Malladi Sameer Kumar, Jaiswal Deepika, Ying Baoling, Alsoussi Wafaa B, Darling Tamarand L, Dadonaite Bernadeta, Civljak Alesandro, Horvath Stephen C, Zhou Julian Q, Kim Wooseob, Turner Jackson S, Schmitz Aaron J, Han Fangjie, Scheaffer Suzanne M, Farnsworth Christopher W, Nachbagauer Raffael, Nestorova Biliana, Chalkias Spyros, Klebert Michael K, Edwards Darin K, Paris Robert, Strnad Benjamin S, Middleton William D, O'Halloran Jane A, Presti Rachel M, Bloom Jesse D, Boon Adrianus C M, Diamond Michael S, Bajic Goran, Ellebedy Ali H
Department of Pathology and Immunology, Washington University School of Medicine; St. Louis, MO, USA.
Department of Microbiology, Icahn School of Medicine at Mount Sinai; New York, NY, USA.
bioRxiv. 2024 Dec 9:2024.12.06.625234. doi: 10.1101/2024.12.06.625234.
SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of the virus impacts the breadth of the induced GC B cell response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes of nine healthy adults following bivalent booster immunization. We show that 77.8% of the B cell clones in the GC expressed as representative monoclonal antibodies recognized the spike protein, with a third (37.8%) of these targeting the receptor binding domain (RBD). Strikingly, only one RBD-targeting mAb, mAb-52, neutralized all tested SARS-CoV-2 strains, including the recent KP.2 variant. mAb-52 utilizes the IGHV3-66 public clonotype, protects hamsters challenged against the EG.5.1 variant and targets the class I/II RBD epitope, closely mimicking the binding footprint of ACE2. Finally, we show that the remarkable breadth of mAb-52 is due to the somatic hypermutations accumulated within vaccine-induced GC reaction.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）信使核糖核酸（mRNA）疫苗可在人体内诱导强烈且持久的生发中心（GC）B细胞反应。目前尚不清楚病毒的持续进化如何影响诱导产生的GC B细胞反应的广度。我们利用超声引导下细针穿刺，检查了9名健康成年人在接种二价加强疫苗后的引流淋巴结。我们发现，GC中77.8%的B细胞克隆（以代表性单克隆抗体表示）可识别刺突蛋白，其中三分之一（37.8%）靶向受体结合域（RBD）。引人注目的是，只有一种靶向RBD的单克隆抗体mAb-52能够中和所有测试的SARS-CoV-2毒株，包括最近的KP.2变体。mAb-52利用IGHV3-66公共克隆型，可保护受到EG.5.1变体攻击的仓鼠，并靶向I/II类RBD表位，紧密模拟血管紧张素转换酶2（ACE2）的结合足迹。最后，我们表明mAb-52的显著广度归因于疫苗诱导的GC反应中积累的体细胞超突变。
