Influenza virus exposure shapes the B cell response to influenza vaccination fifty years later

Pre-existing immunity impacts vaccine responses to endemic respiratory viruses such as influenza, but directly connecting influenza infections early in life with immune responses decades later is difficult. However, H2N2 stopped circulating in the human population in 1968, creating the opportunity to directly evaluate the impact of early H2N2 exposure on vaccine responses 50 years later. Here, we vaccinate individuals born before (H2 Exposed) or after (H2 Naïve) 1968 with an H2 HA DNA plasmid and/or a ferritin nanoparticle vaccine. H2 Exposed individuals generated a rapid B cell recall response that differed in potency, cross-reactivity, immunoglobulin repertoire, epitope targeting and phenotype from the de novo response in H2 Naïve individuals. Furthermore, vaccinating with a DNA versus a protein nanoparticle vaccine altered the response in H2 Naïve but not H2 Exposed individuals. This study clearly establishes and describes the life-long impact of influenza HA-specific memory B cells formed early in life on vaccine responses decades later. Overall design: Memory b cells and plasmablasts were isolated at various timepoints from PBMCs of individuals undergoing vaccination against H2 influenza. Antibody derived tag, whole transcriptome, and VDJ libraries were generated for all samples.

预存免疫（Pre-existing immunity）会影响流感等地方性呼吸道病毒的疫苗应答，但直接关联生命早期的流感感染与数十年后的免疫应答却颇具挑战。H2N2亚型流感病毒已于1968年停止在人群中传播，这为直接评估早期H2N2暴露对50年后疫苗应答的影响提供了契机。
本研究对1968年前后出生的个体实施免疫：1968年前出生者归入H2暴露组（H2 Exposed），1968年后出生者归入H2未暴露组（H2 Naïve），免疫制剂为H2血凝素（Hemagglutinin, HA）DNA质粒及/或铁蛋白纳米颗粒疫苗。
H2暴露组个体可产生快速的B细胞回忆应答，该应答在效力、交叉反应性、免疫球蛋白组库、表位靶向及细胞表型方面，均与H2未暴露组个体的初次（de novo）应答存在显著差异。
此外，采用DNA疫苗与蛋白纳米颗粒疫苗分别免疫，可重塑H2未暴露组个体的应答模式，但对H2暴露组个体无此效果。
本研究明确证实并系统阐述了生命早期形成的流感HA特异性记忆B细胞，对数十年后疫苗应答的终身影响。
实验设计概述：从接受H2流感疫苗免疫的个体的外周血单个核细胞（Peripheral Blood Mononuclear Cells, PBMC）中，于多个时间点分离记忆B细胞与浆母细胞；为所有样本构建抗体衍生标签文库、全转录组文库及VDJ文库。