Chracteristics of An M. Tuberculosis Derived Vaccine

描述（由申请人提供）：结核病已被世界卫生组织宣布为全球紧急情况，并被美国国立卫生研究院列为疫苗开发的优先事项。目前使用的卡介苗对儿童有不同的保护作用，但对成人没有。各种亚单位和DNA疫苗以及减毒分枝杆菌疫苗正在作为较新的疫苗进行评估。我们研制了一种抗原85A缺陷减毒候选疫苗(？它似乎不同于现有的疫苗，具有高度的免疫原性。与野生型H37Rv和一定程度上的卡介苗不同，？双酚a不抑制巨噬细胞或树突状细胞，并增强抗原呈递。研究表明？在小鼠疫苗评价模型中，fbpA疫苗比卡介苗更有效，比卡介苗更有效地启动T细胞，并在小鼠体内诱导更强的T- bet依赖性Th1应答，从而产生更好的保护作用。？单独的双酚a疫苗在减毒活载体中具有免疫优势抗原Ag85B/ESAT-6/CFP-10/TB10.4和phoP的完整补体。我们提议吗？fbpA候选疫苗将以高度免疫原性的形式提供这些抗原，并更好地预防结核病。具体目标是：1)开发一种更安全的候选疫苗。2)研究免疫原性增强的机制。利用动物模型研究双酚a和对致病性结核分枝杆菌的保护作用。我们将a)描述接种卡介苗和？为了更清楚地定义保护性免疫反应，b)描述接种BCG和？为了确定卡介苗保护减弱的原因，c)调查？d)研究长期免疫记忆的产生。注射双酚a疫苗的小鼠。最后，我们将探讨fbpA增强抗原加工的分子机制。这个项目有两个目标，一是研制出尽可能安全的具有增强免疫原性的结核病疫苗，二是确定增强分枝杆菌活疫苗免疫原性的因素。这是一项研究拨款提案，旨在利用野生型结核分枝杆菌的遗传操作开发一种新的结核病疫苗。结核病是细菌感染导致死亡的主要原因，通过疫苗预防这种疾病将对公共卫生和人类的未来产生影响。艾滋病和结核病是撒哈拉以南非洲和亚洲的致命组合，还需要努力开发多价疫苗。这个提案也解决了这个问题。我们已经开发出一种高度免疫原性的疫苗，它最终可以作为多价载体疫苗，以一种更安全的形式用于人类疾病的多种表现。该项目是一项合作提案，涉及休斯顿健康科学中心大学(dr。Jagannath, Hunter and Armitige)和Smith免疫学研究中心，MD Anderson癌症中心，德克萨斯州（Schluns博士），在那里进行免疫记忆的高级研究。俄克拉何马大学教授、CD8表位定位专家希尔德布兰德博士也将担任顾问。

DESCRIPTION (provided by applicant): Tuberculosis has been declared a global emergency by the WHO and a priority for vaccine development by the NIH. The currently used BCG vaccine offers variable protection against children but not adults. Various sub unit and DNA vaccines and attenuated mycobacterial vaccines are being evaluated as newer vaccines. We have developed an antigen 85A deficient attenuated candidate vaccine (?fbpA) from Mycobacterium tuberculosis that appears to be different from available vaccines in being highly immunogenic. Unlike wild type H37Rv and to a certain extent BCG, ?fbpA is not suppressive for macrophages or dendritic cells and enhances antigen presentation. Studies show that ?fbpA vaccine is more effective than BCG in the mouse vaccine evaluation model, primes T cells more effectively than BCG and induces a stronger T- bet dependent Th1 response in mice leading to a better protection. ?fbpA vaccine alone has the full complement of immunodominant antigens, Ag85B/ESAT-6/CFP-10/TB10.4 and phoP in a live attenuated vehicle. We propose that ?fbpA candidate vaccine will deliver these antigens in a highly immunogenic form and protect better against tuberculosis. The Specific Aims are to 1) Develop a safer vaccine candidate using ?fbpA through genetic manipulations and, 2) Investigate the mechanisms of heightened immunogenicity of ?fbpA and protection against virulent M tuberculosis using animal models under the following sub aims. We will a) Characterize the immune responses in mice immunized with BCG and ?fbpA in an effort to more clearly define protective immune responses, b) Characterize the duration of the responses in mice immunized with BCG and ?fbpA in an effort to determine why BCG protection wanes, c) Investigate the ability of ?fbpA to boost the response to BCG, and d) Investigate the production of long term immune memory in??fbpA vaccinated mice. Finally, we will investigate the molecular mechanisms of enhancement of antigen processing by ?fbpA. The twin goals of this project are develop the safest possible vaccine for tuberculosis with enhanced immunogenicity and to characterize factors that enhance the immunogenicity of live mycobacterial vaccines. PUBLIC HEALTH RELEVANCE This is a research grant proposal that seeks to develop a new vaccine for tuberculosis using genetic manipulations on the wild type Mycobacterium tuberculosis. Tuberculosis the leading cause of death due to bacterial infections and prevention of this disease through a vaccine will have an impact on the public health and future of mankind. AIDS and tuberculosis is a deadly combination in sub Saharan Africa and Asia and efforts are also needed to develop polyvalent vaccines. This proposal addresses this issue as well. We have developed a highly immunogenic vaccine that can be eventually used as a polyvalent carrier vaccine and in a safer form for multiple manifestations of the human disease. The project is a collaborative proposal which involves investigators at the University of Heath Sciences Center Houston (Drs. Jagannath, Hunter and Armitige) and Smith Research Center in Immunology, MD Anderson Cancer Center, Texas (Dr. Schluns) where advanced research in immunological memory are carried out. Dr. Hildebrand, Professor at University of Oklahoma and an expert in CD8 epitope mapping will also serve as a consultant.