Development and Manufacture of Adjuvants for Vaccines Targeting MDR Tuberculosis

描述(由申请人提供)：本申请为耐多药结核病快速反应疫苗和疗法的应用研究提供资金，是传染病研究所[一个非营利性研究组织]、疫苗研究中心、NIAID、NIH和科罗拉多州立大学[一个学术机构]的结核病疫苗测试和研究材料合同之间的合作伙伴关系。一些结核分枝杆菌抗原在动物或体外系统中显示出了希望，但由于缺乏或缺乏人类数据，尚未取得进展。一个原因是缺乏有效的佐剂，这些佐剂是当与抗原结合时激发特定保护性免疫反应的分子或化合物。大多数佐剂掌握在大型制药公司手中。使用这些佐剂的新一代疫苗正在开发中，但成本很高。通过成分许可和开发简单的配方，我们将向公共部门提供安全、高效、低成本的替代方案，以取代“大制药公司”生产的佐剂。我们将与结核疫苗测试合同[美国国立卫生研究院，MAID N01-AI-40091]协调活动，优先选择可能受益于IDRI佐剂的结核分枝杆菌候选抗原。我们将根据需要向专利持有人(Intercell、Coley PharmPharmticals、3M制药部门、Dainippon Sumitomo PharmPharmticals)寻求辅助权。我们对吡喃葡萄糖脂佐剂([GLA]；一种MPL类似物[单磷酰脂A，简称MPL])的辅助使用拥有专利地位。我们的工业经验将使我们能够开发新一代有效的佐剂配方，旨在诱导最佳免疫反应。开发工作将强调对小鼠、豚鼠和非人类灵长类动物的安全性、免疫反应和保护的广泛表征，开发可转移和使用非动物来源材料的过程，以及制造/释放用于临床试验的优先结核分枝杆菌抗原的佐剂配方。遴选过程将强调感染前和感染后免疫，作为确定优先次序的标准。选定的候选佐剂将接受工艺开发、效力和稳定性分析。到资助期结束时，我们将定义和开发新一代佐剂，收集耐多药结核病的数据，并通过GLP毒理学研究评估该佐剂的安全性。我们将确保获得有效、高效的佐剂，以促进针对C类药物耐多药结核病的有效生物防御疫苗的开发，并供公共研究部门使用。

DESCRIPTION (provided by applicant): This request for funding for applied research into rapid response vaccines and therapies for MDR-TB is a partnership between the Infectious Disease Research Institute [a not-for-profit research organization], The Vaccine Research Center, NIAID, NIH, and the TB Vaccine Testing and Research Materials Contract at Colorado State University [an academic institution]. Some Mtb antigens have shown promise in animal or in vitro systems, but have not advanced due to either lack of or poor human data. One reason is the paucity of effective adjuvants, which are molecules or compounds that stimulate specific, protective immune responses when combined with antigen. Most adjuvants are in the hands of large pharmaceutical companies. A new generation of vaccines is being developed with these adjuvants but the cost is high. Through component licensing and development of simple formulations, we will provide to the public sector safe, highly effective, low-cost alternatives to adjuvants produced by "big pharma". We will coordinate activities with the TB Vaccine Testing Contract [NIH, MAID N01-AI-40091] to prioritize Mtb antigen candidates that could benefit from IDRI's adjuvants. We will seek adjuvant rights from patent holders (Intercell, Coley Pharmaceuticals, 3M pharma division, Dainippon Sumitomo Pharmaceuticals) as needed. We have a proprietary patent position on the adjuvant use of glucopyranosil lipid adjuvant ([GLA]; an MPL analogue [Monophosphoryl Lipid A, referred to as MPL]). Our industrial experience will enable us to develop a new generation of effective adjuvant formulations designed to induce the optimal immune response. Development work will emphasize extensive characterization of safety, immune responses and protection in mice, guinea pigs and non-human primates, development of processes that can be transferred and that use materials of non-animal origin, and manufacture/release of adjuvant formulations for clinical testing with priority Mtb antigens. The selection process will emphasis both pre- and post-infection immunization as criteria for prioritization. The selected adjuvant candidate will be subjected to process development, potency and stability assays. By the end of the funding period, we will have defined and developed a new generation adjuvant, collected data for MDR-TB, and evaluated safety of the adjuvant with a GLP toxicology study. We will ensure availability of potent, highly effective adjuvants to facilitate the development of not only effective biodefense vaccines against a category C agent, MDR-TB, but also for the use of the public research sector.