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
基本信息
- 批准号:10340603
- 负责人:
- 金额:$ 123.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdjuvantAdultAffectAgeAge-YearsAgingAntibodiesAntibody ResponseAntigensB-Lymphocyte SubsetsB-LymphocytesBiogenesisBloodBlood specimenCarbonCause of DeathCellsCessation of lifeCharacteristicsCoculture TechniquesCryopreservationDefectElderlyEpitopesEvaluationFormulationFunctional disorderGenomicsGoalsHemagglutininHeterogeneityHospitalizationHumoral ImmunitiesImmuneImmune System DiseasesImmunization ProgramsImmunoglobulin Class SwitchingImmunoglobulin Switch RecombinationImmunologicsImmunomodulatorsIn VitroIndividualInfluenzaInfluenza vaccinationInterventionKnowledgeLearningMediatingMemory B-LymphocyteMetabolicMetabolic PathwayMetabolismMitochondriaMolecularOlder PopulationParticipantPersonsPharmacologyPlasmaPneumoniaPopulationPrincipal InvestigatorSamplingSerologySpecificityT-LymphocyteTechniquesTestingTimeTranslatingUnited StatesVaccinationVaccine AntigenVaccine DesignVaccineeVaccinesage effectage relatedagedaging populationanti-influenzacohortexperimental studyfunctional disabilityimmune system functionimprintimprovedinfection riskinfluenza virus vaccinelaboratory experimentmetabolic abnormality assessmentmetabolic profilemetabolomicsnovelrecruitresponserestorationseasonal influenzasmall moleculetranscriptometranscriptomicsvaccine formulationvaccine responsevaccine-induced antibodiesyoung adult
项目摘要
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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Wayne A. Marasco其他文献
Novel genetic immunotoxins and intracellular antibodies for cancer therapy.
用于癌症治疗的新型遗传免疫毒素和细胞内抗体。
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:4
- 作者:
Si;Wayne A. Marasco - 通讯作者:
Wayne A. Marasco
Anticorps humanisés anti-récepteur de la chimiokine cc4 (ccr4) et leurs procédés d'utilisation
Anticorps humanisés anti-recepteur de la chimiokine cc4 (ccr4) 和 leurs procédés dutilization
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
Wayne A. Marasco;De;Quang Zhu - 通讯作者:
Quang Zhu
Anticorps monoclonaux humanisés dirigés contre le virus de la grippe et leurs procédés d'utilisation
- DOI:
- 发表时间:
2016-04 - 期刊:
- 影响因子:0
- 作者:
Wayne A. Marasco - 通讯作者:
Wayne A. Marasco
<strong>Initial evaluation of oncoretroviral vectors carrying HIV-1 inhibitor gene into rhesus CD34+ cells and/or CD4+ T cells: An in vivo model for the gene therapy of AIDS</strong>
- DOI:
10.1016/j.bcmd.2007.10.024 - 发表时间:
2008-03-01 - 期刊:
- 影响因子:
- 作者:
Stephen E. Braun;Fay Eng Wong;Michelle Connole;Ran Taube;Akikazu Murakami;Julianna Lisziewicz;Wayne A. Marasco;R. Paul Johnson - 通讯作者:
R. Paul Johnson
Anti-CD99 Antibody Therapy Triggers Macrophage-Dependent Ewing Cell Death In Vitro and Myeloid Cell Recruitment In Vivo
抗 CD99 抗体治疗在体外触发巨噬细胞依赖性 Ewing 细胞死亡和体内骨髓细胞募集
- DOI:
10.3390/antib13010024 - 发表时间:
2024 - 期刊:
- 影响因子:4.7
- 作者:
Allison F. O’Neill;Evelyn M. Nguyen;Evelyn D. Maldonado;Matthew R. Chang;Jiusong Sun;Q. Zhu;Wayne A. Marasco - 通讯作者:
Wayne A. Marasco
Wayne A. Marasco的其他文献
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{{ truncateString('Wayne A. Marasco', 18)}}的其他基金
Serologic and Molecular Studies of human anti-hCoV antibody cross-immunity and protective responses among endemic HCoVs and SARS-CoV2
人类抗 hCoV 抗体交叉免疫和地方性 HCoV 与 SARS-CoV2 之间保护性反应的血清学和分子研究
- 批准号:
10490889 - 财政年份:2021
- 资助金额:
$ 123.87万 - 项目类别:
Serologic and Molecular Studies of human anti-hCoV antibody cross-immunity and protective responses among endemic HCoVs and SARS-CoV2
人类抗 hCoV 抗体交叉免疫和地方性 HCoV 与 SARS-CoV2 之间保护性反应的血清学和分子研究
- 批准号:
10689125 - 财政年份:2021
- 资助金额:
$ 123.87万 - 项目类别:
Serologic and Molecular Studies of human anti-hCoV antibody cross-immunity and protective responses among endemic HCoVs and SARS-CoV2
人类抗 hCoV 抗体交叉免疫和地方性 HCoV 与 SARS-CoV2 之间保护性反应的血清学和分子研究
- 批准号:
10371789 - 财政年份:2021
- 资助金额:
$ 123.87万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 123.87万 - 项目类别:
Studies of IGHV Germline Gene Polymorphism, Utilization & Shifting for Seasonal Influenza Vaccine Induced Broadly Neutralizing Antibody Responses
IGHV种系基因多态性研究及利用
- 批准号:
9178624 - 财政年份:2015
- 资助金额:
$ 123.87万 - 项目类别:
Studies of IGHV Germline Gene Polymorphism, Utilization & Shifting for Seasonal Influenza Vaccine Induced Broadly Neutralizing Antibody Responses
IGHV种系基因多态性研究及利用
- 批准号:
9009117 - 财政年份:2015
- 资助金额:
$ 123.87万 - 项目类别:
Structural Requirements for Broadly Protecting Antibodies to Influenza A & B
广泛保护甲型流感抗体的结构要求
- 批准号:
8918922 - 财政年份:2014
- 资助金额:
$ 123.87万 - 项目类别:
ANTI-HIV-1 TAT HUMAN SFV INTRABODY GENE THERAPY AGAINST SHIV IN RHESUS MACAQUES
抗 HIV-1 TAT 人类 SFV 体内针对恒河猴 SHIV 的基因治疗
- 批准号:
8357904 - 财政年份:2011
- 资助金额:
$ 123.87万 - 项目类别:
Study of broadly neutralizing antibody generation to HIV gp140 in humanized mice
人源化小鼠体内 HIV gp140 广泛中和抗体生成的研究
- 批准号:
8080503 - 财政年份:2010
- 资助金额:
$ 123.87万 - 项目类别:
Broad Spectrum Neutralizing Human Abs to SARS and Related Coronaviruses
广谱中和人类针对 SARS 和相关冠状病毒的抗体
- 批准号:
7988935 - 财政年份:2010
- 资助金额:
$ 123.87万 - 项目类别:
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