"Subunit Vaccines for Brucella Pathogens"

描述（由申请方提供）：布鲁氏菌属，属于B类病原体，是一种高度传染性的革兰氏阴性细菌，已被确定为潜在的生物武器。布鲁氏菌病是通过摄入未经高温消毒的乳制品自然传播的，表现为流感样系统，尽管进行了抗生素治疗，但仍可能导致复发性后遗症，表现为波状热和关节炎。布鲁氏菌在宿主体内的存活与其抵抗细胞内识别的能力有关，从而使它们能够在各种组织中隔离。到目前为止，还没有有效的疫苗用于人类，但保护是细胞介导的免疫依赖性的，特别是涉及TNF-α和IFN-γ。能够重现这种反应的疫苗应该证明在解决布鲁氏菌感染方面是有效的。两种假定的多胺结合蛋白PotD和PotF与ISCOM + CpG一起配制时，在用强毒B胃肠外激发的小鼠中赋予与Rev-1羊种布鲁氏菌活疫苗等同的免疫保护。melitensis 16 M菌株。这种保护水平（组织定殖>4 log减少）尚未使用亚单位疫苗方法显示。鉴于该疫苗制剂的效力，我们完全准备好测试这些疫苗对肠外和肺B的效力。melitensis，B.流产和B.挑战。因此，我们假设由PotD和PotF组成的适当配制的疫苗，与适合人用的佐剂组合，将提供针对肠外和肺布鲁氏菌攻击的保护。将多胺结合蛋白鉴定为疫苗靶点最终可以进一步适用于其他A类和B类病原体。为了进一步推进这一努力，具体目标1中的研究将优化布鲁氏菌疫苗PotD和PotF的剂量和途径，以提供针对肠外和肺B的保护。melitensis挑战并发展保护性免疫的相关性。特定目标2中的研究将优化佐剂与PotD和PotF联合使用时的剂量，以提供针对胃肠外和雾化B的最佳保护。melitensis，B.流产和B.挑战。特定目标3中的研究将在山羊布鲁氏菌病动物模型中检测PotD和PotF疫苗对B粘膜攻毒山羊的保护能力。melitensis殖民和流产。特定目标4中的研究将评价GLP制备的PotD和PotF亚单位疫苗的各种安全性参数。因此，这些研究将表明，亚单位疫苗，当适当的交付，可以防止肠道外和肺部布鲁氏菌的挑战。

DESCRIPTION (provided by applicant): Brucella species, members of Category B agents, are highly infectious Gram-negative bacteria that have been identified as potential biological weapons. Brucellosis is naturally transmitted via ingestion of unpasteurized dairy products, manifesting with flu-like systems and, despite antibiotic treatment, can cause a recurring sequelae, evident as undulant fever and arthritis. Brucellae survival within the host is linked to its ability to resist intracellular recognition, thus, allowing them to sequester in various tissues. To date, there are no effective vaccines for humans, but protection is cell-mediated immunity-dependent, particularly, involving TNF-α and IFN-γ. Vaccines that can recapitulate such responses should prove effective in resolving Brucella infections. Two putative polyamine-binding proteins, PotD and PotF, when formulated with ISCOMs plus CpG, conferred immune protection equivalent to the live Rev-1 Brucella melitensis vaccine in mice parenterally challenged with virulent B. melitensis 16M strain. This level of protection (>4 log reduction in tissue colonization) has yet to be shown using a subunit vaccine approach. Given the potency of this vaccine formulation, we are uniquely poised to test the efficacy of these vaccines against parenteral and pulmonary B. melitensis, B. abortus, and B. suis challenges. Thus, we hypothesize that an appropriately formulated vaccine composed of PotD and PotF, combined with a suitable adjuvant for human use, will confer protection against parenteral and pulmonary Brucella challenge. Identifying polyamine-binding proteins as vaccine targets could eventually be further adapted for other Category A and B pathogens. To further this effort, studies in Specific Aim 1 will optimize the dosage and route for Brucella vaccines, PotD and PotF, to confer protection against parenteral and pulmonary B. melitensis challenges and develop correlates for protective immunity. Studies in Specific Aim 2 will optimize the dosage for adjuvant when combined with PotD and PotF to confer optimal protection against parenteral and aerosolized B. melitensis, B. abortus, and B. suis challenges. Studies in Specific Aim 3 will test the efficacy of PotD and PotF vaccines in a caprine brucellosis animal model for their ability to confer protection against mucosally challenged goats for B. melitensis colonization and abortion. Studies in Specific Aim 4 will evaluate various safety parameters for GLP- prepared PotD and PotF subunit vaccines. Thus, these studies will show that subunit vaccines, when appropriately delivered, can protect against parenteral and pulmonary Brucella challenges.