"Subunit Vaccines for Brucella Pathogens"

“布鲁氏菌病原体亚单位疫苗”

• 批准号: 8076096
• 负责人: David W Pascual
• 金额: $ 51.55万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-05 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076096
• 关键词: Acute; Adjuvant; Aerosols; Afghanistan; Animal Model; Animals; Antibiotic Therapy; Area; Arthritis; Binding; Binding Proteins; Biological; Brucella; Brucella Vaccine; Brucella abortus; Brucella melitensis; Brucellosis; Candidate Disease Gene; Categories; Cells; Cellular Immunity; Central Asia; Chronic; Coupled; DNA; Dairy Products; Development; Disease; Drug Formulations; Endocarditis; Family; Fever; Fever Chills; Future; Goals; Goat; Gram-Negative Bacteria; Headache; Health; Hepatomegaly; Human; Human Resources; ISCOMs; Immune; Immunity; In Vitro; Incidence; Individual; Infection; Ingestion; Interferon Type II; Interferons; Interleukin-12; Iraq; Life; Link; Livestock; Lung; Malaise; Meat; Middle East; Milk; Modeling; Mus; Neurologic; Polyamines; Preparation; Relapse; Research; Route; Safety; South America; Splenomegaly; Streptococcus pneumoniae; Subunit Vaccines; Symptoms; System; TNF gene; Techniques; Testing; Therapeutic; Tissues; Vaccinated; Vaccines; Virulent; Work; abortion; aerosolized; cytokine; dosage; efficacy testing; flu; human disease; improved; insight; member; microorganism; mortality; pathogen; preclinical study; prophylactic; protective efficacy; respiratory; response; success; transmission process; vaccine candidate; vaccine development; vaccine efficacy; weapons

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-a and IFN-?. 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. PROJECT NARRATIVE Brucellosis can be a debilitating disease, requiring extended antibiotic treatment to clear the brucellae; yet, despite treatment, brucellae can still persist. Thus, studies focused on developing a subunit vaccine for brucellosis and validating the protective efficacy of this vaccine formulation in two susceptible animal hosts and against three species of Brucella. The overall goals of this work are to forward the studies for our vaccines and have many of the preclinical studies completed prior to testing in humans.

描述（由申请人提供）：布鲁氏菌属于 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。布鲁氏菌病通过摄入未经高温消毒的乳制品自然传播，表现为类似流感的系统，尽管进行了抗生素治疗，但仍可能导致反复出现的后遗症，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，从而使它们能够隔离在各种组织中。迄今为止，还没有针对人类的有效疫苗，但保护作用依赖于细胞介导的免疫，特别是涉及 TNF-α 和 IFN-α 的免疫。能够重现这种反应的疫苗应该能有效解决布鲁氏菌感染。两种假定的多胺结合蛋白 PotD 和 PotF，当与 ISCOM 和 CpG 一起配制时，为经肠外注射强毒羊种布鲁氏菌 16M 菌株的小鼠提供了相当于 Rev-1 羊种布鲁氏菌活疫苗的免疫保护。这种保护水平（组织定植减少>4个对数）尚未通过亚单位疫苗方法得到证实。鉴于这种疫苗配方的效力，我们准备测试这些疫苗针对肠外和肺部的羊种芽孢杆菌、流产芽孢杆菌和猪芽孢杆菌挑战的功效。因此，我们假设由 PotD 和 PotF 组成的适当配制的疫苗，与适合人类使用的佐剂相结合，将提供针对肠外和肺部布鲁氏菌攻击的保护。将多胺结合蛋白确定为疫苗靶标最终可以进一步适用于其他 A 类和 B 类病原体。为了进一步推进这项工作，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部羊种布鲁氏菌挑战的保护，并开发保护性免疫的相关性。具体目标 2 中的研究将优化佐剂与 PotD 和 PotF 组合时的剂量，以针对肠胃外和雾化的羊种布鲁氏菌、流产布鲁氏菌和猪布鲁氏菌挑战提供最佳保护。具体目标 3 中的研究将测试 PotD 和 PotF 疫苗在山羊布鲁氏菌病动物模型中的功效，以了解它们针对粘膜受感染的羊种布鲁氏菌定植和流产提供保护的能力。具体目标 4 中的研究将评估 GLP 制备的 PotD 和 PotF 亚单位疫苗的各种安全参数。因此，这些研究将表明，亚单位疫苗在适当递送时可以预防肠外和肺部布鲁氏菌挑战。 项目叙述布鲁氏菌病可能是一种使人衰弱的疾病，需要长期抗生素治疗来清除布鲁氏菌；然而，尽管进行了治疗，布鲁氏菌仍然可以持续存在。因此，研究重点是开发布鲁氏菌病亚单位疫苗，并验证该疫苗制剂对两种易感动物宿主和三种布鲁氏菌的保护功效。这项工作的总体目标是推进我们的疫苗研究，并在人体测试之前完成许多临床前研究。