Evaluation of Live Attenuated B. melitensis Vaccines

我们提出的研究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实的前景。我们 这种方法结合了可交付疫苗的最佳特征，安全，无副作用， 通过微囊化增强免疫刺激，对人体有效。竞争 我们的方法的优点和创新是：（1）使用高度减毒的，安全的，基因敲除，活 B。Melitensis突变体;（2）采用独特的一次性封闭系统技术进行生产，以及（3） 口服/鼻内递送在一种新的微膨胀介导的控制释放配方， 提供保护性免疫所需的长期粘膜免疫刺激。根据我们 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， 口服或鼻内给药，并且通常适用于许多选择的药剂。我们提出了一个精心设计的 5-一年时间轴，包括开发GMP生产的疫苗气雾剂的里程碑 在非人灵长类动物中进行的攻毒研究，作为临床试验性新药研究的途径， FDA生物许可证申请该产品的开发充分利用了 一个强大的团队和正在进行的细菌遗传学研究和在多种动物模型中的测试， 新的制造和微胶囊化技术，平衡产品的安全性，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.