TB VACCINE DEVELOPMENT IN NONHUMAN PRIMATE MODEL

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 超过20亿人，即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。随着抗生素的大量使用，特别是在艾滋病患者中，导致M.结核现有疫苗存在严重局限性。本研究旨在探讨恒河猴对M.结核感染和疾病的病理发展，比以前做得更详细。当TB的免疫相关性已经被很好地定义时，热休克蛋白65（hsp 65）和含有hsp 65 DNA序列的质粒的制剂将与免疫刺激蛋白一起包封在微球中，并作为疫苗进行测试。基本原理是质粒将快速离开微球，整合到宿主DNA中，并产生hsp 65，其将作为免疫原。随后，hsp 65蛋白将缓慢释放长达60天，作为加强免疫的抗原。基于先前对小鼠的实验，该疫苗预计具有预防活性，并且能够刺激比已经感染M的人更有效的免疫应答。结核病，从而降低疾病的严重程度。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.