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

15 年纵向队列中衰老对初次和二次疫苗反应的影响

• 批准号: 9290057
• 负责人: Scott Dexter Boyd
• 金额: $ 75.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290057
• 关键词: Acute; Adjuvant; Affect; Affinity; Age; Aging; Aluminum; Aluminum Hydroxide; Antibodies; Antibody Affinity; Antibody Repertoire; Antibody Response; Antibody Specificity; Antigens; Aspirate substance; Attenuated; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Vaccines; Biological Assay; Blood; Bone Marrow; CD4 Positive T Lymphocytes; Categories; Cells; Clinical; Clinical Data; Clonal Expansion; Clone Cells; Communicable Diseases; Communities; Complement; Data; Defect; Disease; Ebola virus; Elderly; Feces; Flow Cytometry; Frequencies; Generations; Genetic Transcription; Grant; Helper-Inducer T-Lymphocyte; Hepatitis A; Human; Immune response; Immune system; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin M; Immunologic Memory; Immunology procedure; Impairment; Individual; Infection; Influenza; Influenza vaccination; Injectable; Longitudinal cohort; MF59; Mediating; Memory B-Lymphocyte; Methods; Monoclonal Antibodies; Oral; Patients; Persons; Phenotype; Plasma Cells; Plasmablast; Polysaccharides; Population; Recording of previous events; Recurrence; Research Subjects; Route; Salmonella typhi; Serum; Sodium Chloride; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Ty21a typhoid vaccine; Typhoid Fever; Typhoid Vaccine; Vaccinated; Vaccination; Vaccines; Viral Proteins; Viral Vaccines; Zika Virus; adaptive immune response; age effect; age related; clinically relevant; cohort; deep sequencing; design; gut microbiome; gut microbiota; immune function; immune system function; improved; influenza virus vaccine; killings; long term memory; microbiome; microbiota; monoclonal antibody production; novel; novel vaccines; oral vaccine; peripheral blood; residence; response; seasonal influenza; stem; vaccine response; young adult

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.

概括 在流感的背景下，人类免疫功能中与年龄相关的缺陷已被研究最多 疫苗接种和感染，或其他人的先前抗原暴露病史 自适应免疫记忆使分析复杂。相比之下，年轻人和老年人都可以 在新型抗原暴露后形成新的原发性免疫反应。疫苗介导的保护 反对埃博拉病毒和寨卡病毒等新兴疾病的社区将依靠新的主要主要 年龄类别的自适应免疫反应。 我们将全面分析年轻成人和老年受试者的适应性免疫反应 通过肠胃外或口服路线进行的三种不同类型的原发性疫苗：肝炎A（HAV） 灭活和铝盐辅助病毒疫苗和两种伤寒疫苗（注射多糖 或口服细菌疫苗）。重要的是，我们将以独特的方式研究这些主要的免疫反应 临床队列：年轻人（20 - 35岁）和老年人（60-95岁）的纵向斯坦福 - 艾里森队列 在过去的九年中，对年度流感疫苗反应的年度疫苗反应进行了广泛研究，并且 将在赠款期间继续研究，以便对初级和次要的明确比较 可以在同一个人中做出回应。我们将使用新型的单个B细胞和T细胞抗原受体 曲目分析和转录表型方法以及单细胞单克隆抗体表达 和表征，以定义对每种初级疫苗接种反应的B细胞和T细胞克隆。在 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，并确定血液中急性疫苗反应中哪些克隆有助于骨骼 骨髓浆细胞池与内存B细胞池。此外，将收集肠道微生物群数据 评估疫苗与微生物群之间的潜在相互作用。 该项目的影响将源于对主要研究的全面研究的结合 以及次级自适应免疫反应以及衰老对人免疫系统的影响：1）独特的 年轻和老年受试者的纵向纵向队列中，临床上与初级疫苗相关的年轻受试者 可以与对流感疫苗接种的次要反应并行研究反应，2）单细胞 疫苗特异性B细胞和T细胞受体库的表征和表型与A结合 标准免疫学测定面板，3）从急性疫苗跟踪疫苗刺激的B细胞克隆 血液中的反应，居住在骨髓浆细胞库中，4）与微生物组整合 数据和其他重要的临床数据。