Development & Manufacture of an MDR Tuberculosis Vaccine

描述（由申请方提供）：生物防御疫苗：我们基于人类T细胞应答和动物保护，确定了几种新的结核病疫苗候选抗原。优先考虑那些既从PPD阳性健康供体的PBMC中引发Thl应答又在啮齿动物模型中保护的那些。已经建立了非人灵长类动物疫苗模型，目前正用于进一步表征候选疫苗和佐剂/递送系统。我们在AS 02 A中开发了Mtb 72 f，这是第一个进入临床试验的确定性结核病疫苗。然而，最近的数据表明，其他三种抗原可能会增加Mtb 72 f获得的保护。因此，我们已经产生了两种额外的多聚蛋白，其在Mtb 72 f骨架上掺入这些抗原。这两个新的融合蛋白是Mtb 92 f和Mtbl 13 f。使用经验证的啮齿动物感染和疾病模型，我们将选择这些抗原之一用于GMP生产和临床开发。选择过程将强调攻毒前和攻毒后的免疫接种作为确定优先次序的标准。将对选定的候选物进行工艺开发，包括佐剂（AS 02 A）配制抗原的发酵优化、开发效价和稳定性试验。到资助期结束时，我们将确定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。

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.