Genomics and Epigenomics of the Elderly Response to Pneumococcal Vaccines

 描述(申请人提供)：本项目的目标是剖析影响老年人对微生物疫苗接种反应的与年龄相关的免疫细胞变化。衰老与抵抗感染的能力下降有关，并与至少两种免疫变化有关：免疫衰老，即随着时间的推移免疫系统功能下降；以及炎症，一种慢性炎症状态，据信会引发与年龄相关的主要慢性病。这些变化可能解释了老年人对微生物疫苗反应不足的原因，使这一群体非常容易受到肺炎链球菌等严重感染的后果，肺炎链球菌是当前研究的重点。事实上，肺炎链球菌在老年人中会导致显著的发病率和死亡率，目前批准的两种肺炎球菌疫苗--PPSV23(Pappovax(R))和PCV13(Prevnar(R))--已在这一人群中使用，效果参差不齐。例如，虽然PPSV23对健康的年轻人有效，但几项研究表明，对老年人的疗效降低。在那里，它可以预防老年人的肺炎球菌菌血症，但不能降低社区获得性肺炎(CAP)的风险。最近有报道称，PCV13可使疫苗型肺炎球菌、细菌性和非细菌性CAP减少约50%，但仍有相当一部分人缺乏保护。这两种疫苗效果不佳的根本原因尚不清楚。它们可能在质量和数量上产生不同的免疫反应，但这一点仍有待证实。此外，由于在所有老年队列研究中，每种疫苗都与安慰剂进行了比较，而不是彼此之间进行了比较，因此对于它们在老年人中的比较效果还没有得出明确的结论。因此，关于疫苗反应性的性质(和可变性)的许多问题仍然没有得到回答。我们的假设是，老年人对肺炎球菌疫苗的免疫反应的改变是由与衰老相关的基因组改变引起的，这些改变导致三种免疫细胞类型中的一种或多种功能障碍-抗原提呈细胞(APC)、滤泡辅助T细胞(TFH)和B细胞-对适应性免疫至关重要。我们提出了三个特定的目标来验证我们的假设-目标1：用两种不同的肺炎球菌疫苗接种健康老年人，采集纵向血样并评估肺炎球菌特异性抗体反应；目标2：建立与肺炎球菌疫苗抗体反应相关联的老年人血液免疫细胞的转录和表观遗传学特征；以及目标3：根据肺炎球菌疫苗应答者的状态分层检查老年人的免疫细胞功能状态。我们的方法将流式细胞术和其他功能评估与尖端基因组方法相结合，旨在产生这三种关键免疫细胞类型的深入表型、转录、表观遗传和功能数据。这些努力将产生史无前例的大规模数据集和关于健康老年人免疫反应的知识。

 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.