Multi-gene Subunit Vaccine Platform Against Y. pestis

描述(由申请人提供)：本申请的总体目标是开发改进的鼠疫疫苗。我们的建议是基于我们在鼠疫疫苗研究方面的最新进展而制定的，包括1。使用DNA免疫方法寻找额外的保护性抗原和2.)细胞免疫应答在保护鼠疫杆菌感染中的发现。对当前提议的支持将使我们能够开发一个独特的技术平台，将抗原发现、疫苗配方优化和基于亚单位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：继续利用DNA免疫作为筛选额外的鼠疫保护性抗原的工具，包括对单个候选抗原的研究，以及对缺乏优势抗原LcrV和F1的特殊鼠疫菌株免疫的动物血清的高通量筛选。这种方法利用了新构建的鼠疫杆菌表达文库和蛋白质微阵列技术。 具体目的2：研究提高鼠疫疫苗保护效果的重要细胞免疫学机制，包括使用DNA素加蛋白质增强的方法来提高亚单位鼠疫疫苗诱导的保护性抗体反应的水平和寿命。 具体目标3：在非人类灵长类动物中进行晚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DNA输送装置进行临床研究做准备，该装置已被证明在人类中有效。 通俗易懂的语言摘要：这项研究旨在生产针对鼠疫的有效生物防御疫苗，鼠疫是一种导致鼠疫的高致命性细菌，这种感染有可能导致高比例的人类死亡。这项研究是广泛的生物防御努力的一部分，目的是防止此类毒剂被用于生物恐怖主义目的。

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.