Vaccine Induced Immunity in the Young and Aged

年轻人和老年人的疫苗诱导免疫力

• 批准号: 7828050
• 负责人: Rafi Ahmed
• 金额: $ 330.08万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7828050
• 关键词: Vaccine; Induced; Immunity; Young; Aged

DESCRIPTION (provided by applicant): The present application is a competing renewal of a U19 grant that was awarded in 2003. The stated goals of the original application were threefold: (i) To study the human immune response to a vaccine in its entirety; starting from the innate responses, to the peak effector T and B cell responses, to the development and maintenance of immunologic memory, (ii) To understand how a successful vaccine works, and to use this knowledge for designing strategies for enhancing vaccine efficacy, (iii) To understand the cellular basis of immune senescence and develop strategies for improving responses of the elderly to vaccination. A major emphasis of this proposal was to use genomics to define molecular signatures of a successful vaccine, and to use this knowledge to develop new vaccines against emerging infections. To achieve these goals, we studied one of the most effective human vaccines ever developed, the yellow fever vaccine-17D (YFV-17D) as a model. Our efforts resulted in several important advances, including the elucidation of: (i) the dynamics of antigen-specific T cell responses in humans vaccinated with YFV-17D and smallpox, (ii) innate immune mechamisms by which YFV-17D acts to launch a broad and robust T cell immunity, (iii) genomic signatures capable of predicting the T cell immunogenicity of YFV-17D in humans and (iv) identification of potential molecular defects that underlie the sub-optimal response of aged T cells to vaccination. In this renewal application, we aim to follow up on these exciting observations and to determine the extent to which such responses are unique to YFV-17D relative to other vaccines or viruses. This overall goal will be achieved in three Research Projects: 1. Immune Memory (Ahmed/Boss), 2. Innate Immunity (Pulendran/Rice), 3. Immune Senescence (Goronzy), and a Technology Development Project on Human Monoclonal Antibodies (Wilson/Lanzavecchia). This overall research effort will be supported by an Administrative Core (Ahmed/Ansari), a Clinical Research Core (Mulligan/Chokephaibulkit/Yu) and a Genomics & Computational Biology Core (Haining/Lee). In addition, there will be a program for education of scientists aspiring to do human immunology research, and a mechanism for funding pilot projects in human immunology. RELEVANCE: Vaccination is the most effective means of preventing infectious disease. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. In the present proposal, we aim to understand the immune mechamisms by which a successful vaccine induces long-term protective immunity. PROJECT 1: [IMMUNE MEMORY (Ahmed, R)] PROJECT 1 DESCRIPTION (provided by applicant): Our goal is to understand how a successful vaccine induces long-term immunological memory and protective immunity in humans. To achieve this goal we have initiated a detailed cellular and molecular characterization of human immune responses induced by the yellow fever virus (YFV-17D) vaccine. This is one of our most efficacious vaccines and induces long-term immunity that lasts for decades. Also, since YFV-17D is a live attenuated vaccine and most of the US population is not exposed to YFV-, this provides a unique opportunity to analyze antiviral responses in humans during the course of a primary infection and then to monitor the generation and maintenance of immune memory after resolution of the infection. One of the potential benefits of understanding how a successful vaccine induces long-term protective immunity is that this knowledge can be applied to improving other less effective vaccines and, more importantly, to develop new vaccines against emerging diseases. During the previous cycle of funding we have made substantial progress in characterizing human memory T and B cell responses not only to YFV but also after immunization with small pox and influenza vaccines. In this renewal application we will focus our studies on CD8 T cells and examine the mechanisms that regulate human effector and memory CD8 T cell differentiation. The following specific aims are proposed to achieve our goals: 1) To identify transcription factors that regulate naive to effector CD8 T cell differentiation. 2) To analyze the in vivo turnover of human YFV specific CD8 T cells and to examine their homing potential. 3) To define the genomic and epigenetic changes that occur during human memory CD8 T cell differentiation. These studies will provide the first view of the transcriptional changes that occur following CD8 T cell differentiation in humans and will provide unique markers that will enable identification, isolation, and characterization of the differentiated cell subsets. Examination of the epigenetic DMA methylation marks during the progression of the T cell response, as well as between CD8 T cells responding to acute versus chronic viral infections will provide a potential mechanistic view of how memory CD8 T cell differentiation is globally regulated. RELEVANCE: YFV-17D is an ideal model to study memory T cell generation in the context of an acute viral infection. The underlying importance of this study is that the longitudinal analysis of YFV specific CD8 T cells in vaccinees, offers a unique opportunity to track differentiation of highly functional and long-lived human memory CD8 T cells and generate a signature that may be a benchmark for other vaccines.

