"Subunit Vaccines for Brucella Pathogens"

“布鲁氏菌病原体亚单位疫苗”

• 批准号: 8651868
• 负责人: David W Pascual
• 金额: $ 46.36万
• 依托单位: UNIVERSITY OF FLORIDA
• 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/8651868
• 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.

描述（由申请人提供）：Brucella物种，B类代理的成员是高度感染性的革兰氏阴性细菌，已被鉴定为潜在的生物武器。布鲁氏菌病是通过摄入未经糊状的乳制品而自然传播的，这些乳制品表现出流感样系统，尽管抗生素治疗可能会引起经常性后遗症，这显然是起伏的发烧和关节炎。宿主内的布鲁氏菌存活与其抵抗细胞内识别的能力有关，从而使它们可以隔离在各种组织中。迄今为止，没有针对人类的有效疫苗，但是保护是依赖于细胞介导的免疫性的，特别是涉及TNF-A和IFN-？。可以概括此类反应的疫苗应证明有效解决布鲁氏菌感染。两种推定的多胺结合蛋白POTD和POTF用ISCOMS加上CPG配制时，赋予了与Live Rev-1 Brucella Melitensis疫苗相当的免疫保护，这是属于肠胃外脑外部挑战的小鼠B. melitensis 16M菌株的育儿挑战。使用亚基疫苗方法尚未显示这种保护水平（> 4个组织定植的原木降低）。鉴于这种疫苗配方的效力，我们有独特的准备来测试这些疫苗针对肠胃外和肺B. melitensis，B。abortus和B. suis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合适辅助物相结合，将赋予肠胃外和肺泡挑战的保护。将多胺结合蛋白识别为疫苗靶标，最终可以进一步适应其他类别A和B病原体。为了进一步的努力，特定目标1的研究将优化布鲁氏疫苗，POTD和POTF的剂量和途径，以保护肠胃外和肺芽孢杆菌的梅里特氏芽孢杆菌挑战挑战，并产生保护性免疫的相关性。当与POTD和POTF结合使用时，特定目标2中的研究将优化辅助剂量的剂量，以提供最佳的保护，以防止肠胃外和雾化的B. melitensis，B。abortus和B. suis挑战。特定目标3中的研究将测试POTD和POTF疫苗在Caprine Brucellosis动物模型中的功效，以便能够保护粘液芽孢杆菌的粘膜芽孢杆菌定植和流产。特定目标4的研究将评估GLP准备的POTD和POTF亚基疫苗的各种安全参数。因此，这些研究将表明，适当输送的亚基疫苗可以预防肠胃外和肺部布鲁氏菌挑战。