Development and Manufacture of Adjuvants for Vaccines Targeting MDR Tuberculosis

描述（由申请人提供）：本耐多药结核病快速反应疫苗和疗法应用研究资金申请是传染病研究所（一家非营利研究机构）、疫苗研究中心、NIAID、NIH和科罗拉多州立大学（一家学术机构）结核病疫苗测试和研究材料合同之间的合作。一些Mtb抗原在动物或体外系统中显示出前景，但由于缺乏或缺乏人类数据而没有进展。原因之一是缺乏有效的佐剂，佐剂是与抗原结合时刺激特异性、保护性免疫反应的分子或化合物。大多数佐剂都掌握在大型制药公司手中。新一代疫苗正在用这些佐剂开发，但成本很高。通过成分许可和简单配方的开发，我们将为公共部门提供安全、高效、低成本的替代品，以取代“大型制药公司”生产的佐剂。我们将与结核病疫苗测试合同[NIH，MAID N 01-AI-40091]协调活动，以优先考虑可能受益于IDRI佐剂的Mtb抗原候选物。我们将根据需要向专利持有人（Intercell、Coley Pharmaceuticals、3 M制药部门、Dainippon Sumitomo Pharmaceuticals）寻求佐剂权利。我们拥有关于吡喃葡萄糖酯脂质佐剂（[GLA];一种MPL类似物[单磷酰脂质A，简称MPL]）佐剂使用的专有专利。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，旨在诱导最佳的免疫反应。开发工作将强调对小鼠、豚鼠和非人灵长类动物的安全性、免疫应答和保护的广泛表征，开发可转移和使用非动物源材料的工艺，以及生产/放行用于优先Mtb抗原临床试验的佐剂制剂。选择过程将强调感染前和感染后的免疫接种，以此作为确定优先次序的标准。将对选定的候选佐剂进行工艺开发、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毒理学研究评估佐剂的安全性。我们将确保提供强效、高效的佐剂，以促进开发不仅针对C类制剂耐多药结核病的有效生物防御疫苗，而且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.