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

利用正在进行的流感疫苗接种纵向研究来定义 75 岁以上老年人的免疫反应特征和感染风险

• 批准号: 10347918
• 负责人: Jay H. Bream
• 金额: $ 163.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347918
• 关键词: Address; Affect; Age; Aging; American; Antibodies; Antibody titer measurement; Biological; Blood Circulation; Blood specimen; Cause of Death; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Clinical; Clinical Research; Cohort Studies; Collection; Communities; Convalescence; Coupled; Data; Development; Disease; Elderly; Elements; Environmental Exposure; Environmental Risk Factor; Flow Cytometry; Foundations; Geriatrics; Health; Hemagglutination; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Infection; Inflammaging; Inflammation Mediators; Influentials; Influenza; Influenza vaccination; Infrastructure; Integration Host Factors; Kinetics; Laboratories; Longitudinal Studies; Longitudinal cohort; Longitudinal cohort study; Molecular; Molecular Virology; Monitor; Peripheral Blood Mononuclear Cell; Persons; Phage Display; Plasma; Population; Principal Investigator; Public Health; Research; Risk; Sampling; Seasons; Serology; Serum; Specimen; T cell receptor repertoire sequencing; T-Lymphocyte; Technology; Time; Vaccination; Vaccines; Variant; Virus; anti-influenza; base; breakthrough infection; cohort; comorbidity; cross reactivity; cytokine; flu; frailty; functional status; high dimensionality; immune function; immunological status; immunosenescence; infection risk; influenza infection; multiple chronic conditions; next generation sequencing; predicting response; predictive signature; programs; repository; response; sample collection; seasonal influenza; senescence; single-cell RNA sequencing; tool; transcriptome sequencing; universal vaccine; vaccination strategy; vaccine effectiveness; vaccine response

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.

项目摘要 季节性影响力（“流感”）仍然是严重的公共卫生威胁，严重疾病的燃烧最高 以及影响老年人的并发症，尤其是75岁以上的老年人。除了疫苗本身之外，还有反应 老年人的疫苗和疫苗有效性可能受合并症的影响（例如脆弱）， 免疫感觉重塑（即免疫衰老和炎症），重复每年疫苗接种， 疫苗配方和循环中的季节内免疫减退和病毒菌株变化。 自2014年以来，我们在社区居民老年人中建立了一项研究队列> 75。队列有 累积了815个人的季节，具有全面的人口，临床，功能和实验室数据， 以及疫苗前和疫苗后的血清，血浆和外周血单核细胞（PBMC） 样品。我们还确定了15例具有库存后血清，血浆和血浆的突破性流感感染病例 PBMC样品。重要的是，有20名受试者参加了所有7个赛季，在6个赛季中有36个，5个季节中的31个，16个 4个季节，在3个季节或更短的时间内为165个。在这里，我们建议利用这种独特的队列和员工切割 边缘免疫研究工具开发最新的“免疫签名”，反映了一般性的一般性 免疫状态（通过高维流量分析和 RNA-seq;细胞因子分析）和影响特异性免疫（流感特异性T细胞库的广度和深度； 通过流量分析和SCRNA-SEQ，同型/异型抗FLU T细胞的分布/功能；深的 菌株特异性和交叉反应性流感抗体的血清学分析）。我们的目标是表征 免疫特征及其随着时间的推移的季节内变化，作为疫苗的确定性 老年人的反应和突破感染的风险> 75。我们的具体目的是：1）表征 季节性基线（预先存在的）免疫特征作为疫苗反应的确定性以及如何 随着时间的流逝，它们会改变。我们不仅会确定季节间纵向轨迹，还可以确定 特定的基线免疫特征可以预测对疫苗接种的反应； 2）特征季节性免疫 签名对疫苗接种的反应，作为突破性感染风险的决定者以及如何 随着时间的变化。我们将评估和比较免疫特征反应的差异和相似之处 疫苗接种与自然感染引起的探索脆弱性的免疫力学； 3）特征 免疫签名反应及其在整个季节的变化的季节内减弱 通过每月抽血，直到每个流感季节结束多个季节。 完成后，拟议的研究将提高我们对免疫特征作为关键的理解 疫苗反应的免疫机制和典型老年内突破感染的风险 人口。最终，这些研究将有助于定义保护的相关性并发展更有效 免疫策略，包括通用疫苗，用于这一高度脆弱的老年人子集。