Discovery of subunit vaccine candidates against glanders

发现针对鼻疽的候选亚单位疫苗

• 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
• 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

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，已经有作为有效生物武器使用的历史。这自然是一个 马的疾病，但动物传染给人类。即使很快被诊断为鼻疽伯克霍尔德菌， 抗生素治疗显示出低功效，并且疾病控制需要使用多种药物的长期方案。 即使急性期存活，慢性感染也可能长达20年。最 合理的防御计划是一种疫苗，但迄今为止还没有一种疫苗研制成功。免疫 这种复杂病原体的逃避策略，包括基因组的流动性，甚至表现出 活疫苗令人失望必须采取新的办法。因此，我们建议确定一种疫苗 比以前的任何一种都更有效和安全。它将从一个 病原体亚单位的集合，包括刺激保护性宿主免疫反应的抗原 但排除那些免疫规避或多余的。这在概念上解决了整个 病原体疫苗可能提供太多的成分（有用成分被无用成分稀释） 以及可能提供太少组分（有限的抗原性）的亚单位疫苗的问题 覆盖率）。我们将通过对所有B进行基因组规模的搜索来实现这一目标。鼻疽编码序列 通过表达文库免疫在小鼠鼻疽病模型中获得保护性抗原。我们 鉴定这种保护性抗原的浓缩滤液的具体方法是：1）建立最佳的 分子和动物模型协议进行大规模的保护试验2）建立所有的 B编码序列。将鼻疽杆菌转化到用于遗传免疫的表达构建体的文库中，以及3）直接 测定各B的保护能力。鼻疽编码序列。在这个项目结束时，我们 将产生保护亚单位，并将准备交付和模态优化研究。 发展一个B。预期鼻疽疫苗将大大促进A8的发展。伪马利埃和 6.对抗这些古老疾病的洋葱疫苗。