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"Subunit Vaccines for Brucella Pathogens"

“布鲁氏菌病原体亚单位疫苗”

基本信息

批准号：
8827663
负责人：
David W Pascual
金额：
$ 36.34万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-05 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8827663
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 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 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 Techniques Testing Therapeutic Tissues Tumor Necrosis Factor-alpha 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 unpasteurized vaccine candidate vaccine development vaccine efficacy weapons

项目摘要

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.

描述(申请人提供)：布鲁氏菌属B类制剂，是高度传染性的革兰氏阴性菌，已被确定为潜在的生物武器。布鲁氏菌病是通过摄入未经巴氏灭菌的乳制品自然传播的，表现为类似流感的系统，尽管接受了抗生素治疗，但仍可导致反复发作的后遗症，明显表现为波浪热和关节炎。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。到目前为止，还没有对人类有效的疫苗，但保护依赖于细胞介导的免疫，特别是涉及肿瘤坏死因子-α和干扰素-γ。能够概括这种反应的疫苗应该被证明在解决布鲁氏菌感染方面是有效的。两种推定的多胺结合蛋白，PotD和PotF，当与ISCOMS和CpG配方时，在用强毒力马利特氏杆菌16M株非肠道攻击的小鼠中，获得了相当于羊布鲁氏菌活疫苗的免疫保护。这种水平的保护(组织定植的对数减少)还没有用亚单位疫苗方法显示出来。考虑到这种疫苗配方的效力，我们正准备测试这些疫苗对非肠道和肺部感染、流产和猪瘟的有效性。因此，我们推测，由PotD和PotF组成的适当配方的疫苗，加上适合人类使用的佐剂，将提供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能进一步适用于其他A类和B类病原体。为了进一步推动这一努力，针对特定目标1的研究将优化布鲁氏菌疫苗PotD和PotF的剂量和路线，以提供对非肠道和肺性羊瘟杆菌挑战的保护，并开发保护性免疫的相关性。针对特定目标2的研究将优化与PotD和PotF结合时的佐剂剂量，以提供针对非肠道和雾化白僵菌、流产白僵菌和猪白僵菌攻击的最佳保护。具体目标3的研究将在山羊布鲁氏菌病动物模型中测试PotD和PotF疫苗的有效性，以确定它们是否有能力保护山羊免受羊布鲁氏菌定居和流产的黏膜挑战。具体目标4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，当适当地提供亚单位疫苗时，可以预防肠外和肺部布鲁氏菌的挑战。