TB VACCINE DEVELOPMENT IN NONHUMAN PRIMATE MODEL

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 超过20亿人，占世界人口的三分之一，感染了结核分枝杆菌。每年有300万人死于结核病。随着大量使用抗生素，特别是在艾滋病患者中，导致结核分枝杆菌产生抗药性菌株，公共卫生问题正在加剧。现有的疫苗有严重的局限性。该项目正在比以前更详细地确定恒河猴对结核分枝杆菌感染的免疫反应，以及疾病的病理发展。当确定了结核病的免疫相关因素后，热休克蛋白65(Hsp65)的配方和含有hsp65 DNA序列的质粒将与免疫刺激蛋白一起包裹在微球中，并作为疫苗进行测试。其基本原理是，质粒会迅速离开微球，整合到宿主DNA中，并产生hsp65，作为免疫原。随后，hsp65蛋白将被缓慢释放长达60天，作为加强免疫的抗原。根据之前在小鼠身上进行的实验，该疫苗预计将具有预防活性，并能够刺激比已经感染结核分枝杆菌的人的正常免疫反应更有效的免疫反应，从而降低疾病的严重性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. More than 2 billion people, one-third of the world's population, are infected with Mycobacterium tuberculosis. Three million people die each year of TB. The public health problem is intensifying as the heavy use of antibiotics, particularly in AIDS patients, is leading to antibiotic resistant strains of M. tuberculosis. Existing vaccines have serious limitations. This project is determining the immunological responses of rhesus monkeys to M. tuberculosis infection, and the pathological development of disease, in more detail than has been done previously. When the immune correlates of TB have been well defined, a formulation of heat shock protein 65 (hsp65) and a plasmid containing the hsp65 DNA sequence will be encapsulated together with an immunostimulatory protein in microspheres, and tested as a vaccine. The rationale is that the plasmid will quickly exit the microspheres, integrate into host DNA, and produce hsp65, which will serve as an immunogen. Later, the hsp65 protein will be slowly released for up to 60 days, serving as antigen for a booster immunization. Based on prior experiments with mice, the vaccine is expected to have prophylactic activity and also to be capable of stimulating a more effective immune response than is normal in people who already are infected with M. tuberculosis, thereby reducing the severity of disease.