New Antibody Breakthrough Offers Hope Against Evolving SARS-CoV-2 Variants
Researchers at Kumamoto University have discovered a groundbreaking monoclonal antibody capable of neutralizing a wide range of SARS-CoV-2 variants, including the elusive Omicron subvariants. This antibody, named K4-66, was isolated from a Delta breakthrough infection case. The findings, published in the journal eBioMedicine, highlight K4-66’s exceptional ability to target multiple SARS-CoV-2 variants, including recent Omicron strains such as EG.5.1, XBB.1.5, and JN.1.The research team, led by Professor Shuzo Matsushita from the Joint Research Center for Human Retrovirus Infection (JRCHRI), Kumamoto University, found that K4-66 uses a gene known as IGHV3-53/3-66, which allows it to adapt to the virus’s frequent mutations. This gene contributes to the development of "public antibodies," a type of antibody often induced in vaccinated or infected individuals. While many public antibodies lose efficacy against heavily mutated variants, K4-66 exhibits a rare ability to neutralize them, even reducing viral loads in the lungs of hamster models infected with Omicron XBB.1.5. Structural analyses of K4-66 revealed that its broad-spectrum effectiveness lies in its ability to form electrostatic interactions with the receptor-binding domain (RBD) of the spike protein, a crucial region for the virus to infect human cells.
This discovery is particularly significant as the constant evolution of SARS-CoV-2 has created variants that evade immunity from current vaccines and therapeutic antibodies. Omicron subvariants, in particular, have proven highly resistant, complicating global efforts to control the pandemic. K4-66’s ability to neutralize diverse variants offers hope for the development of new vaccines and therapies that remain effective despite the virus's rapid evolution.
The implications of this research extend beyond immediate applications. The study suggests that enhancing the maturation of public antibodies like K4-66 through targeted vaccine strategies could lead to more robust and durable immune defenses. Such advancements have the potential to prevent future outbreaks and mitigate the risks posed by emerging variants.
This breakthrough was achieved through collaboration with institutions across Japan, including the University of Tokyo and Kyoto University, and was supported by grants from AMED and JSPS. Professor Matsushita emphasized the importance of this discovery, noting its potential to guide next-generation vaccine development.
Image Title: How the Antibody K4-66 Binds to SARS-CoV-2 Spike Protein
Image Caption: Cryo-EM analysis on the complex between Fab (Fragment, Antigen-Binding) K4-66 and SARS-CoV-2 XBB.1.5 S ectodomain revealed that K4-66 recognizes the same epitope as previously reported IGHV3-53/3-66 monoclonal antibodies such as CC12.1. However, Fab K4-66 binds at a bonding angle approximately 30°more inclined compared to Fab CC12.1.
Reference
Image Caption: Cryo-EM analysis on the complex between Fab (Fragment, Antigen-Binding) K4-66 and SARS-CoV-2 XBB.1.5 S ectodomain revealed that K4-66 recognizes the same epitope as previously reported IGHV3-53/3-66 monoclonal antibodies such as CC12.1. However, Fab K4-66 binds at a bonding angle approximately 30°more inclined compared to Fab CC12.1.
Reference
| Authors |
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*, and G2P-Japan Consortium |
| Title of original paper |
Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case |
| Journal | eBioMedicine |
| DOI | 10.1016/j.ebiom.2024.105439 |