描述（由申请人提供）：本申请是2003年授予的U19赠款的竞争续签。原始申请的既定目标是三倍：（i）研究人类对疫苗的免疫反应；从先天反应到峰值效应t和b细胞反应，再到免疫记忆的开发和维护，（ii），以了解成功的疫苗如何起作用，并利用这些知识来设计策略来增强疫苗功效，（III），以了解免疫递减的细胞基础，以了解以提高接力量的策略。该提案的主要重点是使用基因组学来定义成功疫苗的分子特征，并使用这些知识来开发针对新兴感染的新疫苗。为了实现这些目标，我们研究了有史以来开发的最有效的人类疫苗之一，即黄热疫苗17D（YFV-17D）作为模型。 Our efforts resulted in several important advances, including the elucidation of: (i) the dynamics of antigen-specific T cell responses in humans vaccinated with YFV-17D and smallpox, (ii) innate immune mechamisms by which YFV-17D acts to launch a broad and robust T cell immunity, (iii) genomic signatures capable of predicting the T cell immunogenicity of YFV-17D in人类和（iv）鉴定潜在的分子缺陷，这些缺陷是老化T细胞对疫苗接种的亚地区反应的基础。在此续订应用中，我们的目标是跟进这些令人兴奋的观察结果，并确定YFV-17D相对于其他疫苗或病毒的YFV-17D独特的程度。这一总体目标将在三个研究项目中实现：1。免疫记忆（Ahmed/Boss），2。先天免疫（Pulendran/Rice），3。免疫衰老（Goronzy）和人类单克隆抗体的技术开发项目（Wilson/Lanzavecchia）。这项整体研究工作将由行政核心（Ahmed/Ansari），临床研究核心（Mulligan/Chokephaibulkit/YU）和基因组学与计算生物学核心（Haining/Lee）支持。此外，还将有一个计划进行人类免疫学研究的科学家教育计划，以及为人类免疫学中试点项目提供资金的机制。 相关性：疫苗接种是预防传染病的最有效手段。尽管许多疫苗成功，但目前对介导其功效的免疫机制知之甚少。这些信息对于针对新旧传染病的未来疫苗设计至关重要。在本提案中，我们旨在了解成功的疫苗可诱导长期保护性免疫的免疫机制。 项目1：[免疫记忆（Ahmed，R）] 项目1描述（由申请人提供）：我们的目标是了解成功的疫苗如何诱导人类的长期免疫记忆和保护性免疫。为了实现这一目标，我们启动了通过黄热病病毒（YFV-17D）疫苗引起的人类免疫反应的细胞和分子表征。这是我们最有效的疫苗之一，并诱发了持续数十年的长期免疫力。同样，由于YFV-17D是一种活的疫苗，并且大多数美国人群不暴露于YFV-，因此在原发性感染过程中，这为分析人类的抗病毒药反应提供了独特的机会，然后监测感染后免疫记忆的产生和维持。了解成功疫苗如何诱导长期保护性免疫的潜在好处之一是，可以将这些知识用于改善其他较不效率较低的疫苗，更重要的是，可以开发针对新兴疾病的新疫苗。在上一个资金周期中，我们在表征人类记忆T和B细胞反应的表征不仅对YFV，而且在用小痘和流感疫苗免疫后取得了重大进展。在此续签应用中，我们将把研究重点放在CD8 T细胞上，并检查调节人体效应子和记忆CD8 T细胞分化的机制。提出了以下特定目的来实现我们的目标：1）确定调节源于效应子C​​D8 T细胞分化的转录因子。 2）分析人类YFV特异性CD8 T细胞的体内周转率并检查其归巢潜力。 3）定义人记忆中CD8 T细胞分化过程中发生的基因组和表观遗传变化。这些研究将提供对人类CD8 T细胞分化后发生的转录变化的第一视图，并将提供独特的标记，以鉴定，隔离和表征分化的细胞子集。检查T细胞反应进展过程中表观遗传学DMA甲基化标记，以及响应急性病毒感染与慢性病毒感染的CD8 T细胞之间的检查将提供潜在的机械性观点，即记忆CD8 T细胞分化如何受到全局调节。 相关性：YFV-17D是在急性病毒感染中研究记忆T细胞产生的理想模型。这项研究的根本重要性是，疫苗中YFV特异性CD8 T细胞的纵向分析提供了一个独特的机会，可以跟踪高度功能和长寿的人类记忆CD8 T细胞的区分，并产生可能是其他疫苗的基准的签名。