Discovery of subunit vaccine candidates against glanders

发现针对鼻疽的候选亚单位疫苗

基本信息

批准号：
7649078
负责人：
Don MARK ESTES
金额：
$ 5.23万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649078
关键词：
Acute Aerosols Animal Model Animals Antibiotic Therapy Antigenic Diversity Antigens Attenuated Vaccines Bacteria Biological Assay Biological Warfare Burkholderia Burkholderia mallei Burkholderia pseudomallei Characteristics Chronic Code Collection Communicable Diseases Complex Cutaneous Development Diagnosis Disease Expression Library Genome Genomics Glanders Goals Gram-Negative Bacteria Horse Diseases Human Immune Immune response Immunization Immunocompromised Host Infection Ingestion Libraries Modality Modeling Molecular Mus Opportunistic Infections Performance Pharmaceutical Preparations Phase Population Problem Solving Proteins Protocols documentation Public Health Recording of previous events Safety Screening procedure Subunit Vaccines Testing Time Vaccines base cost design diabetic disorder control fluidity genetic immunization strategies in vivo novel strategies pathogen vaccine evaluation

项目摘要

Glanders is a severe disease that already has a history of use as an effective bioweapon. It is naturally an equine disease but zoonotically transmits to humans. Even if quickly diagnosed as Burkholderia mallei, antibiotic treatments have shown low efficacy and disease control requires long regimes with multiple drugs. Even if the acute phase is survived, chronic infection can be suffered for as many as 20 years. The most rational plan of defense is a vaccine but to date none have been successfully developed. The immune evading tactics, including genomic fluidity, of this complex pathogen have rendered the performance of even live vaccines disappointing. New approaches are warranted. Therefore, we propose to identify a vaccine against glanders that is both more efficacious and safer than any previous ones. It will be designed from a collection of pathogen subunits that will include antigens that stimulate protective host immune responses yet exclude those that are immune evading or superfluous. This conceptually solves the problem that whole pathogen vaccines are likely to provide too many components (dilution of useful ones by not useful ones) and the problem of subunit vaccines which are likely to provide too few components (limited antigenic coverage). We will accomplish this by engaging in a genomic-scale search of all B. mallei coding sequences for protective antigens by expression library immunization in a murine model of glanders disease. Our specific approach to identifying this condensed filtrate of protective antigens is to 1) establish optimal molecular and animal-model protocols for conducting protection assays on a large-scale 2) build all of the coding sequences of B. mallei into a library of expression constructs for genetic immunization and 3) directly assay the protective capacity of every B. mallei coding sequence in vivo. At the conclusion of this project we will have generated protective subunits and that will be ready for delivery and modality optimization studies. Development of a B. mallei vaccine is anticipated to greatly facilitate development of a 8. pseudomalliei and 6. cepacia vaccines against these ancient diseases.

腺体是一种严重的疾病，已经具有有效的生物武器史。自然是马疾病，但人畜共患疾病向人类传播。即使迅速被诊断为Burkholderia Mallei，抗生素治疗表现出低疗效，疾病控制需要多种药物的长度方案。即使急性期幸存下来，慢性感染也可以多达20年。最多理性国防计划是一种疫苗，但迄今为止，没有成功开发出来。免疫这种复杂病原体的逃避策略，包括基因组流动性，使得偶数的表现现场疫苗令人失望。有必要的新方法。因此，我们建议识别疫苗对抗腺体比以前更有效，更安全的腺体。它将是由病原体亚基的收集，其中包括抗原刺激保护性宿主免疫反应的抗原但是排除那些免疫逃避或多余的人。从概念上讲，这是解决整体的问题病原体疫苗可能会提供太多的成分（无用的疫苗稀释有用的疫苗）以及可能提供太少成分的亚基疫苗的问题（有限的抗原覆盖范围）。我们将通过对所有B. mallei编码序列进行基因组规模来实现这一目标在腺疾病的鼠模型中，通过表达文库免疫来保护保护性抗原。我们的识别这种凝结抗原滤液的具体方法是1）建立最佳用于大规模进行保护测定的分子和动物模型方案2） Mallei的编码序列成遗传免疫的表达构建库，3）直接测定体内每个B. mallei编码序列的保护能力。在这个项目的结尾，我们将产生保护性亚基，这将准备好进行交付和模态优化研究。预计开发麦芽芽孢杆菌疫苗将极大地促进8. pseudomalliei和 6。针对这些古老疾病的卷曲疫苗疫苗。