Attenuated Live and Recombinant Yersinia Pestis Vaccines

描述(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。由于鼠疫不能过腐生的生活，并且在许多啮齿动物种群中居住，鼠疫是由一种专性的动物-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年前就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，我们建议：(I)构建和评价口服免疫小鼠后体内合成鼠疫杆菌Kim抗原的重组减毒鼠伤寒沙门氏菌疫苗(RASV)，以识别能够刺激对所有三种人类致病性耶尔森菌(包括强毒鼠疫菌CO92)的保护性免疫的抗原或抗原组合。(Ii)构建和鉴定重组减毒副伤寒沙门氏菌，以携带多种保护性鼠疫菌Kim抗原。如果发现需要不同的抗原传递方式来诱导对鼠疫挑战的保护性免疫，我们将构建所有被认为必要的重组疫苗，作为鸡尾酒接种。(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，以获得FDA的IND许可证，制作母种并验证其稳定性。我们还将开发我们的主文件，准备和充分描述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身上进行临床评估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。 与公共卫生相关：在美国，目前没有获得许可的疫苗来预防鼠疫。我们正在开发重组减毒沙门氏菌活疫苗，用于运送多种抗原，以预防所有耶尔森氏菌的致病物种，包括鼠疫的病原体--鼠疫耶尔森菌。我们将确定最佳候选疫苗，并准备所有必要的材料和数据，以支持在第一阶段临床试验中对其进行测试。

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.