Institut Necker Enfants Malades, INSERM U1151/CNRS UMR 8253, Action thématique incitative sur programme-Avenir Team, Auto-Immune and Immune B cells, Université Paris Cité, Université Paris Est-Créteil, Créteil, France; Service de Médecine interne, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris Cité, Clichy, France; Service de Médecine Interne, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Est Créteil (UPEC), Créteil, France.
Institut Pasteur, Université de Paris Cité, CNRS UMR 3569, Unité de Virologie Structurale, Paris, France.
Immunity. 2023 Sep 12;56(9):2137-2151.e7. doi: 10.1016/j.immuni.2023.07.007. Epub 2023 Aug 4.
How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after SARS-CoV-2 Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of the COVID-19 mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reactions, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with a marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.
病毒变异株引起的抗原漂移如何影响预先形成的成熟人类记忆 B 细胞 (MBC) 库仍然是一个悬而未决的问题。在这里，我们研究了 COVID-19 mRNA 疫苗接种三剂后的个体在 SARS-CoV-2 奥密克戎 BA.1 突破感染后长达 6 个月的 MBC 反应。使用单细胞多组学和 RBD 特异性 MBC 单克隆抗体的功能分析进行的纵向分析表明，BA.1 突破感染主要招募了具有有限针对 BA.1 限制表位的新反应的预先存在的交叉反应性 MBC。然而，克隆层次结构的重组和新的生发中心反应结合在一起，维持了对常见 Hu-1 和 BA.1 的 MBC 库的多样性，并诱导其针对共同的、不受 BA.5 限制的 SARS-CoV-2 Spike RBD 表位的渐进成熟。这种重塑进一步与整体中和广度和效力的显著提高相关。这些发现对未来疫苗加强策略的设计具有重要意义。
