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造成约2亿人死亡，并且仍然在世界各地流行，造成零星感染。由于鼠疫不能腐生，并且在许多啮齿动物种群中存在，它是由动物-人类专性病原体引起的最令人恐惧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，而今天它是一种更有可能的生物威胁。基于这些考虑，我们建议：(1)在小鼠口服免疫后，构建并评估重组减毒鼠伤寒沙门菌疫苗（RASV），在体内合成鼠疫耶尔森菌KIM抗原，以鉴定抗原或抗原组合，刺激对所有三种人类致病性耶尔森菌的保护性免疫，包括致病性鼠疫耶尔森菌CO92。（ii）构建并评估重组减毒甲型副伤寒沙门氏菌，以传递多种具有保护作用的鼠疫杆菌KIM抗原。如果发现需要不同的抗原递送模式来诱导对鼠疫杆菌的保护性免疫，我们将构建所有被认为必要的重组疫苗作为鸡尾酒给药。（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，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，并执行任何其他必要的工作，以安排最佳候选疫苗在人类志愿者中进行临床评估。我们将在拟议的临床试验期间提供研究支持。

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.