Multi-gene Subunit Vaccine Platform Against Y. pestis

描述（由申请方提供）：本申请的总体目标是开发改良鼠疫疫苗。我们的建议是根据我们最近在鼠疫疫苗研究方面的进展制定的，其中包括1。使用DNA免疫方法来寻找额外的保护性抗原，以及2.）发现细胞介导的免疫应答在保护Y.鼠疫感染对当前提案的支持将使我们能够开发一个独特的技术平台，该平台可以将抗原发现、疫苗配方优化和基于亚基的多基因鼠疫疫苗的高效无针皮内递送结合到一个系统中。 具体目标1：为了继续利用DNA免疫作为筛选鼠疫保护性抗原的工具，包括单个候选抗原的研究和高通量筛选用特异性Y.优势抗原LcrV和F1缺陷的鼠疫菌株。这种方法利用了新构造的Y的可用性。鼠疫菌表达文库和蛋白质微阵列技术。 具体目标二：研究提高鼠疫疫苗保护效力的重要细胞免疫学机制，包括使用DNA初免加蛋白加强的方法来提高亚单位鼠疫疫苗诱导的保护性抗体应答的水平和寿命。 具体目标3：在非人灵长类动物中进行后期临床前免疫原性和保护性研究，为使用优化的鼠疫疫苗配方和已在人体中证明有效的DNA递送装置进行临床研究做准备。 简单，通俗的语言总结：这项研究的目的是生产有效的生物防御疫苗对Y。鼠疫是一种引起鼠疫的高致命性细菌，这种感染有可能导致很高比例的人类死亡。这项研究是广泛的生物防御努力的一部分，以防止这些代理人，如果他们被用于生物恐怖主义的目的。

DESCRIPTION (provided by applicant): The overall goal of this application is to develop improved plague vaccines. Our proposal was developed based on our recent progress in plague vaccine studies which includes 1.) the use of a DNA immunization approach to search for additional protective antigens and 2.) the discovery of cell mediated immune responses in the protection of Y. pestis infection. Support for the current proposal will allow us to develop a unique technological platform which can combine antigen discovery, optimization of vaccine formulation, and efficient needle free intradermal delivery of subunit-based multi-gene plague vaccines into one system. Specific Aim 1: To continue our work using DNA immunization as a tool to screen for additional protective antigens against plague, including both the study of individual candidate antigens and the high throughput screening of animal sera which has been immunized with specialized Y. pestis strains deficient for the dominant antigens LcrV and F1. This approach exploits the availability of a newly constructed Y. pestis expression library and protein microarray techniques. Specific Aim 2: To study the cellular immunological mechanisms that are important for improving the protective efficacy of plague vaccines which includes the use of the DNA prime plus protein boost approach to increase the level and longevity of protective antibody responses induced by subunit plague vaccines. Specific Aim 3: To conduct late-phase preclinical immunogenicity and protection studies in non-human primates to prepare for a clinical study with optimized plague vaccine formulation and DNA delivery device that has been proven effective in humans. Plain, lay language summary: This study is designed to produce effective biodefense vaccines against Y. pestis, the highly lethal bacteria that causes plague, an infection that has the potential to cause a high percentage of human fatalities. This study is part of the broad biodefense effort to protect against such agents if they were to be used for bioterrorism purposes.