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The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines

Yafei Liu, Noriko Arase, Jun-ichi Kishikawa, Mika Hirose, Songling Li, Asa Tada, Sumiko Matsuoka, Akemi Arakawa, Kanako Akamatsu, Chikako Ono, Hui Jin, Kazuki Kishida, Wataru Nakai, Masako Kohyama, Atsushi Nakagawa, Yoshiaki Yamagishi, Hironori Nakagami, Atsushi Kumanogoh, View ORCID ProfileYoshiharu Matsuura, Daron M. Standley, Takayuki Kato, Masato Okada, Manabu Fujimoto, View ORCID ProfileHisashi Arase
doi: https://doi.org/10.1101/2021.08.22.457114
Yafei Liu
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
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Noriko Arase
3Department of Dermatology, Graduate school of Medicine, Osaka University, Osaka, 565-0871, Japan
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Jun-ichi Kishikawa
4Laboratory for CryoEM Structural Biology, Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan
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Mika Hirose
4Laboratory for CryoEM Structural Biology, Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan
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Songling Li
5Dept. Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
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Asa Tada
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
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Sumiko Matsuoka
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
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Akemi Arakawa
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
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Kanako Akamatsu
6Department Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
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Chikako Ono
7Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Osaka, 565-0871, Japan
8Laboratory for Cell Polarity Regulation, RIKEN Center for Biosystems Dynamics Research, Hyogo, 650-0047, Japan
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Hui Jin
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
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Kazuki Kishida
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
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Wataru Nakai
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
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Masako Kohyama
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
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Atsushi Nakagawa
9Laboratory for Supramolecular Crystallography, Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan
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Yoshiaki Yamagishi
10Medical Center for Translational Research, Department of Medical Innovation, Osaka University Hospital, Osaka University, Osaka, 565-0871, Japan
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Hironori Nakagami
11Department of Health Development and Medicine, Graduate school of Medicine, Osaka University, Osaka, 565-0871, Japan
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Atsushi Kumanogoh
12Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
13Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
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Yoshiharu Matsuura
6Department Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
14Laboratory of Virus Control, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
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  • ORCID record for Yoshiharu Matsuura
Daron M. Standley
5Dept. Genome Informatics, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
15Center for Infectious Disease Education and Research, Osaka University, Osaka, 565-0871, Japan
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Takayuki Kato
4Laboratory for CryoEM Structural Biology, Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan
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Masato Okada
6Department Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
15Center for Infectious Disease Education and Research, Osaka University, Osaka, 565-0871, Japan
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Manabu Fujimoto
3Department of Dermatology, Graduate school of Medicine, Osaka University, Osaka, 565-0871, Japan
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Hisashi Arase
1Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan
2Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Centre, Osaka University, Osaka, 565-0871, Japan
15Center for Infectious Disease Education and Research, Osaka University, Osaka, 565-0871, Japan
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  • ORCID record for Hisashi Arase
  • For correspondence: arase@biken.osaka-u.ac.jp
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Abstract

mRNA-based vaccines provide effective protection against most common SARS-CoV-2 variants. However, identifying likely breakthrough variants is critical for future vaccine development. Here, we found that the Delta variant completely escaped from anti-N-terminal domain (NTD) neutralizing antibodies, while increasing responsiveness to anti-NTD infectivity-enhancing antibodies. Although Pfizer-BioNTech BNT162b2-immune sera neutralized the Delta variant, when four common mutations were introduced into the receptor binding domain (RBD) of the Delta variant (Delta 4+), some BNT162b2-immune sera lost neutralizing activity and enhanced the infectivity. Unique mutations in the Delta NTD were involved in the enhanced infectivity by the BNT162b2-immune sera. Sera of mice immunized by Delta spike, but not wild-type spike, consistently neutralized the Delta 4+ variant without enhancing infectivity. Given the fact that a Delta variant with three similar RBD mutations has already emerged according to the GISAID database, it is necessary to develop vaccines that protect against such complete breakthrough variants.

Competing Interest Statement

Osaka University has filed a patent application for the enhancing antibodies. HA and YL are listed as inventors. HA is a stockholder of HuLA immune Inc.

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 August 23, 2021.
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The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines
Yafei Liu, Noriko Arase, Jun-ichi Kishikawa, Mika Hirose, Songling Li, Asa Tada, Sumiko Matsuoka, Akemi Arakawa, Kanako Akamatsu, Chikako Ono, Hui Jin, Kazuki Kishida, Wataru Nakai, Masako Kohyama, Atsushi Nakagawa, Yoshiaki Yamagishi, Hironori Nakagami, Atsushi Kumanogoh, Yoshiharu Matsuura, Daron M. Standley, Takayuki Kato, Masato Okada, Manabu Fujimoto, Hisashi Arase
bioRxiv 2021.08.22.457114; doi: https://doi.org/10.1101/2021.08.22.457114
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The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines
Yafei Liu, Noriko Arase, Jun-ichi Kishikawa, Mika Hirose, Songling Li, Asa Tada, Sumiko Matsuoka, Akemi Arakawa, Kanako Akamatsu, Chikako Ono, Hui Jin, Kazuki Kishida, Wataru Nakai, Masako Kohyama, Atsushi Nakagawa, Yoshiaki Yamagishi, Hironori Nakagami, Atsushi Kumanogoh, Yoshiharu Matsuura, Daron M. Standley, Takayuki Kato, Masato Okada, Manabu Fujimoto, Hisashi Arase
bioRxiv 2021.08.22.457114; doi: https://doi.org/10.1101/2021.08.22.457114

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