Development of a Novel Retrogen Vaccine for Anthrax

描述(申请人提供)：炭疽病是一种致命的败血症，由摄入或吸入炭疽芽胞引起。一旦确定感染，死亡率可能接近90%，使炭疽杆菌成为生物恐怖分子的首选武器。唯一获准在美国使用的炭疽疫苗存在免疫原性低和不良副作用相对较高的问题。这项第一阶段的提案旨在概述一种安全、有效和成本效益高的DNA疫苗可以用来在普通公众中广泛预防炭疽病的方法。不同的炭疽杆菌毒素亚单位(PA、EF和LF)和孢子表面抗原(EA1、SAP、CAPA、CAPB、CAPC和DEP)将与Retrovax一起进行测试，Retrovax是一种专利疫苗技术，可指数级增强树突状细胞抗原呈递，除DNA疫苗典型的CD8+T细胞和抗体反应外，还可诱导持续的CD4+T细胞反应。这种强大的CD4+反应在目前的无细胞递送系统中是独一无二的，它应该协调CD8+T细胞介导的受感染巨噬细胞在炭疽感染早期阶段清除其MHC I类分子上呈现毒素亚单位多肽的受感染巨噬细胞。对孢子表面抗原的体液反应提供了在萌发前清除休眠的炭疽孢子的能力。对毒素亚单位的体液反应应该中和任何受感染的巨噬细胞的毒素活性，这些巨噬细胞逃脱了早期的免疫监视。

DESCRIPTION (provided by applicant): Anthrax is a fatal septicemic disease caused by ingestion or inhalation of Bacillus anthracis spores. Once infection is established, mortality rates may approach 90%, making B. anthracis a weapon of choice among bioterrorists. The only anthrax vaccine licensed for use in the US is plagued with problems related to low immunogenicity and a relatively high level of adverse side effects. This Phase I proposal seeks to outline the methods by which a safe, efficacious, and cost-effective DNA vaccine may be developed for the widespread prevention of anthrax disease among the general public. Various B. anthracis toxin subunits (PA, EF, and LF) and spore surface antigens (EA1, Sap, CapA, CapB, CapC, and Dep) will be tested in conjunction with Retrovax, a proprietary vaccine technology which exponentially enhances dendritic cell antigen presentation, inducing a sustained CD4+ T cell response in addition to the CD8+ T cell and antibody responses typical of DNA vaccination. This robust CD4+ response, unique among current cell-free delivery systems, should coordinate the CD8+ T cell mediated clearing of infected macrophages presenting toxin subunit peptides on their MHC Class I molecules in the early stages of anthrax infection. Humoral responses to spore surface antigens offer the ability to clear dormant anthrax spores prior to germination. Humoral responses to toxin subunits should neutralize toxin activity from any infected macrophages, which escape early immune surveillance.