Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy.
Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, Siena, Italy; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy.
Cell Rep. 2024 Sep 24;43(9):114645. doi: 10.1016/j.celrep.2024.114645. Epub 2024 Aug 27.
Understanding the evolution of the B cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is fundamental to design the next generation of vaccines and therapeutics. We longitudinally analyze at the single-cell level almost 900 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people and from individuals with hybrid and super hybrid immunity (SH), developed after three mRNA vaccine doses and two breakthrough infections. The most potent neutralization and Fc functions against highly mutated variants belong to the SH cohort. Repertoire analysis shows that the original Wuhan antigenic sin drives the convergent expansion of the same B cell germlines in vaccinated and SH cohorts. Only Omicron breakthrough infections expand previously unseen germ lines and generate broadly nAbs by restoring IGHV3-53/3-66 germ lines. Our analyses find that B cells initially expanded by the original antigenic sin continue to play a fundamental role in the evolution of the immune response toward an evolving virus.
了解针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 变体的 B 细胞反应的演变对于设计下一代疫苗和疗法至关重要。我们在单细胞水平上对近 900 种从接种疫苗的人和具有混合和超级混合免疫 (SH) 的个体中分离出的中和人单克隆抗体 (nAb) 进行了纵向分析，这些个体是在接种了三剂 mRNA 疫苗并发生两次突破性感染后产生的。针对高度突变变体，最有效的中和和 Fc 功能属于 SH 队列。受体库分析表明，最初的武汉抗原决定簇驱动了接种疫苗和 SH 队列中相同 B 细胞胚系的趋同扩张。只有奥密克戎突破性感染通过恢复 IGHV3-53/3-66 胚系，扩展了以前从未见过的胚系，并产生了广泛的 nAb。我们的分析发现，最初由原始抗原决定簇扩张的 B 细胞在针对不断进化的病毒的免疫反应的演变中继续发挥着重要作用。
