Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Kazuki Kishida
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Hui Jin
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Wataru Nakai
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Noriko Arase
6Department of Dermatology, Graduate school of Medicine, Osaka University, Osaka, Japan
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Atsushi Nakagawa
7Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan
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Yasuhiro Shindo
8Drug Discovery Research Center, HuLA immune Inc., Osaka, Japan
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Masako Kohyama
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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Hironori Nakagami
9Department of Health Development and Medicine, Graduate school of Medicine, Osaka University, Osaka, Japan
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Keisuke Tomii
7Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Hyogo, Japan
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Koichiro Ohmura
10Department of Rheumatology, Kobe City Medical Center General Hospital, Hyogo, Japan
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Shiro Ohshima
11Department of Clinical Research, Osaka Minami Medical Center, Kawachinagano, Osaka, Japan
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Masato Okada
12Department Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Yoshiharu Matsuura
5Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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  • ORCID record for Yoshiharu Matsuura
Daron M. Standley
4Dept. Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Tatsuo Shioda
3Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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Hisashi Arase
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, Japan
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  • ORCID record for Hisashi Arase
  • For correspondence: arase@biken.osaka-u.ac.jp
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Abstract

SARS-CoV-2 infection causes severe symptoms in a subset of patients, suggesting the presence of certain unknown risk factors. Although antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike have been shown prevent SARS-CoV-2 infection, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients. Furthermore, the antibodies against the infectivity-enhancing site were detected in 3 out of 48 uninfected donors, albeit at low levels. These findings suggest that the production of antibodies against SARS-CoV-2 infectivity-enhancing site could be considered as a possible exacerbating factors for COVID-19 and that a spike protein lacking such antibody epitopes may be required for safe vaccine development, especially for individuals with pre-existing enhancing antibodies.

Competing Interest Statement

Osaka Univ. and HuLA immune Inc. filed a patent related to this study. YL, YS, and HA are inventors of the patent. YS is an employee of HuLA immune Inc. HA and YS are stock holders of HuLA immune.

Copyright 
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 December 18, 2020.
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An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies
Yafei Liu, Wai Tuck Soh, Asa Tada, Akemi Arakawa, Sumiko Matsuoka, Emi E. Nakayama, Songling Li, Chikako Ono, Shiho Torii, Kazuki Kishida, Hui Jin, Wataru Nakai, Noriko Arase, Atsushi Nakagawa, Yasuhiro Shindo, Masako Kohyama, Hironori Nakagami, Keisuke Tomii, Koichiro Ohmura, Shiro Ohshima, Masato Okada, Yoshiharu Matsuura, Daron M. Standley, Tatsuo Shioda, Hisashi Arase
bioRxiv 2020.12.18.423358; doi: https://doi.org/10.1101/2020.12.18.423358
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An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies
Yafei Liu, Wai Tuck Soh, Asa Tada, Akemi Arakawa, Sumiko Matsuoka, Emi E. Nakayama, Songling Li, Chikako Ono, Shiho Torii, Kazuki Kishida, Hui Jin, Wataru Nakai, Noriko Arase, Atsushi Nakagawa, Yasuhiro Shindo, Masako Kohyama, Hironori Nakagami, Keisuke Tomii, Koichiro Ohmura, Shiro Ohshima, Masato Okada, Yoshiharu Matsuura, Daron M. Standley, Tatsuo Shioda, Hisashi Arase
bioRxiv 2020.12.18.423358; doi: https://doi.org/10.1101/2020.12.18.423358

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