Germinal center–mediated broadening of B cell responses to SARS-CoV-2 booster immunization

IF 16.3 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-10-10 DOI:10.1126/sciimmunol.adu4107

Sameer Kumar Malladi, Deepika Jaiswal, Baoling Ying, Wafaa B. Alsoussi, Tamarand L. Darling, Bernadeta Dadonaite, Alesandro Civljak, Stephen C. Horvath, Julian Q. Zhou, Wooseob Kim, Jackson S. Turner, Aaron J. Schmitz, Fangjie Han, Suzanne M. Scheaffer, Christopher W. Farnsworth, Raffael Nachbagauer, Biliana Nestorova, Spyros Chalkias, Michael K. Klebert, Darin K. Edwards, Robert Paris, Benjamin S. Strnad, William D. Middleton, Jane A. O’Halloran, Rachel M. Presti, Jesse D. Bloom, Adrianus C. M. Boon, Michael S. Diamond, Goran Bajic, Ali H. Ellebedy

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Abstract

Germinal centers (GCs) are key sites for antibody diversification and affinity maturation. SARS-CoV-2 messenger RNA (mRNA) vaccines elicit robust GC B cell responses in humans, but how these responses influence the breadth of immunity against viral variants remains unclear. We analyzed GC B cell responses in nine healthy adults after mRNA booster immunization. We show that 77.8% of the B cell clones in the GC expressed representative monoclonal antibodies (mAbs) recognizing the spike protein, with 37.8% of these targeting the receptor binding domain (RBD). One RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent XEC variant. mAb-52 used the IGHV3-66 public clonotype, protected hamsters challenged against the EG.5.1 variant, and targeted the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Its broad reactivity was driven by extensive somatic hypermutation, underscoring the critical role of GC reactions in shaping cross-variant B cell immunity after SARS-CoV-2 booster vaccination.

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生发中心介导的B细胞对SARS-CoV-2加强免疫反应的扩大

生发中心（GCs）是抗体多样化和亲和成熟的关键位点。SARS-CoV-2信使RNA （mRNA）疫苗在人体内引起强烈的GC B细胞反应，但这些反应如何影响对病毒变体的免疫广度仍不清楚。我们分析了9名健康成人mRNA增强免疫后GC B细胞的反应。结果表明，GC中77.8%的B细胞克隆表达了识别刺突蛋白的代表性单克隆抗体（mab），其中37.8%的单克隆抗体靶向受体结合域（RBD）。一种靶向rbd的单克隆抗体mAb-52可以中和所有测试的SARS-CoV-2毒株，包括最近的XEC变种。mAb-52使用IGHV3-66公共克隆型，保护仓鼠免受EG.5.1变体的攻击，并靶向I/II类RBD表位，密切模仿ACE2的结合足迹。其广泛的反应性是由广泛的体细胞超突变驱动的，这强调了GC反应在SARS-CoV-2加强疫苗接种后形成交叉变异B细胞免疫中的关键作用。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.