Non-replicative Vaccine for Human Brucellosis

人类布鲁氏菌病非复制疫苗

• 批准号: 7372590
• 负责人: Ramesh Vemulapalli
• 金额: $ 30.16万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372590
• 关键词: Adverse reactions; Affect; Animals; Antibodies; Antibody Formation; Antigens; Attenuated; Attenuated Vaccines; Bacteria; Breathing; Brucella; Brucella Vaccine; Brucella abortus; Brucella melitensis; Brucellosis; Categories; Cellular Immunity; Chronic; Clinical; Complement; Cuprozinc Superoxide Dismutase; Cytoplasm; Developed Countries; Developing Countries; Development; Disease; Domestic Animals; Dose; Exposure to; Gamma Rays; Genes; Histologic; Human; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Infertility; Inflammatory; Ingestion; Intramuscular; Laboratories; Life; Lipopolysaccharides; Malaise; Mammals; Meat Products; Modeling; Mucosal Immunity; Mus; National Institute of Allergy and Infectious Disease; O Antigens; Oral; Plasmids; Play; Polysaccharides; Prevention; Protein Overexpression; Proteins; Public Health; Publishing; Recombinant Vaccines; Recombinants; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Resistance; Risk; Role; Route; Safety; Serum; Site; Skin; Spleen; System; Testing; Time; Treatment Protocols; Vaccination; Vaccines; Virulence; Virulent; abortion; animal tissue; base; body system; conjunctiva; cytokine; day; irradiation; lymph nodes; member; mouse model; mutant; nonhuman primate; pathogen; protein B; research study; response; vaccine efficacy

DESCRIPTION (provided by applicant): Brucellosis is a zoonotic disease caused by members of the genus Brucella, which are Gram-negative, facultatively intracellular bacteria. Of the six well-recognized species of Brucella, B. melitensis, B. suis and B. abortus are highly virulent to humans. These 3 Brucella species are considered potential bioterror agents and they belong to NIAID Category B priority pathogens list. At present there is no vaccine available for human brucellosis. Cell-mediated immunity (CMI) and antibodies to the O polysaccharide (O antigen) of the lipopolysaccharide play important roles in acquired resistance against brucellosis. Attenuated, live Brucella strains such as B. abortus RB51 and 19, and B. melitensis Rev1 are being used as vaccines to control brucellosis in domestic animals. However, these live vaccines are virulent in humans. In general, all live vaccines possess an inherent safety risk. The overall hypothesis of this research project is that a gamma- irradiated, recombinant RB51 strain expressing low amounts of O antigen in its cytoplasm and simultaneously overexpressing the protective protein(s) of B. melitensis, B. suis and B. abortus would be a highly effective and safe vaccine for human brucellosis. We have previously demonstrated that the vaccine efficacy of strain RB51 can be enhanced significantly by overexpressing a Brucella protection protein or by expressing O antigen in its cytoplasm. Our recent research indicates that strain RB51 and its recombinants subjected to an appropriate dose of gamma radiation are unable to replicate but are still as efficient as live strains in inducing protective immune responses. In the current proposal, under Specific Aim 1, we will carryout experiments to identify common Brucella protective proteins by overexpressing selected proteins in strain RB51 and then checking for the induction of enhanced protection in mice against all 3 virulent Brucella species infections. Under Specific Aim 2, we will construct a recombinant RB51 strain that overexpresses the identified Brucella protective protein(s) and simultaneously expresses low amounts of O antigen in its cytoplasm. The recombinant RB51 strain will then be rendered non-replicative by gamma-irradiation and tested for its ability to provide superior protective immunity against all 3 virulent Brucella species infections. Under Specific Aim 3, we will evaluate the efficacy and safety of the non-replicative, brucellosis vaccine in mice following different immunization routes and regimens that facilitate the development of mucosal and systemic protective immune responses. Successful completion of the proposed studies will result in a non-replicative, strain RB51-based human brucellosis vaccine that could be tested for its efficacy and safety in large animal/nonhuman primate models. Relevance: Brucellosis is an important zoonotic disease caused by the bacteria belonging to genus Brucella. Three of the Brucella species that are highly virulent to humans are considered potential bioterror agents. At present there is no vaccine available for prevention of brucellosis in humans. Research proposed in this application focuses on developing a highly effective and safe Brucella vaccine for human use.

描述(申请人提供)：布鲁氏菌病是一种人畜共患病，由布鲁氏菌属的成员引起，这种细菌是革兰氏阴性的兼性胞内细菌。在布鲁氏菌的六个广为人知的物种中，羊布鲁氏菌、猪布鲁氏菌和流产布鲁氏菌对人类具有高度的毒力。这3种布鲁氏菌被认为是潜在的生物恐怖因子，属于NIAID B类优先病原体名单。目前还没有针对人类布鲁氏菌病的疫苗。细胞免疫(CMI)和抗内毒素O多糖(O抗原)抗体在布鲁氏菌病获得性抵抗中起重要作用。减毒的活布鲁氏菌菌株，如流产布鲁氏菌RB51和19，以及羊布鲁氏菌Rev1，正被用作疫苗来控制家畜中的布鲁氏菌病。然而，这些活疫苗对人类是致命的。一般来说，所有活疫苗都存在固有的安全风险。本研究的总体假设是，经伽玛射线照射后，在细胞质中低表达O抗原，同时高表达羊、猪和流产布鲁氏菌保护性蛋白(S)的重组RB51株，将是一种高效、安全的人布鲁氏菌病疫苗。我们先前已经证明，通过过度表达布鲁氏菌保护蛋白或在其细胞质中表达O抗原，可以显著提高RB51株的疫苗效力。我们最近的研究表明，在适当剂量的伽马辐射下，菌株RB51及其重组体无法复制，但在诱导保护性免疫反应方面仍与活菌株一样有效。在目前的方案中，在特定目标1下，我们将进行实验，通过在菌株RB51中过表达选定的蛋白来鉴定常见的布鲁氏菌保护蛋白，然后检查对小鼠对所有3种毒力布鲁氏菌感染的增强保护作用。在特定目标2下，我们将构建一株高表达已鉴定的布鲁氏菌保护蛋白(S)的重组RB51菌株，同时在其细胞质中低水平表达O抗原。然后，重组的RB51菌株将通过伽马辐射变得不可复制，并测试其对所有3种毒力布鲁氏菌感染提供卓越保护性免疫的能力。在具体目标3下，我们将评估非复制型布鲁氏菌病疫苗在不同免疫途径和方案下的有效性和安全性，以促进粘膜和系统保护性免疫反应的发展。拟议研究的成功完成将产生一种基于RB51菌株的非复制型人类布鲁氏菌病疫苗，该疫苗可以在大型动物/非人类灵长类动物模型中测试其有效性和安全性。目的：布鲁氏菌病是由布鲁氏菌属细菌引起的一种重要的人畜共患病。其中三种对人类高度毒力的布鲁氏菌被认为是潜在的生物恐怖因子。目前还没有预防人类布鲁氏菌病的疫苗。在这项申请中提出的研究重点是开发一种高效、安全的人类使用的布鲁氏菌疫苗。