Genetically-Programmed APC Vaccines Against Viruses

描述(申请人提供)：在R21基金(AI49771：转基因B细胞免疫原)的支持下，我们以甲型流感病毒为模型系统，开发了一种基于抗原提呈细胞(APC)的疫苗。对CD8T细胞记忆反应的研究表明，高表达CD62L的CD8T细胞介导了保护作用。这些细胞被称为中央记忆T细胞。这一关于体内保护相关性的发现现在被认为是一项新实验的基础，该实验旨在了解通过接种疫苗诱导保护性记忆CD8 T细胞的要求。我们想要检验的假设是，成功的中央记忆CD8 T细胞诱导的APC基因疫苗编程可能受到一系列一般性质的考虑，如剂量和引发与病原体相遇的间隔时间，与环境的相互作用，如树突状细胞和IL-15，以及CD62L作为签名基因的关键表型特征的存在。 我们的目标是进一步利用新开发的APC疫苗接种系统作为原理证明，以了解针对3型病毒病原体产生保护性中央记忆CD8T细胞的要求。我们研究的重要性还在于，新的疫苗接种方法虽然建立在疫苗接种的基本公理--免疫--&gt；保护的基础上，但目的是诱导对疾病的保护，从而为以疫苗为导向的旧的或新出现的传染病的控制设定新的目标。我们相信，我们的研究将对开发一种替代方法，使用新的APC疫苗方法有效地接种甲型流感病毒具有重要意义。

DESCRIPTION (provided by applicant): Under the aegis of an R21 grant (AI49771: Transgenic B cell immunogens), we developed an antigen-presenting cell (APC)-based vaccine using the influenza A virus as a model system. Studies focused on CD8 T cell memory responses revealed that protection is mediated by CD8 T cells with high CD62L expression. These are referred to as central memory T cells. This finding on the correlate of protection in vivo is now proposed as the basis for a new experiment to understand the requirements to induce protective memory CD8 T cells by vaccination. The hypothesis we wish to test is that successful programming by a genetic APC vaccine of central memory CD8 T cell induction may be subject to a series of considerations of general nature such as dose and interval between priming and encounter with the pathogen, the interaction with the environment such as dendritic cells and IL-15, and the presence of CD62L as a key phenotypic feature of the signature gene. Our objective is to further use the newly developed APC vaccination system as a proof of principle to understand the requirements for the generation of protective central memory CD8 T cells against a category 3 viral pathogen. The importance of our studies is also that the new vaccination approach while built on the cardinal axiom Vaccination--> Immunity--> Protection is intended at inducing protection against disease, hence setting a new target for vaccine-directed control of old or emerging infectious diseases. We believe that our studies will have implications in the development of an alternative approach to effectively vaccinate against influenza A virus using novel APC vaccine approach.