Activation Dynamics and Immunoglobulin Evolution of Pre-existing and Newly Generated Human Memory B-cell Responses to Influenza Hemagglutinin. Activation Dynamics and Immunoglobulin Evolution of Pre-existing and Newly Generated Human Memory B-cell Responses to Influenza Hemagglutinin

Understanding human vaccine-induced memory B cell responses is critical to developing effective vaccines to evolving viruses like Influenza A. B cell responses to influenza exposure involve activation of pre-existing immunity and generation of new responses. To characterize these two types of responses, we analyzed the response to H7N9 vaccination in H7N9 naïve adults. This allowed us to distinguish responses of pre-existing B cells towards conserved epitopes versus newly generated H7-specific epitopes using hemagglutinin (HA) probes by flow cytometry. The recall response to conserved epitopes on H7 HA involved a transient expansion of memory B cells with little observed adaptation. However, the B cell response to newly encountered epitopes was phenotypically distinct and generated a sustained memory population that evolved and affinity matured months after vaccination. These findings establish clear differences between newly generated and pre-existing memory B cells, highlighting the challenges in achieving long-lasting, broad protection against an ever-evolving virus. Overall design: 34 Samples

解析人类疫苗诱导的记忆B细胞应答，对于研发针对甲型流感（Influenza A）这类持续变异病毒的高效疫苗至关重要。机体针对流感暴露的B细胞应答，涵盖预先存在的免疫激活与新生应答的产生两个环节。为表征这两类应答，我们对未接触过H7N9的成人受试者开展了H7N9疫苗接种后的免疫应答分析。借助血凝素（hemagglutinin, HA）探针，通过流式细胞术，我们得以区分两类B细胞应答：一类是靶向保守表位的预先存在B细胞应答，另一类是靶向全新H7特异性表位的新生B细胞应答。针对H7 HA上保守表位的回忆应答，表现为记忆B细胞的一过性扩增，且几乎未观察到适应性演化。但针对新暴露表位的B细胞应答则表型迥异：其产生的记忆细胞群可长期存续，并在疫苗接种后数月内发生演化与亲和力成熟。本研究明确了新生与预先存在的记忆B细胞应答之间的显著差异，同时凸显了针对持续变异病毒实现长效广谱保护所面临的挑战。实验整体设计：共纳入34份样本。