Discovery of subunit vaccine candidates against glanders

扁桃体是一种严重的疾病，作为有效的生物武器已经有过使用的历史。它自然是一种 马病，但通过人畜共患病传播给人类。即使很快被诊断为伯克霍尔德氏菌， 抗生素治疗显示效果不佳，疾病控制需要长期服用多种药物。 即使急性期存活下来，慢性感染也可能长达20年之久。最多的 合理的防御计划是一种疫苗，但到目前为止还没有一种疫苗成功研制出来。免疫者 这种复杂病原体的逃避策略，包括基因组流动性，使其表现得甚至 活疫苗令人失望。新的方法是有必要的。因此，我们建议确定一种疫苗 对抗扁桃体，比以往任何药物都更有效和更安全。它将从一个 包括刺激保护性宿主免疫反应的抗原的病原体亚基的收集 然而，将那些免疫规避或多余的排除在外。这从概念上解决了整个 病原体疫苗可能会提供太多的成分(有用的成分被无用的成分稀释) 以及亚单位疫苗可能提供的成分太少(抗原性有限)的问题 覆盖范围)。我们将通过对所有马来芽胞杆菌编码序列进行基因组规模的搜索来实现这一点 在腺病小鼠模型中通过表达文库免疫来寻找保护性抗原。我们的 鉴定这种浓缩的保护性抗原滤液的具体方法是：1)建立最佳 用于在大规模上进行保护分析的分子和动物模型协议2)建立所有 将马来芽胞杆菌的序列编码到用于遗传免疫的表达构建体库中，以及3)直接 在体内检测每一条马来杆菌编码序列的保护能力。在这个项目结束时，我们 将产生保护性亚单位，并将为交付和模式优化研究做好准备。 马来假单胞菌疫苗的开发有望极大地促进8.假马利氏杆菌和 6.针对这些古老疾病的洋葱疫苗。

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.