Evaluation fo Live Attenuated B. Melitensis Vaccines in Nonhuman Primates

我们提出的研究的目标是开发一种对人类使用安全的布鲁氏菌疫苗。我们的方法 已经探索了减毒活疫苗的使用，因为亚单位疫苗几乎没有显示出真正的希望。我们的 该方法结合了可交付疫苗的最佳特性，即安全、无副作用和 通过微胶囊增强免疫刺激，对人类有效。有竞争力的 我们的方法的优点和创新之处在于：(1)使用高度减毒、安全的基因敲除活体 羊草突变体；(2)采用独特的一次性封闭系统技术制造；以及(3) 新型微囊化控释制剂的口服/鼻腔给药优化 提供保护性免疫所需的长期粘膜免疫刺激。基于我们的 根据初步数据，我们假设我们的疫苗输送系统最终将是储存稳定的， 口服或鼻腔给药，一般适用于一些选定的药物。我们展示了一种精心设计的 开发GMP生产的疫苗的5年时间表和里程碑-气雾剂 非人灵长类动物的挑战研究作为临床研究新药研究的途径 FDA生物许可证申请路径。提议的产品的开发充分利用了 一支强大的团队，正在进行细菌遗传学研究，并在多个动物模型中进行测试 采用新的制造和微胶囊技术，平衡产品安全性、稳定性、成本 和力量。

The goal of our proposed research is to develop a Brucella vaccine that is safe for human use. Our approach has explored the use of live attenuated vaccines, since subunit vaccines have shown little real promise. Our approach combines the optimal features of a deliverable vaccine that is safe, free of side effects and efficacious in humans with enhanced immune stimulation through microencapsulation. The competitive advantages and innovations of our approach are: (1) use of a highly attenuated, safe, gene knockout, live B. melitensis mutants; (2) manufacturing with unique disposable closed system technologies, and (3) oral/intranasal delivery in a novel microencapsulation-mediated controlled release formula to optimally provide the long term mucosal immunostimulation required for protective immunity. Based upon our preliminary data, we postulate that our vaccine delivery system will ultimately be storage stable, administered orally or intranasally, and generally applicable to a number of select agents. We present a welldesigned 5-year timeline with milestones for developing GMP-produced vaccine for vaccination-aerosol challenge studies in non-human primates as a pathway to a clinical Investigational New Drug studies on the path to FDA Biological License Application. The development of the proposed product takes full advantage of a strong team and ongoing research with bacterial genetics and testing in multiple animal models coupled with novel manufacturing and microencapsulation technologies that balance product safety, stability, costs, and potency.