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（由申请方提供）：布鲁氏菌病是由布鲁氏菌属成员引起的人畜共患疾病，布鲁氏菌属是革兰氏阴性、兼性胞内细菌。在已知的6种布鲁氏菌中，B. melitensis，B. suis和B.流产杆菌对人类具有高度毒性。这3种布鲁氏菌被认为是潜在的生物恐怖因子，属于NIAID B类优先病原体列表。目前，没有针对人类布鲁氏菌病的疫苗。细胞介导的免疫（CMI）和针对脂多糖的O多糖（O抗原）的抗体在对布鲁氏菌病的获得性抗性中起重要作用。减毒活布鲁氏菌菌株，如B。流产菌RB 51和19，以及B.羊种布氏杆菌Rev 1被用作疫苗来控制家畜中的布鲁氏菌病。然而，这些活疫苗在人类中是有毒的。一般而言，所有活疫苗都具有固有的安全风险。该研究项目的总体假设是γ-辐照的重组RB 51菌株在其细胞质中表达少量O抗原并同时过表达B的保护性蛋白。melitensis，B. suis和B.牛种布氏杆菌是一种高效、安全的人布鲁氏菌病疫苗。我们先前已经证明，通过过表达布鲁氏菌保护蛋白或通过在其细胞质中表达O抗原，可以显著增强菌株RB 51的疫苗效力。我们最近的研究表明，菌株RB 51及其重组体受到适当剂量的γ辐射不能复制，但在诱导保护性免疫应答方面仍然与活菌株一样有效。在当前提案中，根据具体目标1，我们将通过在菌株RB 51中过表达选定的蛋白质，然后检查小鼠对所有3种强毒株布鲁氏菌感染的增强保护诱导，进行实验以鉴定常见的布鲁氏菌保护蛋白。在特定目标2下，我们将构建一种重组RB 51菌株，该菌株过表达已鉴定的布鲁氏菌保护蛋白，同时在其细胞质中表达少量O抗原。然后通过γ-辐射使重组RB 51菌株成为非复制型，并测试其提供针对所有3种强毒布鲁氏菌属感染的上级保护性免疫的能力。在具体目标3下，我们将在小鼠中评价非复制型布鲁氏菌病疫苗在不同免疫途径和方案（促进粘膜和全身保护性免疫应答的发展）后的有效性和安全性。成功完成拟定研究将产生一种非复制型、基于菌株RB 51的人布鲁氏菌病疫苗，可在大型动物/非人灵长类动物模型中检测其有效性和安全性。相关性：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。三种对人类具有高度毒性的布鲁杆菌被认为是潜在的生物恐怖分子。目前还没有预防人类布鲁氏菌病的疫苗。本申请中提出的研究重点是开发一种高效安全的人用布鲁氏菌疫苗。