Genomics and Epigenomics of the Elderly Response to Pneumococcal Vaccines

老年人对肺炎球菌疫苗反应的基因组学和表观基因组学

• 批准号: 9483251
• 负责人: Jacques F Banchereau
• 金额: $ 64.32万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9483251
• 关键词: ATAC-seq; Address; Adult; Affect; Aging; Antibodies; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; B-Lymphocytes; Bacteremia; Biological Assay; Biology; Blood; Blood specimen; Categories; Cell Culture Techniques; Cells; Cellular biology; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Disease; Communities; Competence; Complement; DNA Sequence Alteration; Data; Data Set; Dendritic Cells; Deterioration; Disease; Elderly; Epigenetic Process; Flow Cytometry; Functional disorder; Genetic Transcription; Genomic approach; Genomics; Goals; Guidelines; Health; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immune system; Immunity; Immunization; Immunogenomics; Individual; Infection; Inflammaging; Inflammation; Knowledge; Left; Link; Measures; Moon; Morbidity - disease rate; Nature; Output; Phenotype; Placebos; Pneumococcal Infections; Pneumococcal vaccine; Pneumonia; Pneumovax; Polysaccharides; Population; Prevention; Prevnar; Reporting; Risk; Sampling; Serotyping; Streptococcus pneumoniae; Technology; Testing; Time; Vaccinated; Vaccination; Vaccines; Whole Blood; adaptive immunity; age related; aged; base; cell type; cohort; combat; comparative efficacy; design; disability; epigenomics; functional decline; functional genomics; functional status; healthy aging; immunogenicity; immunological status; immunosenescence; insight; microbial; monocyte; mortality; prevent; public health relevance; response; success; transcriptome; transcriptome sequencing; vaccine response; young adult

 DESCRIPTION (provided by applicant): The goal of this project is to dissect the age-related changes in immune cells that affect responses to microbial vaccination in the elderly. Aging is associated with a decline in the ability to combat infections and is linked with at least two immune alterations: immunosenescence, or the functional decline of the immune system over time; and inflammaging, a chronic inflammation status believed to trigger major age-related chronic diseases. These alterations may explain insufficient responses to microbial vaccines in the elderly, leaving this population highly vulnerable to the consequences of serious infections like S. pneumoniae, the focus of the current study. Indeed, S. pneumoniae causes significant morbidity and mortality in the elderly, and the two currently approved pneumococcal vaccines-PPSV23 (Pneumovax(r)) and PCV13 (Prevnar(r))-have been used with mixed success in this population. For example, while PPSV23 is efficacious in healthy young adults, several studies have shown decreased efficacy in elderly. There, it prevents pneumococcal bacteremia in elderly, but does not reduce the risk of Community-Acquired Pneumonia (CAP). PCV13 was recently reported to reduce by ~50% vaccine-type pneumococcal, bacteremic and non-bacteremic CAP, but still left a significant subset of individuals underprotected. The underlying reasons for the suboptimal efficacy of these two vaccines is unclear. It is possible that they elict qualitatively and quantitatively different immune responses, but this remains to be established. Furthermore, no definitive conclusions can be drawn as to their comparative efficacy in the elderly, since in all studies in elderly cohorts each vaccine was compared to placebo and not each other. Thus, many questions as to the nature of (and variability in) vaccine responsiveness remain unanswered. Our hypothesis is that the altered immune responses of the elderly to pneumococcal vaccines are caused by genomic alterations associated with aging that result in dysfunction in one or more of three immune cell types-antigen presenting cells (APCs), follicular helper T cells (Tfh) and B cells-critical for adaptive immunity. We propose three Specific Aims to test our hypothesis - Aim 1: To vaccinate healthy elderly with two distinct pneumococcal vaccines, collect longitudinal blood samples and assess pneumococcal-specific antibody responses; Aim 2: To establish the transcriptional and epigenetic profiles of elderly blood immune cells linked with antibody responses to pneumococcal vaccination; and Aim 3: To examine the functional status of immune cells in the elderly stratified according to their pneumococcal vaccine responder status. Our approach integrates flow cytometry and other functional assessments with cutting-edge genomic approaches, and is designed to yield in-depth phenotypic, transcriptional, epigenetic and functional data for these three key immune cell types. These efforts are poised to yield unprecedented large-scale datasets and knowledge concerning immune responses in healthy elderly.

 描述（由适用提供）：该项目的目的是剖析影响古老的对微生物疫苗反应的免疫电池的与年龄相关的变化。衰老与对抗感染的能力的下降有关，并与至少两种免疫球改变有关：免疫衰老或免疫系统随着时间的推移的功能下降；和炎症是一种慢性炎症状态，被认为会引发与年龄有关的主要慢性疾病。这些变化可能解释了对微生物疫苗的反应不足，使该人群极易受到当前研究的重点等严重感染的后果。实际上，肺炎链球菌在古老的情况下引起了明显的发病率和死亡率，目前两者批准肺炎球菌疫苗-PPSV23（Pneumovax（r））和PCV13（PrevNar（r）） - 在该人群中都使用了混合成功。例如，尽管PPSV23在健康的年轻人中有效，但几项研究表明，较早的效率提高了。在那里，它可以防止长期以来的肺炎球菌血症，但不会降低社区获得性肺炎（CAP）的风险。最近据报道，PCV13降低了约50％的疫苗型肺炎球菌，细菌和非细菌性帽，但仍留下很大的受受保护的个体的子集。这两种疫苗的次优效率的根本原因尚不清楚。它们可能在定性和定量上引起不同的免疫回报，但这还有待确定。此外，对于较早的比较效率，无法得出明确的结论，因为在所有基础同类研究中，每种疫苗与安慰剂相比，而不是彼此之间。这是关于疫苗反应能力（和变异性）的性质的许多问题。我们的假设是，古老的对肺炎球菌疫苗的免疫复杂改变是由与衰老相关的基因组改变引起的，这些变化导致三种或多个免疫类抗菌素抗原 - 抗原抗菌细胞（APCS），卵泡盔Helper T细胞（TFH）和B细胞（TFH）和B细胞 - 细胞和B细胞的抗原领域的功能障碍。我们提出了三个特定的目的来检验我们的假设 - 目标1：用两种不同的肺炎球菌疫苗较早地接种健康，收集纵向血液样本和评估肺炎球菌特异性抗体反应；目的2：建立与抗体对肺炎球菌疫苗的抗体反应相关的基本血液免疫细胞的转录和表观遗传特征；和目标3：检查免疫细胞在基本分层中根据其肺炎球菌疫苗响应者状态的功能状态。我们的方法将流式细胞术和其他功能评估与最先进的基因组方法相结合，旨在为这三种关键的免疫细胞类型产生深入的表型，转录，表观遗传和功能数据。这些努力被毒死，以产生前所未有的大规模数据集以及有关健康中免疫反应的知识。