Discovery of new anti-bacteremia vaccines for anthrax

描述（由申请人提供）：炭疽是由美国政府和其他一些国家开发的生物战剂。尽管有终止这些计划的条约和决议，炭疽仍然是一个非常真实的世界防御问题。由于炭疽疫苗将是任何有效防御计划的关键组成部分，我们的目标是找到一种。炭疽疫苗的努力几乎完全集中在改善PA或其他毒素抗原之一的纯化或配制上。我们认为，直接针对孢子或细菌的疫苗成分对于保护军事和平民人口免受自然炭疽病和特别是生物工程炭疽病的影响将是重要的。因此，我们建议筛选炭疽芽孢杆菌的所有基因，以了解它们对小鼠吸入性炭疽的保护能力。我们的方法将是建立所有的炭疽ORF作为基因疫苗，然后设计一个矩阵排列系统，使我们能够筛选高复杂性的库，在一个动物挑战实验的几个疫苗候选人。基本的功能基因组学方法是在DARPA的资助下开发的：表达文库免疫和线性表达元件。这些平台技术使我们的方法在技术上可行，并且它们的实用性已经在我们的实验室中得到验证。我们现在准备将它们应用于炭疽。具体来说，我们的目标将是产生B的4,000多个基因。炭疽杆菌的基因组中有超过14，000个重叠的基因片段，能够均匀地高水平表达。 利用我们独特的技术，候选疫苗将被迅速确定。免疫测定将用于指导啮齿动物保护的优化。然后，一组我们最好的候选人将在兔子身上进行测试，以对抗吸入性炭疽菌的挑战。在这个项目完成后，我们将提供一套基础广泛的炭疽病候选疫苗，这些疫苗可以与毒素抗原一起使用，也可以不使用。这些将准备进行临床前试验。我们还应该建立一个高通量的抗原发现系统，可以应用于其他生物威胁和新出现的病原体。

DESCRIPTION (provided by applicant): Anthrax was developed as a biowarfare agent by the US government and a number of other countries. Despite treaties and resolutions to terminate these programs, anthrax remains a very real, world defense issue. Since an anthrax vaccine will be a critical component of any effective defense plan, our objective is to find one. Vaccine efforts for anthrax have focused almost entirely on improving the purification or formulation of PA or one of the other toxin antigens. We believe that vaccine components that target the spore or bacterium directly will be important in protecting both military and civilian populations against both natural and especially bio-engineered anthrax disease. Therefore, we propose to screen all the genes of Bacillus anthracis for their ability to protect against inhalation anthrax in mice. Our approach will be to build all anthrax ORFs as gene vaccines, and then design a matrix arraying system that allows us to screen the high complexity library down to a few vaccine candidates in one animal challenge experiment. The underlying functional genomic methods were developed with DARPA funding: expression library immunization and linear expression elements. These platform technologies make our approach technically feasible, and their utility has been validated in our labs. We are now poised for their application to anthrax. Specifically, our aims will be to generate the more than 4,000 genes of B. anthracis as more than 14,000 overlapping gene fragments that are capable of uniformly high-level expression. Using our unique technologies, vaccine candidates will be identified quickly. Immune assays will be used to direct the optimization of protection in rodents. Then, a set of our best candidates will be tested in rabbits against an inhalation anthrax challenge. At the completion of this project, we will deliver a set of broad-based vaccine candidates against anthrax that might be administered with or without toxin antigens. These will be ready for preclinical trials. We should also have in place a high-throughput antigen discovery system that could be applied to other biothreat and emerging pathogens.