Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case

Takeo Kuwata; Yu Kaku; Shashwata Biswas; Kaho Matsumoto; Mikiko Shimizu; Yoko Kawanami; Ryuta Uraki; Kyo Okazaki; Rumi Minami; Yoji Nagasaki; Mami Nagashima; Isao Yoshida; Kenji Sadamasu; Kazuhisa Yoshimura; Mutsumi Ito; Maki Kiso; Seiya Yamayoshi; Masaki Imai; Terumasa Ikeda; Kei Sato; Mako Toyoda; Takamasa Ueno; Takako Inoue; Yasuhito Tanaka; Kanako Tarakado Kimura; Takao Hashiguchi; Yukihiko Sugita; Takeshi Noda; Hiroshi Morioka; Yoshihiro Kawaoka; Shuzo Matsushita; Genotype to Phenotype Japan (G2P-Japan) Consortium

doi:10.1016/j.ebiom.2024.105439

Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case

EBioMedicine. 2024 Dec:110:105439. doi: 10.1016/j.ebiom.2024.105439. Epub 2024 Nov 1.

Authors

Takeo Kuwata¹, Yu Kaku², Shashwata Biswas³, Kaho Matsumoto³, Mikiko Shimizu³, Yoko Kawanami³, Ryuta Uraki⁴, Kyo Okazaki⁵, Rumi Minami⁶, Yoji Nagasaki⁶, Mami Nagashima⁷, Isao Yoshida⁷, Kenji Sadamasu⁷, Kazuhisa Yoshimura⁷, Mutsumi Ito⁴, Maki Kiso⁴, Seiya Yamayoshi⁴, Masaki Imai⁴, Terumasa Ikeda⁸, Kei Sato⁹, Mako Toyoda¹⁰, Takamasa Ueno¹⁰, Takako Inoue¹¹, Yasuhito Tanaka¹², Kanako Tarakado Kimura¹³, Takao Hashiguchi¹³, Yukihiko Sugita¹⁴, Takeshi Noda¹⁴, Hiroshi Morioka⁵, Yoshihiro Kawaoka⁴, Shuzo Matsushita¹⁵; Genotype to Phenotype Japan (G2P-Japan) Consortium

Collaborators

Genotype to Phenotype Japan (G2P-Japan) Consortium:
Jumpei Ito, Naoko Misawa, Arnon Plianchaisuk, Ziyi Guo, Alfredo Hina Jr, Keiya Uriu, Kaoru Usui, Wilaiporn Saikruang, Spyridon Lytras, Ryo Yoshimura, Shusuke Kawakubo, Luca Nishimura, Yusuke Kosugi, Shigeru Fujita, Luo Chen, Jarel Elgin M Tolentino, Lin Pan, Wenye Li, Maximilian Stanley Yo, Kio Horinaka, Mai Suganami, Adam P Strange, Mika Chiba, Keiko Iida, Naomi Ohsumi, Kaho Okumura, Shiho Tanaka, Eiko Ogawa, Kyoko Yasuda, Tsuki Fukuda, Rina Osujo, Takasuke Fukuhara, Tomokazu Tamura, Rigel Suzuki, Saori Suzuki, Hayato Ito, Keita Matsuno, Hirofumi Sawa, Naganori Nao, Shinya Tanaka, Masumi Tsuda, Lei Wang, Yoshikata Oda, Zannatul Ferdous, Kenji Shishido, Keita Mizuma, Isshu Kojima, Jingshu Li, Tomoya Tsubo, Shuhei Tsujino, So Nakagawa, Kotaro Shirakawa, Akifumi Takaori-Kondo, Kayoko Nagata, Ryosuke Nomura, Yoshihito Horisawa, Yusuke Tashiro, Yugo Kawai, Kazuo Takayama, Rina Hashimoto, Sayaka Deguchi, Yukio Watanabe, Ayaka Sakamoto, Naoko Yasuhara, Tateki Suzuki, Kanako Kimura, Jiei Sasaki, Yukari Nakajima, Hisano Yajima, Yoshitaka Nakata, Hiroki Futatsusako, Takashi Irie, Ryoko Kawabata, Kaori Tabata, Hesham Nasser, Ryo Shimizu, Mst Monira Begum, Michael Jonathan, Yuka Mugita, Otowa Takahashi, Kimiko Ichihara, Chihiro Motozono, Sharee Leong, Akatsuki Saito, Maya Shofa, Yuki Shibatani, Tomoko Nishiuchi, Hiroyuki Asakura, Jiri Zahradnik, Prokopios Andrikopoulos, Miguel Padilla-Blanco, Aditi Konar

