Development of a Novel Retrogen Vaccine for Anthrax

描述（由申请人提供）：炭疽是一种致命的败血症疾病，由摄入或吸入炭疽芽孢杆菌孢子引起。一旦感染确定，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副作用相对较高的问题。这一第一阶段提案旨在概述开发一种安全、有效和具有成本效益的DNA疫苗的方法，以便在公众中广泛预防炭疽病。各种炭疽杆菌毒素亚基（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是一种专有的疫苗技术，可以成倍地增强树突状细胞抗原呈递，除了CD8+ T细胞和DNA疫苗典型的抗体反应外，还可以诱导持续的CD4+ T细胞反应。这种强大的CD4+反应，在当前的无细胞递送系统中是独一无二的，应该协调CD8+ T细胞介导的清除感染巨噬细胞，在炭疽感染的早期阶段在其MHC I类分子上呈现毒素亚基肽。对孢子表面抗原的体液反应提供了在萌发之前清除休眠炭疽孢子的能力。对毒素亚单位的体液反应应该中和来自任何感染巨噬细胞的毒素活性，这些巨噬细胞逃脱了早期免疫监视。

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.