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: 10340603
• 负责人: Wayne A. Marasco
• 金额: $ 123.87万
• 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/10340603
• 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; Pharmacology; Plasma; Pneumonia; Population; Principal Investigator; Sampling; Serology; Specificity; T-Lymphocyte; Techniques; Testing; Time; Translating; United States; Vaccination; Vaccine Antigen; Vaccine Design; Vaccinee; Vaccines; 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; 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.

项目摘要 流感是古老和当前疫苗的主要死亡原因，只能保护这一人群的一部分 尽管疫苗接种计划和专门公式。更好地理解分子 迫切需要控制免疫老化的机制，以便新设计的疫苗，调节器 可以雇用药物干预措施以恢复较老的年轻抗体（AB）反应 人口。我们的总体目标集中于确定衰老对介导的免疫细胞的影响 抗Influenza AB疫苗反应。我们将对 循环T卵泡辅助器（TFH），T卵泡调节（TFR）细胞和B细胞以及它们的子集 在季节性影响力疫苗接种之前和之后的年轻人和年龄较大的人。我们将检验以下假设 增长年龄的结果是TFH/TFR细胞单个子集的分布改变，导致 代谢重编程和有缺陷的B细胞引起的影响疫苗反应。我们的综合分析 包括研究在有机和细胞水平与年龄相关的新陈代谢途径下降的研究， 例如有缺陷的线粒体生物发生和一种碳代谢，并确定这些变化是否变化 导致免疫功能障碍。最后，从这些研究中获得的知识将用于执行 概念验证救援实验，以恢复最佳影响力疫苗的反应性。支持 这些研究，将使用153名参与者的季节性影响者疫苗队列（21-76岁，21-76岁）使用样品。 包括15个≥65岁的个体），在二次血凝素之后第0、7和32天捐赠了血液 （HA）疫苗接种。我们计划对该队列的有针对性扩展招募≥65岁的100个捐助者 单细胞基因组和代谢组学研究的年龄和一组25名成年人（≤40yr，n = 25） 新鲜的血液样本。我们将暂时遵循流感疫苗的反应并比较年轻人和年龄较大 特别是，在AIM 1中，我们将检查子集组成和代谢重编程的变化 在卵泡T细胞中，年轻人和年龄个体。这些研究的完成将使我们能够理解 与衰老相关的体液免疫学缺陷是否由TFH和TFR子集的变化介导 固有功能，或两者兼而有之。在AIM 2中，我们将评估AB响应的特征并确定 年轻人和老年人的B细胞种群的组成和代谢变化。完成 这些研究我们还将了解导致免疫印迹的变化。在AIM 3中，我们将分析年龄 - TFH，TFR和B细胞的相关功能障碍在体外响应影响疫苗抗原。 TFH/B细胞共培养 将用免疫调节剂和小分子处理，以恢复免疫学和代谢功能 克服疫苗反应中与年龄相关的缺陷。我们已经组建了一支成就卓著的团队来携带 这些研究的目的是测试新的范式并建立有关如何采取行动的路线图 提高疫苗的反应性。