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

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-11-01 DOI:10.1016/j.ebiom.2024.105439

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

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引用次数: 0

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).

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在一个三角洲突破性感染病例中，诱导出对 SARS-CoV-2 包括 Omicron 亚变体具有广泛中和活性的 IGHV3-53 公共抗体。

背景：可逃避中和抗体的 SARS-CoV-2 变体的出现阻碍了针对 SARS-CoV-2 的疫苗和治疗性抗体的开发。IGHV3-53/3-66 衍生的公共抗体通常对原型病毒具有特异性，并经常在感染者或接种疫苗者中诱导产生，它对原型 SARS-CoV-2 的亲和力成熟度最低，效力很高：方法：分析了从一个三角洲突破性感染病例中分离出来的单克隆抗体对 SARS-CoV-2 变体的交叉中和活性。在仓鼠模型中进一步分析了广泛中和抗体 K4-66，并利用推断出的种系前体评估了体细胞高突变的影响：研究结果：与IGHV1-69和其他IGHV基因衍生的抗体相比，IGHV3-53/3-66衍生的抗体显示出更广泛的中和活性。与IGHV1-69抗体相比，IGHV3-53/3-66抗体对Delta变体的中和效果更好，这表明IGHV3-53/3-66抗体在Delta突破感染后进一步成熟。一种名为K4-66的IGHV3-53/3-66抗体中和了所有测试过的奥米克龙亚变体，包括EG.5.1、BA.2.86和JN.1，并降低了感染奥米克龙亚变体XBB.1.5的仓鼠肺部的病毒载量。推断出的 K4-66 种系前体对 Beta 和 Omicron 变体失去了中和活性，这证明了体细胞高突变的重要性：广泛中和的IGHV3-53/3-66抗体有可能成为针对新出现的SARS-CoV-2变体开发有效疫苗和治疗性抗体的目标：这项工作得到了AMED（JP23ym0126048、JP22ym0126048、JP21ym0126048、JP23wm0125002、JP233fa627001、JP223fa627009、JP24jf0126002和JP22fk0108572）和JSPS（JP21H02970、JK23K20041和JPJSCCA20240006）的资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.