Restimulating memory T cell responses in elderly by a novel, live influenza vaccine

通过新型活流感疫苗重新刺激老年人的记忆 T 细胞反应

• 批准号: 9408434
• 负责人: Pamuk Bilsel
• 金额: $ 74.63万
• 依托单位: FLUGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408434
• 关键词: Accounting; Affect; Age; Aging; Aging-Related Process; Animals; Antibody Response; Antibody titer measurement; Antigen-Presenting Cells; Antiviral Agents; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Chronic Disease; Clinical; Clinical Research; Data; Defect; Dendritic Cells; Disease; Down-Regulation; Elderly; Epitopes; Exhibits; Failure; FluMist; Gene Expression; Gene Expression Regulation; Genes; Hospitalization; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunotherapeutic agent; Impairment; In Vitro; Inactivated Vaccines; Individual; Infection; Inflammasome; Inflammation; Inflammatory Response; Influenza; Influenza A virus; Influenza prevention; Innate Immune Response; Interferon Type I; Interferons; Interleukin-1; Interleukin-18; Intervention; Ion Channel; Lung diseases; M2 protein; Mediating; Memory; Methods; Molecular; Morbidity - disease rate; Natural Immunity; Outcome; Pathologic; Pathway interactions; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Population; Predisposition; Production; Receptor Signaling; Research; Respiratory Tract Infections; Retinoic Acid Receptor; Risk; Sampling; Signal Transduction; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tretinoin; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral Load result; Virus; Virus Diseases; Vulnerable Populations; Work; adaptive immune response; adaptive immunity; age group; aged; cytokine; disability; experimental study; flu; genetic signature; human old age (65+); human subject; immune function; immunogenicity; immunosenescence; improved; in vivo; influenza virus vaccine; influenzavirus; insight; monocyte; mortality; novel; prevent; protein expression; response; transcriptome; vaccine candidate; vaccine response

Respiratory infections with influenza viruses cause severe morbidity and mortality in humans and animals worldwide. Importantly, in humans, the majority of morbidity and mortality following flu infection is seen in older individuals (> 65 years old). Yet, clear understanding of how aging impacts on innate immune responses, and how to improve vaccine design in this age group is lacking. Restimulating preexisting memory T cells against conserved epitopes in influenza virus by a vaccine might confer protective immunity in this age group. An ideal vaccine for elderly should therefore engage pattern recognition receptors (PRRs) that activate antigen-presenting cells (APCs), generate conserved antigenic epitopes, while avoiding overt inflammatory responses. In Phase I, we showed that M2SR virus results in robust restimulation of memory CD4 and CD8 T cells in older humans without causing pathological inflammation by engaging non-inflammasome dependent innate pathways. In this Phase II proposal, we will explore how M2SR stimulates antiviral immune responses in older subjects in the following aims: Aim 1. Examine dendritic cell survival and function in response to M2SR infection. Aim 2: Determine the molecular mechanism of interferon stimulated gene expression regulation in dendritic cells. Aim 3: Evaluate the early immune response in human subjects vaccinated with M2SR. These experiments are aimed at improving protection of older humans from influenza-mediated disease, by understanding the fundamental innate immune defects that contribute to failure to mount protective immunity. The outcome of the experiments is expected to have high impact, both with respect to the fundamental understanding of the underlying mechanism of flu-related illnesses in the susceptible elderly population, and in providing a basis with which to design vaccine and immunotherapeutic interventions.

流感病毒引起的呼吸道感染导致人类严重发病和死亡 世界各地的动物。重要的是，在人类中，流感后的大部分发病率和死亡率 感染常见于老年人（> 65 岁）。然而，清楚地了解衰老是如何发生的 对先天免疫反应的影响，以及如何改进这个年龄段的疫苗设计 缺乏。重新刺激先前存在的记忆 T 细胞对抗流感病毒的保守表位 疫苗可能会为这个年龄段的人带来保护性免疫力。适合老年人的理想疫苗应该 因此，激活抗原呈递细胞的模式识别受体（PRR） （APC），产生保守的抗原表位，同时避免明显的炎症反应。在 第一阶段，我们证明 M2SR 病毒会导致记忆 CD4 和 CD8 T 的强烈再刺激 老年人体内的细胞不会通过参与非炎症小体而引起病理性炎症 依赖的先天途径。在此第二阶段提案中，我们将探讨 M2SR 如何刺激 老年受试者的抗病毒免疫反应的目的如下： 目标 1. 检查树突状细胞对 M2SR 感染的存活和功能。 目标2：确定干扰素刺激基因表达调控的分子机制 在树突状细胞中。 目标 3：评估接种 M2SR 疫苗的人类受试者的早期免疫反应。 这些实验旨在加强对老年人的保护，使其免受流感介导的侵害 疾病，通过了解导致失败的基本先天免疫缺陷 安装保护免疫力。实验结果预计将产生重大影响， 两者都涉及对流感相关潜在机制的基本了解 易感老年人群的疾病，并为设计提供基础 疫苗和免疫治疗干预措施。