Attenuated Live and Recombinant Yersinia Pestis Vaccines

减毒活疫苗和重组鼠疫耶尔森氏菌疫苗

• 批准号: 8074038
• 负责人: ROY CURTISS III
• 金额: $ 37.74万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074038
• 关键词: Accounting; Animals; Antibody Formation; Antigens; Area; Attenuated; Bacillus (bacterium); Biological; Blood; Cessation of life; Chromosomes; Clinical Trials; Data; Disease; Evaluation; Feces; Fright; Grant; Human; Human Volunteers; Immunity; Immunization; Immunosuppression; Individual; Infection; Institutional Review Boards; Interleukin-10; Lead; Legal patent; Licensing; Life; Membrane Proteins; Mus; Operon; Oral; Organism; Outcome; Pasteurella pseudotuberculosis; Phase I Clinical Trials; Plague; Plasmid Cloning Vector; Plasmids; Plasminogen; Population; Property; Protocols documentation; Recombinant Vaccines; Recombinants; Research Support; Rodent; Safety; Salmonella Vaccines; Salmonella paratyphi; Salmonella typhimurium; Secure; Seeds; Serum; Specific qualifier value; Testing; Typhoid Fever; United States; Vaccines; Virulent; Work; Yersinia; Yersinia enterocolitica; Yersinia infections; Yersinia pestis; design and construction; immunogenicity; in vivo; mutant; pandemic disease; pathogen; prevent; public health relevance; research study; residence; vaccine candidate; vaccine delivery; weapons

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.

描述（由申请人提供）：三种大流行病的耶尔森尼亚鼠尾草导致了大约2亿张鼠疫死亡，并且在世界范围内仍然流行，导致零星的感染。由于无法过腐生生命及其在许多啮齿动物种群中的住所，因此瘟疫是最担心的对人的人畜共患病疾病的恐惧之一。至少在800年前，瘟疫开始被用作生物武器，如今已成为最可能的生物威胁之一。由于这些考虑因素，我们建议：（i）构建和评估重组鼠伤寒沙门氏菌疫苗（RASV）合成Y. pestis kim抗原在体内口服后，小鼠的体内免疫以鉴定抗原或抗原的组合，抗原抗原的抗原，促进三种人类质量的抗原，包括三种蛋白质的蛋白质蛋白质质量。 （ii）构建和评估重组链球菌A的重组，以提供多种保护性鼠疫杆菌Kim抗原。如果发现需要不同的抗原递送模式以诱导Y.柴油挑战的保护性免疫，我们将建造所有被认为是必要的重组疫苗，以作为鸡尾酒给予。 （iii）进行实验以建立所有安全性，有效性和免疫原性特征，并提供数据以从FDA获得IND许可证，制造主种子并验证其稳定性。我们还将开发我们的主文件，准备并充分表征候选疫苗主种子以稳定和安全，准备IRB批准的协议，提交必要的信息以获取IND，并执行任何其他工作，以安排在人类志愿者中对临床评估的最佳候选疫苗进行临床评估。我们将在拟议的临床试验期间提供研究支持。 公共卫生相关性：目前尚无持牌疫苗可以防止美国疾病。我们正在开发活的重组衰减的沙门氏菌疫苗，用于递送多种抗原，以防止耶尔森氏菌的所有病原体，包括鼠疫的耶尔森氏菌，鼠疫的病因。我们将确定最佳疫苗候选者，并准备所有必要的材料和数据，以支持在I期临床试验中对其进行测试。