Chracteristics of An M. Tuberculosis Derived Vaccine

描述（由申请人提供）：世界卫生组织已宣布结核病为全球紧急情况，并已被美国国立卫生研究院宣布为疫苗开发的优先事项。目前使用的卡介苗疫苗可以针对儿童提供多种保护，但不能针对成人。各种亚单位疫苗和 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。我们开发了一种来自结核分枝杆菌的抗原 85A 缺陷减毒候选疫苗 (?fbpA)，它与现有疫苗的不同之处在于具有高度免疫原性。与野生型H37Rv和一定程度上的BCG不同，?fbpA不会抑制巨噬细胞或树突状细胞，并且会增强抗原呈递。研究表明，在小鼠疫苗评估模型中，fbpA 疫苗比 BCG 更有效，比 BCG 更有效地启动 T 细胞，并在小鼠中诱导更强的 T-bet 依赖性 Th1 反应，从而提供更好的保护。单独的 fbpA 疫苗在减毒活载体中具有完整的免疫显性抗原、Ag85B/ESAT-6/CFP-10/TB10.4 和 phoP。我们建议 ?fbpA 候选疫苗将以高免疫原性形式提供这些抗原，并更好地预防结核病。具体目标是 1) 通过基因操作使用 ?fbpA 开发更安全的候选疫苗，2) 根据以下子目标，研究 ?fbpA 增强免疫原性的机制以及使用动物模型预防烈性结核分枝杆菌的机制。我们将 a) 表征用 BCG 和 ?fbpA 免疫的小鼠的免疫反应，以更清楚地定义保护性免疫反应，b) 表征用 BCG 和 ?fbpA 免疫的小鼠的反应持续时间，以确定 BCG 保护作用减弱的原因，c) 研究 ?fbpA 增强对 BCG 反应的能力，以及 d) 研究 ?fbpA 疫苗接种小鼠中长期免疫记忆的产生。最后，我们将研究 ?fbpA 增强抗原加工的分子机制。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 这是一项研究拨款提案，旨在利用野生型结核分枝杆菌的基因操作来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众健康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。该提案也解决了这个问题。我们开发了一种高免疫原性疫苗，最终可用作多价载体疫苗，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，涉及休斯敦健康科学中心大学（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，该中心开展免疫记忆方面的高级研究。俄克拉荷马大学教授、CD8表位图谱专家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.