Non-replicative Vaccine for Human Brucellosis

人类布鲁氏菌病非复制疫苗

• 批准号: 7995977
• 负责人: Ramesh Vemulapalli
• 金额: $ 29.39万
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995977
• 关键词: Address; Affect; Animals; Antibodies; Antibody Formation; Antigen Presentation; Antigens; Ascaridil; Attenuated; Attenuated Vaccines; Back; Bacteria; Biological Assay; Breathing; Brucella; Brucella Vaccine; Brucella abortus; Brucella melitensis; Brucellosis; Categories; Cells; Cellular Immunity; Chronic; Clinical; Complement; Cuprozinc Superoxide Dismutase; Cytoplasm; DNA; Dairy Products; Developing Countries; Development; Disease; Domestic Animals; Dose; Exposure to; Gamma Rays; Genes; Genome; Human; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Infertility; Ingestion; Laboratories; Lead; Left; Life; Lipopolysaccharides; Malaise; Mammals; Meat Products; Mediating; Modeling; Mus; National Institute of Allergy and Infectious Disease; O Antigens; Organ; Phenotype; Plasmids; Play; Polysaccharides; Prevention; Principal Investigator; Proteins; Public Health; Published Comment; Publishing; Recombinants; Regimen; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Resistance; Risk; Role; Route; Safety; Skin; System; T cell response; T-Cell Activation; Testing; Time; Tissues; Vaccines; Virulence; Virulent; abortion; animal tissue; base; body system; conjunctiva; hazard; irradiation; member; mouse model; mutant; nonhuman primate; overexpression; pathogen; programs; protein B; research study; response; vaccine candidate; vaccine development; 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成员引起的人畜共患疾病，布鲁氏菌属革兰氏阴性、兼性细胞内细菌。在六种公认的布鲁氏菌中，羊布鲁氏菌、猪布鲁氏菌和流产布鲁氏菌对人类具有高毒力。这 3 种布鲁氏菌被认为是潜在的生物恐怖因子，属于 NIAID B 类优先病原体清单。目前还没有针对人类布鲁氏菌病的疫苗。细胞介导的免疫（CMI）和脂多糖的 O 多糖（O 抗原）抗体在获得性布鲁氏菌病抵抗中发挥着重要作用。减毒活布鲁氏菌菌株，例如流产布鲁氏菌 RB51 和 19，以及羊种布鲁氏菌 Rev1，被用作控制家畜布鲁氏菌病的疫苗。然而，这些活疫苗对人类来说是有毒的。一般来说，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，经过 γ 射线照射的重组 RB51 菌株在其细胞质中表达少量 O 抗原，同时过表达羊种布鲁氏菌、猪布鲁氏菌和流产布鲁氏菌的保护蛋白，这将是一种高效且安全的人类布鲁氏菌病疫苗。我们之前已经证明，通过过表达布鲁氏菌保护蛋白或在其细胞质中表达O抗原，可以显着增强RB51菌株的疫苗功效。我们最近的研究表明，受到适当剂量伽马辐射的菌株 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。在当前的提案中，在具体目标 1 下，我们将进行实验，通过在菌株 RB51 中过表达选定的蛋白质来鉴定常见的布鲁氏菌保护蛋白，然后检查是否诱导小鼠抵抗所有 3 种剧毒布鲁氏菌物种感染的增强保护。在具体目标 2 下，我们将构建重组 RB51 菌株，该菌株过表达已鉴定的布鲁氏菌保护蛋白，并同时在其细胞质中表达少量 O 抗原。然后，重组 RB51 菌株将通过伽马射线照射而变得不可复制，并测试其针对所有 3 种剧毒布鲁氏菌属感染提供卓越保护性免疫的能力。在具体目标 3 下，我们将评估非复制性布鲁氏菌病疫苗在小鼠中的有效性和安全性，这些疫苗采用不同的免疫途径和方案，促进粘膜和全身保护性免疫反应的发展。成功完成拟议的研究将产生一种基于 RB51 菌株的非复制型人类布鲁氏菌病疫苗，可以在大型动物/非人灵长类动物模型中测试其有效性和安全性。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疾病。三种对人类具有高毒力的布鲁氏菌被认为是潜在的生物恐怖分子。目前尚无疫苗可用于预防人类布鲁氏菌病。本申请提出的研究重点是开发一种高效且安全的人类布鲁氏菌疫苗。

项目成果

Oral immunization of mice with gamma-irradiated Brucella neotomae induces protection against intraperitoneal and intranasal challenge with virulent B. abortus 2308.

用伽马射线照射的新瘤布鲁氏菌口服免疫小鼠可诱导针对有毒的流产布鲁氏菌 2308 的腹膜内和鼻内攻击的保护。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Dabral, Neha;Martha;Sriranganathan, Nammalwar;Vemulapalli, Ramesh
• 通讯作者: Vemulapalli, Ramesh

Overexpression of wbkF gene in Brucella abortus RB51WboA leads to increased O-polysaccharide expression and enhanced vaccine efficacy against B. abortus 2308, B. melitensis 16M, and B. suis 1330 in a murine brucellosis model.

在鼠类布鲁氏菌病模型中，流产布鲁氏菌 RB51WboA 中 wbkF 基因的过表达导致 O-多糖表达增加，并增强针对流产布鲁氏菌 2308、羊布鲁氏菌 16M 和猪布鲁氏菌 1330 的疫苗功效。

• 发表时间: 2019
• 影响因子: 3.7
• 作者: Dabral, Neha;Burcham, Grant N;Jain;Sriranganathan, Nammalwar;Vemulapalli, Ramesh
• 通讯作者: Vemulapalli, Ramesh

Pluronic P85 enhances the efficacy of outer membrane vesicles as a subunit vaccine against Brucella melitensis challenge in mice.

Pluronic P85 增强了外膜囊泡作为亚单位疫苗对抗小鼠布鲁氏菌攻击的功效。

• DOI: 10.1111/1574-695x.12010
• 发表时间: 2012-12
• 期刊: FEMS immunology and medical microbiology
• 作者: Jain-Gupta N;Contreras-Rodriguez A;Vemulapalli R;Witonsky SG;Boyle SM;Sriranganathan N
• 通讯作者: Sriranganathan N

Immunization of mice with gamma-irradiated Brucella neotomae and its recombinant strains induces protection against virulent B. abortus, B. melitensis, and B. suis challenge.

用伽马射线照射的新生布鲁氏菌及其重组菌株对小鼠进行免疫，可诱导小鼠免受有毒的流产布鲁氏菌、羊布鲁氏菌和猪布鲁氏菌的攻击。

• 发表时间: 2011-01-17
• 影响因子: 5.5
• 作者: Moustafa, Dina;Garg, Virendra K.;Jain, Neeta;Sriranganathan, Nammalwar;Vemulapalli, Ramesh
• 通讯作者: Vemulapalli, Ramesh

Immunotherapeutics to prevent the replication of Brucella in a treatment failure mouse model.

免疫疗法可防止治疗失败的小鼠模型中布鲁氏菌的复制。

• 发表时间: 2014-02-12
• 影响因子: 5.5
• 作者: Jain;Contreras;Smith, G P;Garg, V K;Witonsky, S G;Isloor, S;Vemulapalli, R;Boyle, S M;Sriranganathan, N
• 通讯作者: Sriranganathan, N