在一例德尔塔突破性感染病例中诱导出具有针对包括奥密克戎亚变体在内的SARS-CoV-2广泛中和活性的IGHV3-53公共抗体。
Induction of IGHV3-53 public antibodies with broadly neutralising activity against SARS-CoV-2 including Omicron subvariants in a Delta breakthrough infection case.
作者信息
Kuwata Takeo, Kaku Yu, Biswas Shashwata, Matsumoto Kaho, Shimizu Mikiko, Kawanami Yoko, Uraki Ryuta, Okazaki Kyo, Minami Rumi, Nagasaki Yoji, Nagashima Mami, Yoshida Isao, Sadamasu Kenji, Yoshimura Kazuhisa, Ito Mutsumi, Kiso Maki, Yamayoshi Seiya, Imai Masaki, Ikeda Terumasa, Sato Kei, Toyoda Mako, Ueno Takamasa, Inoue Takako, Tanaka Yasuhito, Kimura Kanako Tarakado, Hashiguchi Takao, Sugita Yukihiko, Noda Takeshi, Morioka Hiroshi, Kawaoka Yoshihiro, Matsushita Shuzo
机构信息
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.
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.
出版信息
EBioMedicine. 2024 Dec;110:105439. doi: 10.1016/j.ebiom.2024.105439. Epub 2024 Nov 1.
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).
背景
逃避中和抗体的新型冠状病毒2（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，并且在感染或接种疫苗的个体中经常诱导产生，对原型SARS-CoV-2显示出最小的亲和力成熟和高效力。
方法
分析从一例德尔塔突破性感染病例中分离出的单克隆抗体对SARS-CoV-2变体的交叉中和活性。在仓鼠模型中进一步分析广泛中和抗体K4-66，并使用推断的种系前体评估体细胞超突变的影响。
研究结果
IGHV3-53/3-66衍生的抗体比IGHV1-69和其他IGHV基因衍生的抗体具有更广泛的中和活性。IGHV3-53/3-66抗体对德尔塔变体的中和作用优于IGHV1-69抗体，表明IGHV3-53/3-66抗体通过德尔塔突破性感染进一步成熟。一种IGHV3-53/3-66抗体K4-66中和了所有测试的奥密克戎亚变体，包括EG.5.1、BA.2.86和JN.1，并降低了感染奥密克戎亚变体XBB.1.5的仓鼠肺部的病毒载量。K4-66推断的种系前体对贝塔和奥密克戎变体的中和活性丧失证明了体细胞超突变的重要性。
解读
广泛中和的IGHV3-53/3-66抗体有潜力作为开发针对新出现的SARS-CoV-2变体的有效疫苗和治疗性抗体的靶点。
资金支持
本研究得到了日本医疗研究与开发机构（AMED）（JP23ym0126048、JP22ym0126048、JP21ym0126048、JP23wm0125002、JP233fa627001、JP223fa627009、JP24jf0126002和JP22fk0108572）以及日本学术振兴会（JSPS）（JP21H02970、JK23K20041和JPJSCCA20240006）的资助。
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