Matz Hanover C, Yu Tae-Geun, Zhou Julian Q, Peyton Lowrey, Madsen Anders, Han Fangjie, Schmitz Aaron J, Horvath Stephen C, Dixit Kritika, Keplinger Hunter K, Strnad Benjamin S, Hoegger Mark J, Middleton William D, Klebert Michael K, Lin Nina H, Nachbagauer Raffael, Paris Robert, Turner Jackson S, Presti Rachel M, Lee Jiwon, Ellebedy Ali H
Department of Pathology and Immunology, Washington University School of Medicine; St. Louis, MO 63110, USA.
Thayer School of Engineering, Dartmouth College; Hanover, NH 03755, USA.
bioRxiv. 2024 Oct 13:2024.10.10.617255. doi: 10.1101/2024.10.10.617255.
Eliciting broad and durable antibody responses against rapidly evolving pathogens like influenza viruses remains a formidable challenge. The germinal center (GC) reaction enables the immune system to generate broad, high-affinity, and durable antibody responses to vaccination. mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines induce persistent GC B cell responses in humans. Whether an mRNA-based influenza vaccine could induce a superior GC response in humans compared to the conventional inactivated influenza virus vaccine remains unclear. We assessed B cell responses in peripheral blood and draining lymph nodes in cohorts receiving the inactivated or mRNA-based quadrivalent seasonal influenza vaccine. Participants receiving the mRNA-based vaccine produced more robust plasmablast responses and higher antibody titers to H1N1 and H3N2 influenza A viruses and comparable antibody titers against influenza B virus strains. Importantly, mRNA-based vaccination stimulated robust recall B cell responses characterized by sustained GC reactions that lasted at least 26 weeks post-vaccination in three of six participants analyzed. In addition to promoting the maturation of responding B cell clones, these sustained GC reactions resulted in enhanced engagement of low-frequency pre-existing memory B cells, expanding the landscape of vaccine-elicited B cell clones. This translated to expansion of the serological repertoire and increased breadth of serum antibody responses. These findings reveal an important role for the induction of persistent GC responses to influenza vaccination in humans to broaden the repertoire of vaccine-induced antibodies.
引发针对流感病毒等快速进化病原体的广泛且持久的抗体反应仍然是一项艰巨的挑战。生发中心（GC）反应使免疫系统能够对疫苗接种产生广泛、高亲和力且持久的抗体反应。基于信使核糖核酸（mRNA）的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）疫苗可在人体内诱导持续的GC B细胞反应。与传统的灭活流感病毒疫苗相比，基于mRNA的流感疫苗是否能在人体内诱导出更优的GC反应仍不清楚。我们评估了接受灭活或基于mRNA的四价季节性流感疫苗的队列中，外周血和引流淋巴结中的B细胞反应。接受基于mRNA疫苗的参与者对甲型H1N1和H3N2流感病毒产生了更强的浆母细胞反应和更高的抗体滴度，对乙型流感病毒株的抗体滴度相当。重要的是，基于mRNA的疫苗接种刺激了强烈的回忆性B细胞反应，其特征是在分析的六名参与者中有三名在接种疫苗后至少26周持续出现GC反应。除了促进反应性B细胞克隆的成熟外，这些持续的GC反应还导致低频预先存在的记忆B细胞的参与增加，扩大了疫苗诱导的B细胞克隆的范围。这转化为血清学库的扩大和血清抗体反应广度的增加。这些发现揭示了在人类流感疫苗接种中诱导持续GC反应以扩大疫苗诱导抗体库的重要作用。
