Attenuated Live and Recombinant Yersinia Pestis Vaccines

描述（由申请人提供）：鼠疫耶尔森氏菌在三次大流行中导致约2亿人死亡，目前仍在世界各地流行，导致零星感染。由于鼠疫不能过上嗜血的生活，并且在许多啮齿动物种群中存在，因此鼠疫是由专性动物-人类病原体引起的最可怕的人畜共患疾病之一。鼠疫杆菌至少在800年前开始被用作生物武器，今天是最有可能的生物威胁之一。基于这些考虑，我们提出：（i）构建和评价合成Y.鼠疫KIM抗原，以鉴定刺激针对所有三种人类致病性耶尔森氏菌物种（包括毒性耶尔森氏菌）的保护性免疫的抗原或抗原组合。鼠疫CO 92。(ii)重组减毒沙门氏菌的构建及鉴定。甲型副伤寒可提供多种保护性Y。鼠疫KIM抗原。如果发现诱导对Y的保护性免疫需要不同的抗原递送模式。鼠疫的挑战，我们将构建所有被认为必要的重组疫苗作为鸡尾酒施用。(iii)进行实验以确定所有安全性、有效性和免疫原性特征，并提供数据以确保获得FDA的IND许可，制作主种子并验证其稳定性。我们还将开发我们的主文件，准备和充分表征候选疫苗主种子的稳定性和安全性，准备和提交IRB批准的方案，提交获得IND所需的信息，并执行安排最佳候选疫苗在人类志愿者中进行临床评价所需的任何其他工作。我们将在拟议的临床试验期间提供研究支持。 公共卫生相关性：目前在美国没有获得许可的疫苗来预防鼠疫。我们正在开发用于递送多种抗原的活重组减毒沙门氏菌疫苗，以保护免受耶尔森氏菌的所有致病物种的侵害，包括鼠疫耶尔森氏菌，鼠疫的病原体。我们将确定最佳候选疫苗，并准备所有必要的材料和数据，以支持在I期临床试验中进行测试。

DESCRIPTION (provided by applicant): Yersinia pestis, in three pandemics, resulted in some 200 million plague deaths and is still endemic throughout the world resulting in sporadic infections. Due to its inability to lead a saprophytic life and its residence in many rodent populations, plague is one of the most feared of zoonotic diseases caused by an obligate animal-human pathogen. The plague bacillus began to be used as a biological weapon at least 800 years ago and is today one of the more likely biological threats. Because of these considerations, we propose to: (i) Construct and evaluate recombinant attenuated Salmonella Typhimurium vaccines (RASV) synthesizing Y. pestis KIM antigens in vivo after oral immunization of mice to identify antigens or combinations of antigens that stimulate protective immunity against all three human pathogenic Yersinia species, including virulent Y. pestis CO92. (ii) Construct and evaluate a recombinant attenuated S. Paratyphi A to deliver multiple protective Y. pestis KIM antigens. If it is found that different antigen delivery modes are required to induce protective immunity to Y. pestis challenge, we will construct all deemed necessary recombinant vaccines to be administered as a cocktail. (iii) Conduct experiments to establish all safety, efficacy and immunogenicity features and provide data to secure an IND license from the FDA, make Master Seeds and validate their stability. We will also develop our Master File, prepare and fully characterize candidate vaccine Master Seeds for stability and safety, prepare and submit protocols for IRB approvals, submit information necessary to obtain INDs, and perform any other work needed to arrange that the best candidate vaccines be clinically evaluated in human volunteers. We will provide research support during the proposed clinical trials. PUBLIC HEALTH RELEVANCE: There is currently no licensed vaccine to protect against plague in the United States. We are developing live recombinant attenuated Salmonella vaccines for delivery of multiple antigens to protect against all pathogenic species of Yersinia, including Yersinia pestis, the causative agent of plague. We will identify the optimal vaccine candidate and prepare all necessary materials and data to support testing it in a Phase I clinical trial.