Affiliations

¹ Collaborative Research Program with the Chemo-Sero-Therapeutic Research Institute for Anti-viral Agents and Hematological Diseases, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan. Electronic address: [email protected].
² Collaborative Research Program with the Chemo-Sero-Therapeutic Research Institute for Anti-viral Agents and Hematological Diseases, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan; Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
³ Collaborative Research Program with the Chemo-Sero-Therapeutic Research Institute for Anti-viral Agents and Hematological Diseases, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
⁴ Division of Virology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁵ Department of Analytical and Biophysical Chemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
⁶ Internal Medicine, Clinical Research Institute, NHO Kyushu Medical Center, Fukuoka, Japan.
⁷ Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
⁸ Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
⁹ Division of Systems Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁰ Division of Infection and Immunity, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
¹¹ Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan.
¹² Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
¹³ Laboratory of Medical Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
¹⁴ Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
¹⁵ Collaborative Research Program with the Chemo-Sero-Therapeutic Research Institute for Anti-viral Agents and Hematological Diseases, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan. Electronic address: [email protected].

Abstract

Background: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public antibodies, which are generally specific to the prototype virus and are frequently induced in infected or vaccinated individuals, show minimal affinity maturation and high potency against prototype SARS-CoV-2.

Methods: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 was further analysed in a hamster model, and the effect of somatic hypermutations was assessed using the inferred germline precursor.

Findings: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant better than the IGHV1-69 antibodies, suggesting that the IGHV3-53/3-66 antibodies were further maturated by Delta breakthrough infection. One IGHV3-53/3-66 antibody, K4-66, neutralised all Omicron subvariants tested, including EG.5.1, BA.2.86, and JN.1, and decreased the viral load in the lungs of hamsters infected with Omicron subvariant XBB.1.5. The importance of somatic hypermutations was demonstrated by the loss of neutralising activity of the inferred germline precursor of K4-66 against Beta and Omicron variants.

Interpretation: Broadly neutralising IGHV3-53/3-66 antibodies have potential as a target for the development of effective vaccines and therapeutic antibodies against newly emerging SARS-CoV-2 variants.

Funding: This work was supported by grants from AMED (JP23ym0126048, JP22ym0126048, JP21ym0126048, JP23wm0125002, JP233fa627001, JP223fa627009, JP24jf0126002, and JP22fk0108572), and the JSPS (JP21H02970, JK23K20041, and JPJSCCA20240006).

Keywords: Neutralising antibody; Public antibody; SARS-CoV-2; Variant.

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Antibodies, Neutralizing* / immunology
Antibodies, Viral* / immunology
Breakthrough Infections
COVID-19* / immunology
Cricetinae
Disease Models, Animal
Humans
Immunoglobulin Heavy Chains / genetics
Immunoglobulin Heavy Chains / immunology
Neutralization Tests
SARS-CoV-2* / immunology
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology

Substances

Antibodies, Viral
Antibodies, Neutralizing
Antibodies, Monoclonal
Immunoglobulin Heavy Chains
Spike Glycoprotein, Coronavirus

Supplementary concepts

SARS-CoV-2 variants
COVID-19 breakthrough infections