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

摘要 人类免疫功能中与年龄相关的缺陷大多是在流感的背景下进行研究的 疫苗接种和感染，或个人先前抗原接触史和 适应性免疫记忆使分析变得复杂。相比之下，年轻人和老年人也都能够 在新的抗原暴露后形成新的初级免疫反应。疫苗介导的免疫保护作用 社区抗击埃博拉和寨卡病毒等新发传染病将依靠新的初级 各年龄段的适应性免疫反应。 我们将综合分析青年和老年受试者的适应性免疫反应，以 通过非肠道或口服途径接种的三种不同类型的初级疫苗：甲型肝炎(HAV) 灭活疫苗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，我们将在一个独特的 临床队列：由青年(20-35岁)和老年人(60-95岁)组成的纵向Stanford-Ellison队列 其年度流感疫苗反应在过去九年中得到广泛研究的受试者，以及 将在资助期内继续研究，以便明确比较小学和中学 同样的个体也可以做出回应。我们将使用新的单一B细胞和T细胞抗原受体 谱系分析和转录表型方法以及单细胞单抗的表达 和鉴定，以确定对每一次初级疫苗接种有反应的B细胞和T细胞克隆。在一个 受试者的子集，我们还将获得骨髓抽吸物来分析骨髓浆细胞 种群，并识别血液中急性疫苗反应中的哪些克隆对骨骼有贡献 骨髓浆细胞池和记忆B细胞池。此外，还将收集肠道微生物区系数据，以 评估疫苗和微生物区系之间的潜在相互作用。 该项目的影响将来自于综合学习小学 二次适应性免疫反应和衰老对人类免疫系统的影响：1)独一无二的 临床相关初级疫苗的青年和老年受试者的特征明确的纵向队列 反应可以与流感疫苗的二次反应并行研究，2)单细胞 疫苗特异性B细胞和T细胞受体谱系和表型的鉴定 标准免疫学分析小组，3)追踪来自急性疫苗的疫苗刺激的B细胞克隆 在血液中对滞留在骨髓浆细胞池中的反应，以及4)与微生物组的整合 数据和其他重要的临床数据。

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.