Identification of Metabolic and Immune Deficits in the Aged Population and Their Restoration to Achieve Youthful Anti-Influenza Vaccine Responsiveness

老年人群代谢和免疫缺陷的识别及其恢复以实现年轻的抗流感疫苗反应

• 批准号: 10531263
• 负责人: Wayne A. Marasco
• 金额: $ 117.67万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-22 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531263
• 关键词: Adjuvant; Adult; Affect; Age; Age Years; Aging; Antibodies; Antibody Response; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biogenesis; Blood; Blood specimen; Carbon; Cause of Death; Cells; Cessation of life; Characteristics; Coculture Techniques; Cryopreservation; Defect; Elderly; Epitopes; Evaluation; Formulation; Functional disorder; Genomics; Goals; Hemagglutinin; Heterogeneity; Hospitalization; Humoral Immunities; Immune; Immune System Diseases; Immunization Programs; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunologics; Immunomodulators; In Vitro; Individual; Influenza; Influenza vaccination; Intervention; Knowledge; Learning; Mediating; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Older Population; Participant; Persons; Plasma; Pneumonia; Population; Principal Investigator; Sampling; Serology; Specificity; T-Lymphocyte; Techniques; Testing; Time; Translating; United States; Vaccination; Vaccine Antigen; Vaccine Design; Vaccinee; Vaccines; Writing; age effect; age related; aged; aging population; anti-influenza; cohort; experimental study; functional disability; immune system function; imprint; improved; infection risk; influenza virus vaccine; laboratory experiment; metabolic abnormality assessment; metabolic profile; metabolomics; novel; pharmacologic; recruit; response; restoration; seasonal influenza; small molecule; transcriptome; transcriptomics; vaccine formulation; vaccine response; vaccine-induced antibodies; young adult

Project Summary Influenza is a leading cause of death in the elderly and current vaccines only protect a fraction of this population despite widespread vaccination programs and specialized formulations. A better understanding of the molecular mechanisms that control immunological aging is urgently needed so that newly designed vaccines, adjuvants and pharmacologic interventions can be employed to restore youthful antibody (Ab) responses in the older population. Our overarching goals are focused on determining the effects of aging on immune cells that mediate the anti-influenza Ab vaccine response. We will perform an integrated and comprehensive evaluation of circulating T follicular helper (Tfh), T follicular regulatory (Tfr) cells and B cells as well as their subsets from young and older individuals prior to and after seasonal influenza vaccination. We will test the hypothesis that a consequence of advancing age is an altered distribution of individual subsets of Tfh/Tfr cells resulting in metabolic reprogramming and defective B cell elicited influenza vaccine responses. Our integrated analysis includes studies to investigate at the organismal and cellular level age-related declines in metabolic pathways, such as defective mitochondrial biogenesis and one carbon metabolism and to determine if these changes contribute to the immune dysfunction. Finally, knowledge gained from these studies will be used to perform proof of concept rescue experiments in vitro to restore optimal influenza vaccine responsiveness. To support these studies, samples will be used from a seasonal influenza vaccinee cohort of 153 participants (ages 21-76, including 15 individuals ≥ 65yr) who have donated blood at days 0, 7 and 32 after quadrivalent hemagglutinin (HA) vaccination. We plan a targeted expansion of this cohort to recruit an additional 100 donors ≥ 65 years of age and a group of 25 younger adults (≤ 40yr, n=25) for single cell genomic and metabolomic studies that require fresh blood samples. We will temporally follow the influenza vaccine response and compare young and older groups. Specifically, in Aim 1 we will examine alterations in subset composition and metabolic reprogramming in follicular T cells in young and aged individuals. The completion of these studies will allow us to understand whether defects in humoral immunity associated with aging are mediated by changes in Tfh and Tfr subsets, intrinsic functionality, or both. In Aim 2 we will assess characteristics of the Ab response and determine composition and metabolic changes in B cell populations in young and aged individuals. At the completion of these studies we will also understand changes that result in immune imprinting. In Aim 3 we will analyze age- related dysfunction of Tfh, Tfr and B cells in vitro in response to influenza vaccine antigens. Tfh/B cell co-cultures will be treated with immune modulators and small molecules to restore immunologic and metabolic function to overcome age-related defects in vaccine responses. We have assembled a highly accomplished team to carry out these studies with the goal of testing new paradigms and establishing an actionable roadmap on how to improve vaccine responsiveness in the elderly.

项目概要 流感是老年人死亡的主要原因，目前的疫苗只能保护这一人群的一小部分 尽管有广泛的疫苗接种计划和专门的配方。更好地了解分子 迫切需要控制免疫衰老的机制，以便新设计的疫苗、佐剂 可以采用药物干预来恢复老年人年轻时的抗体 (Ab) 反应 人口。我们的首要目标是确定衰老对介导免疫细胞的影响 抗流感抗体疫苗反应。我们将进行综合、全面的评估 循环滤泡辅助 T (Tfh)、滤泡调节 T (Tfr) 细胞和 B 细胞及其亚群 季节性流感疫苗接种前后的年轻人和老年人。我们将检验以下假设： 年龄增长的后果是 Tfh/Tfr 细胞个体亚群分布的改变，导致 代谢重编程和有缺陷的 B 细胞引发了流感疫苗反应。我们的综合分析 包括在有机体和细胞水平上调查与年龄相关的代谢途径下降的研究， 例如线粒体生物合成和一碳代谢缺陷，并确定这些变化是否 导致免疫功能失调。最后，从这些研究中获得的知识将用于执行 体外概念验证救援实验可恢复流感疫苗的最佳反应性。支持 在这些研究中，样本将来自 153 名参与者（年龄 21-76 岁， 包括 15 名 ≥ 65 岁的个体，他们在四价血凝素注射后第 0、7 和 32 天献血 （医管局）疫苗接种。我们计划有针对性地扩大这一群体，招募另外 100 名年龄≥65 年的捐赠者。 年龄和 25 名年轻人（≤ 40 岁，n=25）组成的小组进行单细胞基因组和代谢组学研究，需要 新鲜血液样本。我们将暂时跟踪流感疫苗的反应并比较年轻人和老年人 组。具体来说，在目标 1 中，我们将检查子集组成和代谢重编程的变化 年轻人和老年人的滤泡 T 细胞。完成这些研究将使我们了解 与衰老相关的体液免疫缺陷是否是由 Tfh 和 Tfr 亚群的变化介导的， 内在功能，或两者兼而有之。在目标 2 中，我们将评估抗体反应的特征并确定 年轻人和老年人 B 细胞群的组成和代谢变化。完成时 通过这些研究，我们还将了解导致免疫印记的变化。在目标 3 中，我们将分析年龄- 体外 Tfh、Tfr 和 B 细胞响应流感疫苗抗原的相关功能障碍。 Tfh/B 细胞共培养 将接受免疫调节剂和小分子治疗，以恢复免疫和代谢功能 克服疫苗反应中与年龄相关的缺陷。我们组建了一支高素质的团队来承载 进行这些研究的目的是测试新的范例并建立一个可行的路线图 提高老年人的疫苗反应性。