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宣布为疫苗开发的优先事项。目前使用的BCG疫苗对儿童提供不同的保护，但对成人没有保护作用。各种亚单位和DNA疫苗以及减毒分枝杆菌疫苗正在作为新疫苗进行评估。我们研制了一种抗原85 A缺陷型弱毒候选疫苗（？fbpA），其似乎与可获得的疫苗的不同之处在于具有高免疫原性。不像野生型H37 Rv和在一定程度上BCG，？fbpA不抑制巨噬细胞或树突细胞，并增强抗原呈递。研究表明，？在小鼠疫苗评估模型中，fbpA疫苗比BCG更有效，比BCG更有效地引发T细胞，并在小鼠中诱导更强的T-bet依赖性Th 1应答，从而导致更好的保护。?单独的fbpA疫苗在减毒活载体中具有免疫显性抗原Ag 85 B/ESAT-6/CFP-10/TB 10.4和phoP的完全补体。我们提议？fbpA候选疫苗将以高免疫原性形式递送这些抗原，并更好地保护免受结核病的侵害。具体目标是1）使用？fbpA通过遗传操作和，2）调查机制提高免疫原性？fbpA和针对毒性结核分枝杆菌的保护，使用动物模型，在以下子目标下。我们将a）描述BCG和？fbpA，以更清楚地定义保护性免疫应答，B）表征用BCG和？fbpA在努力确定为什么BCG的保护减弱，c）调查的能力？fbpA以增强对BCG的反应，以及d）研究在？？fbpA疫苗接种的小鼠。最后，我们将研究增强抗原加工的分子机制？fbpA。该项目的双重目标是开发具有增强免疫原性的最安全的结核病疫苗，并表征增强活分枝杆菌疫苗免疫原性的因素。公共卫生相关性这是一项研究资助提案，旨在利用野生型结核分枝杆菌的基因操作开发一种新的结核疫苗。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众健康和人类的未来产生影响。艾滋病和肺结核在撒哈拉以南非洲和亚洲是一种致命的组合，还需要努力开发多价疫苗。本提案也涉及这一问题。我们已经开发了一种高免疫原性疫苗，最终可以用作多价载体疫苗，并以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，涉及休斯顿大学健康科学中心（Jagannath，Hunter和Armitige博士）和德克萨斯州MD安德森癌症中心史密斯免疫学研究中心（Schluns博士）的研究人员，在那里进行了免疫记忆的高级研究。俄克拉荷马州大学教授、CD 8表位作图专家Hildebrand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.