Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5

Izumi Kimura; Daichi Yamasoba; Tomokazu Tamura; Naganori Nao; Tateki Suzuki; Yoshitaka Oda; Shuya Mitoma; Jumpei Ito; Hesham Nasser; Jiri Zahradnik; Keiya Uriu; Shigeru Fujita; Yusuke Kosugi; Lei Wang; Masumi Tsuda; Mai Kishimoto; Hayato Ito; Rigel Suzuki; Ryo Shimizu; Mst Monira Begum; Kumiko Yoshimatsu; Kanako Terakado Kimura; Jiei Sasaki; Kaori Sasaki-Tabata; Yuki Yamamoto; Tetsuharu Nagamoto; Jun Kanamune; Kouji Kobiyama; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Kotaro Shirakawa; Akifumi Takaori-Kondo; Jin Kuramochi; Gideon Schreiber; Ken J Ishii; Genotype to Phenotype Japan (G2P-Japan) Consortium; Takao Hashiguchi; Terumasa Ikeda; Akatsuki Saito; Takasuke Fukuhara; Shinya Tanaka; Keita Matsuno; Kei Sato

doi:10.1016/j.cell.2022.09.018

Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5

Cell. 2022 Oct 13;185(21):3992-4007.e16. doi: 10.1016/j.cell.2022.09.018. Epub 2022 Sep 14.

Authors

Izumi Kimura¹, Daichi Yamasoba², Tomokazu Tamura³, Naganori Nao⁴, Tateki Suzuki⁵, Yoshitaka Oda⁶, Shuya Mitoma⁷, Jumpei Ito¹, Hesham Nasser⁸, Jiri Zahradnik⁹, Keiya Uriu¹⁰, Shigeru Fujita¹⁰, Yusuke Kosugi¹⁰, Lei Wang¹¹, Masumi Tsuda¹¹, Mai Kishimoto¹², Hayato Ito³, Rigel Suzuki³, Ryo Shimizu¹³, Mst Monira Begum¹³, Kumiko Yoshimatsu¹⁴, Kanako Terakado Kimura⁵, Jiei Sasaki⁵, Kaori Sasaki-Tabata¹⁵, Yuki Yamamoto¹⁶, Tetsuharu Nagamoto¹⁶, Jun Kanamune¹⁶, Kouji Kobiyama¹⁷, Hiroyuki Asakura¹⁸, Mami Nagashima¹⁸, Kenji Sadamasu¹⁸, Kazuhisa Yoshimura¹⁸, Kotaro Shirakawa¹⁹, Akifumi Takaori-Kondo¹⁹, Jin Kuramochi²⁰, Gideon Schreiber⁹, Ken J Ishii¹⁷; Genotype to Phenotype Japan (G2P-Japan) Consortium; Takao Hashiguchi²¹, Terumasa Ikeda²², Akatsuki Saito²³, Takasuke Fukuhara²⁴, Shinya Tanaka²⁵, Keita Matsuno²⁶, Kei Sato²⁷

Affiliations

¹ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
² Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Faculty of Medicine, Kobe University, Kobe, Japan.
³ Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁴ Division of International Research Promotion, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; One Health Research Center, Hokkaido University, Sapporo, Japan.
⁵ Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
⁶ Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
⁷ Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
⁸ Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan; Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁹ Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
¹⁰ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹¹ Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan.
¹² Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
¹³ Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan.
¹⁴ Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
¹⁵ Department of Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
¹⁶ HiLung Inc., Kyoto, Japan.
¹⁷ Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁸ Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
¹⁹ Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
²⁰ Interpark Kuramochi Clinic, Utsunomiya, Japan; Department of Global Health Promotion, Tokyo Medical and Dental University, Tokyo, Japan.
²¹ Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan. Electronic address: hashiguchi.takao.1a@kyoto-u.ac.jp.
²² Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan. Electronic address: ikedat@kumamoto-u.ac.jp.
²³ Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan; Center for Animal Disease Control, University of Miyazaki, Miyazaki, Japan; Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan. Electronic address: sakatsuki@cc.miyazaki-u.ac.jp.
²⁴ Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Electronic address: fukut@pop.med.hokudai.ac.jp.
²⁵ Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan. Electronic address: tanaka@med.hokudai.ac.jp.
²⁶ One Health Research Center, Hokkaido University, Sapporo, Japan; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan; Division of Risk Analysis and Management, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan. Electronic address: matsuk@czc.hokudai.ac.jp.
²⁷ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan; Collaboration Unit for Infection, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Japan. Electronic address: keisato@g.ecc.u-tokyo.ac.jp.

Abstract

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.

Keywords: BA.2; BA.2.12.1; BA.4; BA.5; COVID-19; Omicron; SARS-CoV-2; immune resistance; pathogenicity; transmissibility.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2*
Antibodies, Viral
COVID-19*
Humans
Peptidyl-Dipeptidase A / genetics
Peptidyl-Dipeptidase A / metabolism
SARS-CoV-2
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism

Substances

Antibodies, Viral
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Peptidyl-Dipeptidase A
Angiotensin-Converting Enzyme 2