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（由申请人提供）：布鲁氏菌病是由布鲁氏菌属的成员引起的，革兰氏阴性菌是革兰氏阴性菌的成员。在布鲁氏菌的六种良好认可的物种中，梅利特西斯（B. Melitensis），苏伊斯（B.这三种布鲁氏菌被认为是潜在的生物逆转剂，它们属于NIAID类别B优先病原体清单。目前，没有可用于人性化的疫苗。细胞介导的免疫（CMI）和对脂多糖多糖（O抗原）抗体的抗体在获得对布鲁氏菌病的耐药性中起着重要作用。衰减，活的布鲁氏菌菌株，例如Abortus rb51和19，以及Melitensis Rev1，用作控制家畜中的布鲁氏菌病的疫苗。但是，这些活疫苗在人类中是有力的。通常，所有活疫苗都有固有的安全风险。该研究项目的总体假设是，γ辐照的，重组的RB51菌株在其细胞质中表达低量的O抗原，同时过表达了梅利氏芽孢杆菌，B. suis和Abortus的保护蛋白（s），是对人胸膜的高效且安全的疫苗。我们先前已经证明，可以通过过表达布鲁氏菌保护蛋白或通过在其细胞质中表达O抗原来显着增强菌株RB51的疫苗功效。我们最近的研究表明，菌株RB51及其经过适当剂量的伽马辐射的重组因素无法复制，但仍与活菌株一样有效，在诱导保护性免疫反应方面。在当前的提案中，在特定目标1下，我们将进行实验，以通过过度表达RB51菌株中所选蛋白的过表达，然后检查对所有3种毒性布鲁氏菌感染的诱导诱导，以鉴定常见的布鲁氏菌保护蛋白。在特定目标2下，我们将构建一个重组RB51菌株，该菌株过表达已鉴定的布鲁氏菌保护蛋白（S），并同时表达其细胞质中O抗原的含量较低。然后，重组RB51菌株将通过γ-辐照进行非复制性，并测试其能够针对所有3种毒性布鲁氏菌感染提供优质的保护性免疫。在特定的目标3下，我们将评估遵循不同免疫途径和方案的小鼠中非复制性布鲁氏菌病疫苗的疗效和安全性，从而促进粘膜和全身性保护性免疫反应的发展。成功完成拟议的研究将导致基于RB51菌株的人性化疫苗的非复制性菌株疫苗，该疫苗可以在大型动物/非人类灵长类动物模型中测试其功效和安全性。相关性：布鲁塞病是由属于布鲁氏菌属的细菌引起的重要人畜共患病。对人的高度毒性的三种布鲁氏菌种类被认为是潜在的生物逆转剂。目前，尚无疫苗可预防人类的布鲁氏菌病。该应用程序中提出的研究重点是开发一种高效，安全的布鲁氏疫苗，用于人类使用。