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.

项目概要 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 岁以上老年人的并发症。除了疫苗本身之外，应对措施 老年人的疫苗接种和疫苗有效性可能受到合并症（例如虚弱）的影响， 免疫衰老重塑（即免疫衰老和炎症），每年重复接种疫苗， 季节性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，我们针对 75 岁以上的社区老年人建立了一个研究队列。 累计了 815 个人季，具有全面的人口统计、临床、功能和实验室数据，如 以及储存的疫苗接种前和疫苗后血清、血浆和外周血单核细胞 (PBMC) 我们还通过储存的感染后血清、血浆和样本鉴定了 15 例突破性流感感染病例。 重要的是，20 名受试者参加了所有 7 个季节，36 名受试者参加了 6 个季节，31 名受试者参加了 5 个季节，16 名受试者参加了 7 个季节。 4 季，3 季或更短时间内 165 季，我们建议利用这个独特的群体并进行剪辑。 边缘免疫学研究工具，开发反映一般情况的最先进的“免疫特征” 免疫状态（通过高维流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 细胞库的广度和深度； 通过流式分析和 scRNA 测序了解同型/异型抗流感 T 细胞的分布/功能； 毒株特异性和交叉反应性流感抗体的血清学分析）。 免疫特征及其随时间的季节内和季节间变化作为疫苗的决定因素 75 岁以上老年人的反应和突破性感染的风险我们的具体目标是：1) 描述特征。 季节性基线（预先存在的）免疫特征作为疫苗反应的决定因素以及如何 它们随着时间的推移而变化。我们不仅会确定季节间的纵向轨迹，还会识别出。 2）表征季节性免疫 对疫苗接种的标志性反应作为突破性感染风险的决定因素以及它们如何 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来探索脆弱性的免疫机制；3) 表征 对疫苗接种的免疫特征反应的季节性减弱及其跨季节的变化 通过每月血液采样，直到多个季节的每个流感季节结束。 完成后，拟议的研究将增进我们对免疫特征作为关键的理解 典型老年人疫苗反应的免疫机制和突破性感染的风险 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措施。 免疫策略包括针对这一高度脆弱的老年人群体的通用疫苗。