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TitleInduction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case.
Journal, issue, pagesEBioMedicine, Vol. 110, Page 105439, Year 2024
Publish dateNov 1, 2024
AuthorsTakeo 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 / /
PubMed AbstractBACKGROUND: 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 ...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).
External linksEBioMedicine / PubMed:39488016 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.9 - 3.76 Å
Structure data

EMDB-60274: SARS-CoV-2 XBB.1.5 spike glycoprotein trimer in complex with antigen-binding fragments (Fabs)
Method: EM (single particle) / Resolution: 3.76 Å

PDB-9ii9:
Crystal structure of SARS-CoV-2 neutralizing antibody K4-66
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

Source
  • SARS-CoV-2 (virus)
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / antigen-binding fragments (Fabs)

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