Plague vaccine candidates by a functional genomic screen

通过功能基因组筛选候选鼠疫疫苗

• 批准号: 6555454
• 负责人: KATHRYN Frances SYKES
• 金额: $ 13.38万
• 依托单位: ELIANCE BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-06 至 2003-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555454
• 关键词: Yersinia pestis disease; bacterial antigens; bacterial vaccines; bioterrorism /chemical warfare; functional /structural genomics; gene dosage; gene expression; genetic library; genetic screening; informatics; molecular biology information system; vaccine development; vector vaccine

DESCRIPTION (provided by applicant): The long-term objective of our work is to produce a comprehensive set of vaccines that would effectively protect a large population against even genetically-engineered pathogens. The immediate objective of the proposal described here is to screen the whole genome of Yersinia pestis for the most potent vaccine candidates. Plague is a significant target for at least two reasons. 1) It is an extremely virulent, often lethal disease that has been suffered by humans since antiquity. 2) There is an immediate need to produce a broadly effective, safe, and inexpensive vaccine to counter the threat of bioterrorism. The immunogenic simplicity of a subunit vaccine currently under study may limit its ability to protect the diverse human population, and may render it ineffectual against a genetically-modified pathogen. Our phase I specific aims are to i) establish the informatics required to support a technically demanding, functional screen of the entire Y. pestis genome for protective antigens, ii) identify protocols for producing a complete Y. pestis gene library iii) define the optimal gene dose and design for this genome screen by testing Y. pestis genes in immune and protection assays. Our experimental approach combines three of our technologies: genetic immunization, expression library screening, and linear gene expression elements. In phase II we will apply this system to evaluate every Y. pestis gene as a PCR product in an arrayed matrix for protection of mice against infection. Positively scoring genes will constitute a portfolio of antigenic options to protect a broad population against natural and unnatural Y. pestis infections. In addition to identifying the components for a future vaccine, these protective antigens will reveal immune markers of protection, and thereby facilitate clinical validation of these as well as other potential plague vaccines.

描述（由申请人提供）：我们工作的长期目标是生产一套全面的疫苗，即使是基因工程病原体也能有效保护大量人群。 这里所描述的建议的直接目标是筛选鼠疫耶尔森氏菌的全基因组，以寻找最有效的候选疫苗。 鼠疫是一个重要的目标，至少有两个原因。1)这是一种极其致命的疾病，自古以来就一直困扰着人类。2)迫切需要生产广泛有效、安全和廉价的疫苗来应对生物恐怖主义的威胁。 目前正在研究的亚单位疫苗的免疫原性简单性可能限制其保护不同人群的能力，并可能使其对转基因病原体无效。 我们第一阶段的具体目标是i）建立支持整个Y的技术要求高的功能屏幕所需的信息学。鼠疫菌基因组的保护性抗原，ii）确定用于产生完整的Y.鼠疫菌基因文库iii）确定最佳基因剂量并通过测试Y.免疫和保护试验中的鼠疫基因。我们的实验方法结合了我们的三种技术：基因免疫，表达文库筛选和线性基因表达元件。 在第二阶段，我们将应用这个系统来评估每个Y。pestis基因作为PCR产物在阵列矩阵中用于保护小鼠免受感染。 阳性评分基因将构成一个抗原选择组合，以保护广泛的人口对自然和非自然的Y。鼠疫感染 除了确定未来疫苗的成分外，这些保护性抗原还将揭示保护的免疫标记，从而促进这些以及其他潜在鼠疫疫苗的临床验证。