Development & Manufacture of an MDR Tuberculosis Vaccine

发展

• 批准号: 7010219
• 负责人: STEVEN GREGORY REED
• 金额: $ 409.56万
• 依托单位: ACCESS TO ADVANCED HEALTH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010219
• 关键词: Mycobacterium tuberculosis; biotechnology; bioterrorism /chemical warfare; disease /disorder model; drug design /synthesis /production; guinea pigs; laboratory mouse; nonhuman therapy evaluation; tuberculosis; tuberculosis vaccines; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): VACCINES FOR BIODEFENSE: We have identified several new TB vaccine candidate antigens based on human T cell responses and animal protection. Priority has been given to those that both elicit a Thl response from PBMC from PPD positive healthy donors and protect in rodent models. A non-human primate vaccine model has been established and is currently being used to further characterize vaccine candidates and adjuvant/delivery systems. We have developed Mtb72f in AS02A, the first defined TB vaccine to enter clinical trials. However, more recent data indicate that three other antigens may add to the protection obtained with Mtb 72f. Therefore, we have generated two additional polyproteins that incorporate these antigens on the Mtb72f backbone. The two new fusion proteins are Mtb92f and Mtbl 13f. Using validated rodent models of infection and disease we will select one of these antigens for GMP manufacture and clinical development. The selection process will emphasis both pre- and post-challenge immunization as criteria for prioritization. The selected candidate will be subjected to process development, including optimization of fermentation, development potency and stability assays of adjuvant (AS02A) formulated antigen. By the end of the funding period, we will have defined and developed a second generation vaccine candidate, collected data for MDR-TB, evaluated safety with a GLP toxicology study and manufactured vials under cGMPs. This will enable us to immediately proceed to human clinical trials after the end of the funding period.

描述（由申请人提供）：用于生物防御的疫苗：我们已经根据人类T细胞反应和动物保护确定了几种新的结核病疫苗候选抗原。优先考虑那些既能引起PPD阳性健康供体PBMC的Thl反应，又能在啮齿动物模型中起到保护作用的药物。已经建立了一种非人类灵长类动物疫苗模型，目前正在用于进一步表征候选疫苗和佐剂/递送系统。我们在AS02A中开发了mt72f，这是第一个进入临床试验的确定结核病疫苗。然而，最近的数据表明，另外三种抗原可能会增加Mtb 72f获得的保护。因此，我们产生了另外两种将这些抗原结合到mt72f主链上的多蛋白。这两种新的融合蛋白是Mtb92f和mtb13f。使用经过验证的啮齿动物感染和疾病模型，我们将选择其中一种抗原用于GMP生产和临床开发。选择过程将强调将挑战前和挑战后的免疫接种作为确定优先次序的标准。选定的候选物将进行工艺开发，包括优化发酵、开发效力和佐剂（AS02A）配制抗原的稳定性测定。在资助期结束时，我们将确定并开发第二代候选疫苗，收集耐多药结核病的数据，通过GLP毒理学研究评估安全性，并根据cgmp生产小瓶。这将使我们能够在资助期结束后立即进行人体临床试验。