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Non-replicative Vaccine for Human Brucellosis

人类布鲁氏菌病非复制疫苗

基本信息

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
项目类别：
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

项目摘要

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，这是革兰氏阴性的兼性细胞内细菌。在六种公认的布鲁氏菌中，melitensis、猪B.和abortus B.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制剂，它们属于NIAID B类优先病原体清单。目前没有针对人类布鲁氏菌病的疫苗。细胞介导免疫（CMI）和针对脂多糖O多糖（O抗原）的抗体在获得性抗布鲁氏菌病中发挥重要作用。布氏菌减毒活菌株，如流产布氏菌RB51和19，以及梅利特布氏菌Rev1，正被用作控制家畜布氏菌病的疫苗。然而，这些活疫苗对人类有毒性。一般来说，所有活疫苗都具有固有的安全风险。本研究项目的总体假设是，一种γ辐照的重组RB51菌株在其细胞质中表达少量的O抗原，同时过表达B. melitensis、B. suis和B. abortus的保护蛋白，将是一种高效安全的人类布鲁氏菌病疫苗。我们之前已经证明，菌株RB51的疫苗效力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抗原而显着增强。我们最近的研究表明，菌株RB51及其重组体在适当剂量的伽马辐射下无法复制，但在诱导保护性免疫反应方面仍然与活菌株一样有效。在目前的提案中，在Specific Aim 1下，我们将开展实验，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对所有3种致病性布鲁氏菌感染的增强保护。在Specific Aim 2下，我们将构建一个重组RB51菌株，该菌株过表达鉴定的布鲁氏菌保护蛋白，同时在其细胞质中表达低量的O抗原。然后，重组RB51菌株将通过γ辐照使其不具有复制性，并测试其对所有3种毒性布鲁氏菌感染提供卓越保护性免疫的能力。在特异性目标3下，我们将评估非复制性布鲁氏菌病疫苗在不同免疫途径和方案下的小鼠的有效性和安全性，这些免疫途径和方案促进了粘膜和全身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菌株的非复制性人布鲁氏菌病疫苗，可在大型动物/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。三种对人类具有高度毒性的布鲁氏菌被认为是潜在的生物恐怖制剂。目前尚无预防人间布鲁氏菌病的疫苗。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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。

DOI：
10.1016/j.vaccine.2013.12.058
发表时间：
2014
期刊：
Vaccine
影响因子：
5.5
作者：
Jain-Gupta,N;Contreras-Rodriguez,A;Smith,GP;Garg,VK;Witonsky,SG;Isloor,S;Vemulapalli,R;Boyle,SM;Sriranganathan,N
通讯作者：
Sriranganathan,N

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基疫苗的疗效，以针对小鼠的布鲁氏菌Melitensis挑战。

DOI：
10.1111/1574-695x.12010
发表时间：
2012-12
期刊：
FEMS immunology and medical microbiology
影响因子：
0
作者：
Jain-Gupta N;Contreras-Rodriguez A;Vemulapalli R;Witonsky SG;Boyle SM;Sriranganathan N
通讯作者：
Sriranganathan N

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