Effects of aging on primary and secondary vaccine responses in a 15-year longitudinal cohort

总结 在流感的背景下，对人类免疫功能中与病毒相关的缺陷的研究最多 疫苗接种和感染，或个体先前抗原暴露史和 适应性免疫记忆使分析复杂化。相比之下，年轻人和老年人也能够 在新抗原暴露后形成新的初次免疫应答。疫苗介导的 预防埃博拉和寨卡病毒等突发传染病的社区将依靠新的主要 不同年龄段的适应性免疫反应 我们将全面分析年轻成人和老年受试者的适应性免疫应答， 三种不同的主要疫苗接种管理的肠胃外或口服途径：甲型肝炎（HAV） 灭活和铝盐佐剂病毒疫苗，以及两种伤寒疫苗（注射多糖 或口服减毒细菌疫苗）。重要的是，我们将研究这些主要的免疫反应，在一个独特的 临床队列：年轻成人（20-35岁）和老年人（60-95岁）的纵向Stanford-Ellison队列 在过去九年中对其每年流感疫苗反应进行了广泛研究的受试者，以及 将继续研究在补助金期间，使明确比较小学和中学 可以在相同的个体中做出响应。我们将使用新的单B细胞和T细胞抗原受体 库分析和转录表型分析方法，以及单细胞单克隆抗体表达 和表征，以确定应答每次初次接种的B细胞和T细胞克隆。中 受试者亚组，我们还将获得骨髓穿刺液以分析骨髓浆细胞 群体，并确定血液中急性疫苗反应的哪些克隆有助于骨骼 骨髓浆细胞池与记忆B细胞池。此外，还将收集肠道微生物群数据， 评估疫苗和微生物群之间的潜在相互作用。 该项目的影响将来自于综合研究小学教育的机会， 和次级适应性免疫反应以及衰老对人类免疫系统的影响：1）一种独特的 一个充分表征的年轻和老年受试者纵向队列，其中临床相关的一级疫苗 可以与对流感疫苗接种的二次应答平行研究应答，2）单细胞 疫苗特异性B细胞和T细胞受体库和表型的表征， 一组标准免疫学测定，3）追踪来自急性疫苗的疫苗刺激的B细胞克隆 在血液中的反应，在骨髓浆细胞池中的驻留，以及4）与微生物组的整合 数据和其他重要临床数据。

Summary Age-related defects in human immune function have been most studied in the context of influenza vaccination and infection, or other settings where an individual's history of prior antigenic exposures and adaptive immune memory complicates analysis. In contrast, both young and elderly individuals are also able to form new primary immune responses following novel antigen exposures. Vaccine-mediated protection of communities against emergent infectious diseases such as Ebola and Zika viruses will rely on new primary adaptive immune responses across age categories. We will comprehensively analyze the adaptive immune responses in young adult and elderly subjects to three different kinds of primary vaccinations administered by parenteral or oral routes: the Hepatitis A (HAV) inactivated and aluminum salt-adjuvanted viral vaccine, and two vaccines for Typhoid (injected polysaccharide or oral attenuated bacterial vaccine). Importantly, we will study these primary immune responses in a unique clinical cohort: the longitudinal Stanford-Ellison cohort of young adult (20-35 years) and elderly (60-95 years) subjects whose yearly influenza vaccine responses have been studied extensively for the past nine years, and will continue to be studied during the grant period so that explicit comparison of primary and secondary responses can be made in the same individuals. We will use novel single B cell and T cell antigen receptor repertoire analysis and transcriptional phenotyping methods, and single cell monoclonal antibody expression and characterization, to define the B cell and T cell clones that respond to each primary vaccination. In a subset of subjects, we will also obtain bone marrow aspirates to analyze the bone marrow plasma cell populations, and identify which clones from the acute vaccine responses in the blood contribute to the bone marrow plasma cell pool versus the memory B cell pool. In addition, gut microbiota data will be collected to evaluate for potential interactions between vaccines and microbiota. The impact of this Project will stem from a combination of opportunities for comprehensive study of primary and secondary adaptive immune responses and the effects of aging on human immune systems: 1) a uniquely well-characterized longitudinal cohort of young and elderly subjects in whom clinically-relevant primary vaccine responses can be studied in parallel with secondary responses to influenza vaccination, 2) single-cell characterization of vaccine-specific B cell and T cell receptor repertoires and phenotypes in combination with a panel of standard immunological assays, 3) tracking of vaccine-stimulated B cell clones from the acute vaccine response in the blood, to residence in the bone marrow plasma cell pool, and 4) integration with microbiome data and other significant clinical data.