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

项目摘要 季节性流感（“流感”）仍然是严重的公共卫生威胁，严重疾病负担最高 以及影响老年人，特别是75岁以上的老年人的并发症。除了疫苗本身， 老年人的疫苗接种和疫苗有效性可能受合并症的影响（例如，脆弱）， 免疫衰老重塑（即，免疫衰老和炎症），每年重复接种， 季节内免疫力减弱，以及疫苗配方和流通中的病毒株变异。 自2014年以来，我们在75岁以上的社区老年人中建立了一个研究队列。该队列已 累积了815人季，具有全面的人口统计学、临床、功能和实验室数据， 以及疫苗接种前和接种后储存的血清、血浆和外周血单核细胞（PBMC） 样品我们还确定了15例突破性流感感染病例，其中包括感染后血清、血浆和 PBMC样品。重要的是，20名受试者参加了所有7个赛季，36名参加了6个赛季，31名参加了5个赛季，16名参加了6个赛季。 在这里，我们建议利用这个独特的群体，并采用削减 边缘免疫学研究工具，以开发最先进的“免疫签名”，反映一般 免疫状态（通过高维流分析免疫细胞亚群的分布和功能， RNA-Seq;细胞因子谱）和流感特异性免疫（流感特异性T细胞库的宽度和深度; 通过流式分析和scRNA-Seq分析同型/异型抗流感T细胞的分布/功能; 菌株特异性和交叉反应性流感抗体的血清学分析）。我们的目标是描述 作为疫苗决定因素的免疫特征及其季节内和季节间变化 老年人突破性感染的反应和风险>75。我们的具体目标是：1）描述 季节性基线（预先存在的）免疫特征作为疫苗应答的决定因素， 它们会随着时间而改变。我们不仅要确定季节间的纵向轨迹， 特异性基线免疫特征预测对疫苗接种的应答; 2）表征季节性免疫应答， 对疫苗接种的特征反应是突破性感染风险的决定因素， 随着时间的推移而改变。我们将评估和比较免疫特征反应的差异和相似之处 通过疫苗接种与自然感染引发，以探索脆弱性的免疫机制;以及3）表征 对疫苗接种的免疫特征应答的季节内减弱及其季节间变化 通过每月的血液采样，直到多个季节的每个流感季节结束。 完成后，拟议的研究将促进我们对免疫特征的理解， 典型老年人中疫苗应答和突破性感染风险免疫机制 人口最终，这些研究将有助于确定保护的相关性，并制定更有效的 免疫战略，包括为这一高度脆弱的老年人群体接种通用疫苗。

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.