Leveraging an ongoing longitudinal study of influenza vaccination to define immune signatures of response and risk of infection in older adults >75

项目总结 季节性流感(“流感”)仍然是一个严重的公共卫生威胁，是严重疾病的最大负担。 以及影响老年人的并发症，特别是那些75岁以上的人。除了疫苗本身，反应 老年人接种疫苗和疫苗效力可能受到共病(例如，虚弱)的影响， 免疫衰老重塑(即免疫衰老和炎症)，重复每年接种疫苗， 季节内免疫减弱，以及疫苗配方和流通中的病毒株变异。 自2014年以来，我们已经在社区居住的老年人中建立了一个研究队列。这群人有 累积了815个人季，具有全面的人口统计、临床、功能和实验室数据，如 以及疫苗接种前后的血清、血浆和外周血单核细胞(PBMC) 样本。我们还确定了15例突破性流感感染病例，储存了感染后血清、血浆和 PBMC样本。重要的是，20名受试者参加了所有7个赛季，36人参加了6个赛季，31人参加了5个赛季，16人参加了 4个季节，3个或更少季节165个。在这里，我们建议利用这一独特的队列，并采用切割 边缘免疫学研究工具，以开发最先进的“免疫签名”，反映了普通的 免疫状态(通过高维流动分析和免疫细胞亚群的分布和功能 RNA-Seq；细胞因子分析)和流感特异性免疫(流感特异性T细胞谱系的广度和深度； 同型/异型抗流感T细胞分布/功能的流式分析和单链RNA序列分析 毒株特异性和交叉反应流感抗体的血清学特征)。我们的目标是将 作为疫苗决定因素的免疫特征及其季节内和季节间的变化 老年人的反应和突破性感染的风险&75。我们的具体目标是：1)塑造 作为疫苗应答决定因素的季节性基线(预先存在)免疫特征以及如何 它们会随着时间的推移而改变。我们不仅要确定赛季间的纵向轨迹，还要确定 特定的基线免疫特征预测接种疫苗的反应；2)描述季节性免疫 疫苗接种作为突破性感染风险决定因素的特征反应以及它们是如何 随着时间的推移而改变。我们将评估和比较免疫签名反应的异同 疫苗接种与自然感染相比，探讨易损性的免疫机制；3)表征 对接种疫苗的免疫特征反应的季节内减弱及其季节变化 通过每月采血，直到每个流感季节结束，跨越多个季节。 完成后，拟议的研究将促进我们对免疫签名作为关键的理解。 典型老年人疫苗应答和突破性感染风险的免疫学机制 人口。最终，这些研究将有助于确定保护的相关性，并开发出更有效的方法 免疫战略，包括为这一高度脆弱的老年人亚群提供通用疫苗。

Project summary Seasonal influenza (“flu”) remains a serious public health threat with the highest burden of severe disease and complications affecting older adults, particularly those over age 75. In addition to vaccine itself, responses to vaccination and vaccine effectiveness in older adults are likely influenced by comorbidity (e.g., frailty), immune senescent remodeling (i.e., immunosenescence and inflammaging), repeated annual vaccination, intra-seasonal immune waning, and virus strain variations both in vaccine formula and in circulation. Since 2014, we have established a study cohort in community-dwelling older adults >75. The cohort has accumulated 815 person-seasons with comprehensive demographic, clinical, functional and laboratory data, as well as banked pre- and post-vaccination serum, plasma, and peripheral blood mononuclear cell (PBMC) samples. We also identified 15 breakthrough flu infection cases with banked post-infection serum, plasma and PBMC samples. Importantly, 20 subjects participated in all 7 seasons, 36 in 6 seasons, 31 in 5 seasons, 16 in 4 seasons, and 165 in 3 seasons or less. Here, we propose to leverage this unique cohort and employ cutting edge immunologic research tools to develop state-of-the-art “immune signatures” reflecting both general immune status (distribution and function of immune cell subsets through high-dimensional flow analysis and RNA-Seq; cytokine profiling) and influenza-specific immunity (breadth and depth of flu-specific T cell repertoire; distribution/function of homotypic/heterotypic anti-flu T cells through flow analysis and scRNA-Seq; deep serological profiling of strain-specific and cross-reactive flu antibodies). Our objective is to characterize immune signatures and their intra- and inter-seasonal changes over time as determinants of vaccine responses and risk of breakthrough infection in older adults >75. Our specific aims are: 1) Characterize seasonal baseline (pre-existing) immune signatures as determinants of vaccine response and how they change over time. We will not only determine inter-season longitudinal trajectory, but also identify specific baseline immune signatures predict responses to vaccination; 2) Characterize seasonal immune signature responses to vaccination as determinants of risk of breakthrough infection and how they change over time. We will evaluate and compare differences and similarities of immune signature responses elicited by vaccination vs natural infection to explore immune mechanisms of vulnerability; and 3) Characterize intra-seasonal waning of immune signature responses to vaccination and its change across seasons through monthly blood sampling until the end of each flu season across multiple seasons. Upon completion, the proposed studies will advance our understanding of immune signatures as key immunologic mechanisms for vaccine responses and risk of breakthrough infection in a typical geriatric population. Ultimately, these studies will help define correlates of protection and develop more effective immunization strategies including a universal vaccine for this highly vulnerable subset of older adults.