Vaccine Induced Immunity in the Young and Aged

描述（由申请人提供）：目前的申请是2003年颁发的U19补助金的竞争性续期。最初申请的既定目标有三个：(i)全面研究人体对疫苗的免疫反应；从先天反应开始，到T和B细胞反应的峰值，到免疫记忆的发展和维持，（ii）了解成功的疫苗是如何起作用的，并利用这些知识设计增强疫苗效力的策略，（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利用基因组学来确定成功疫苗的分子特征，并利用这些知识开发针对新发感染的新疫苗。为了实现这些目标，我们研究了迄今为止开发的最有效的人类疫苗之一，黄热病疫苗- 17d （YFV-17D）作为模型。我们的努力取得了若干重要进展，包括阐明：(i)接种了YFV-17D和天花疫苗的人体内抗原特异性T细胞反应的动力学，（ii） YFV-17D启动广泛而强大的T细胞免疫的先天免疫机制，（iii）能够预测YFV-17D在人体内的T细胞免疫原性的基因组特征，以及（iv）识别衰老T细胞对疫苗接种的次优反应的潜在分子缺陷。在这项更新申请中，我们的目标是跟进这些令人兴奋的观察结果，并确定相对于其他疫苗或病毒，YFV-17D的这种反应在多大程度上是独特的。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/Rice）， 3。免疫衰老（Goronzy）和人类单克隆抗体技术开发项目（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）提供支持。此外，还将有一个培养有志从事人体免疫学研究的科学家的计划，以及一个资助人体免疫学试点项目的机制。

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.