Development & Manufacture of an MDR Tuberculosis Vaccine

描述(申请人提供)：生物防御疫苗：我们根据人类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。那些既能引起PPD阳性健康捐赠者PBMC的Th1反应，又能在啮齿动物模型中保护的药物被优先考虑。非人灵长类疫苗模型已经建立，目前正在用于进一步确定候选疫苗和佐剂/递送系统的特征。我们已经在AS02A中开发了Mtb72f，这是第一个进入临床试验的明确结核病疫苗。然而，最近的数据表明，其他三种抗原可能会增加结核分枝杆菌72F的保护作用。因此，我们在Mtb72f主干上产生了另外两个包含这些抗原的多蛋白。这两个新的融合蛋白是Mtb92f和Mtb113f。利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的生产和临床开发。遴选过程将强调挑战前和挑战后的免疫接种，作为确定优先次序的标准。选定的候选者将接受工艺开发，包括发酵优化、开发效力和佐剂(AS02A)配方抗原的稳定性测试。到资助期结束时，我们将定义和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生产瓶装疫苗。这将使我们能够在资助期结束后立即进行人体临床试验。

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.