Vaccine Induced Immunity in the Young and Aged

描述(由申请人提供)：本申请是2003年授予的U19奖学金的竞争性续期。最初申请的目标有三个：(I)全面研究人类对疫苗的免疫反应；从先天反应、最高效应者T细胞和B细胞反应开始，到免疫记忆的发展和维持；(Ii)了解成功的疫苗是如何工作的，并利用这些知识设计提高疫苗效力的策略；(Iii)了解免疫衰老的细胞基础，并制定改善老年人对疫苗接种反应的策略。这项建议的一个主要重点是使用基因组学来定义成功疫苗的分子签名，并利用这一知识来开发针对新出现的感染的新疫苗。为了实现这些目标，我们研究了有史以来最有效的人类疫苗之一--黄热病疫苗-17D(YFV-17D)作为模型。我们的努力取得了一些重要进展，包括阐明了：(I)接种YFV-17D和天花疫苗的人中抗原特异性T细胞反应的动态，(Ii)YFV-17D启动广泛而强大的T细胞免疫的天然免疫机制，(Iii)能够预测YFV-17D在人类中的T细胞免疫原性的基因组特征，以及(Iv)确定导致老龄T细胞对疫苗的次优反应的潜在分子缺陷。在这次更新申请中，我们的目标是跟踪这些令人兴奋的观察结果，并确定与其他疫苗或病毒相比，YFV-17D的这种反应是独一无二的。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/莱斯)，3.免疫衰老(Goronzy)，以及人类单抗技术开发项目(Wilson/Lanzavecchia)。这一总体研究工作将得到一个行政核心(Ahmed/Ansari)、一个临床研究核心(Mulrigan/ChokephaiBulkit/Yu)和一个基因组学与计算生物学核心(Haining/Lee)的支持。此外，还将有一个对有志于进行人类免疫学研究的科学家进行教育的计划，以及一个资助人类免疫学试点项目的机制。 相关性：接种疫苗是预防传染病的最有效手段。尽管许多疫苗取得了成功，但目前对调节其疗效的免疫学机制知之甚少。这些信息将在未来针对新旧传染病的疫苗设计中发挥关键作用。在目前的提案中，我们的目标是了解成功的疫苗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)：我们的目标是了解一种成功的疫苗是如何在人类中诱导长期免疫记忆和保护性免疫的。为了实现这一目标，我们已经开始对黄热病病毒(YFV-17D)疫苗诱导的人类免疫反应进行详细的细胞和分子表征。这是我们最有效的疫苗之一，可以诱导持续数十年的长期免疫。此外，由于YFV-17D是一种减毒活疫苗，而且大多数美国人都没有接触YFV-，这提供了一个独特的机会来分析人类在初次感染过程中的抗病毒反应，然后监测感染消除后免疫记忆的产生和维持。了解一种成功的疫苗如何诱导长期保护性免疫的潜在好处之一是，这种知识可以用于改进其他效果较差的疫苗，更重要的是，可以开发针对新出现的疾病的新疫苗。在前一个供资周期中，我们不仅在确定人类记忆T和B细胞对YFV的反应方面取得了实质性进展，而且在接种天花和流感疫苗后也取得了实质性进展。在这次更新应用中，我们将重点研究CD8 T细胞，并探讨调节人类效应性和记忆性CD8 T细胞分化的机制。为了实现我们的目标，我们提出了以下具体目标：1)寻找调节NAIVE的转录因子，以影响CD8 T细胞的分化。2)分析YFV特异性CD8T细胞在体内的周转情况，并检测其归巢潜能。3)明确人类记忆CD8 T细胞分化过程中发生的基因组和表观遗传学变化。这些研究将提供人类CD8 T细胞分化后发生的转录变化的第一个视角，并将提供独特的标记，使识别、分离和鉴定分化的细胞亚群成为可能。检测T细胞反应过程中表观遗传的DMA甲基化标记，以及CD8 T细胞对急性和慢性病毒感染的反应，将提供一个潜在的机制观点，了解记忆CD8 T细胞分化是如何受到全球调控的。 相关性：YFV-17D是研究急性病毒感染背景下记忆T细胞生成的理想模型。这项研究的潜在重要性在于，对YFV特异性CD8T细胞在接种者中的纵向分析，提供了一个独特的机会来追踪高功能和长寿命的人类记忆CD8T细胞的分化，并产生一个可能成为其他疫苗基准的特征。

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.