Recombinant Adenovirus Vaccines Against B. anthracis

描述(申请人提供)：炭疽芽孢杆菌通过产生两种毒素，致命毒素和水肿毒素来发挥其致病作用。每种毒素都是一种二元毒素，分别由一个共同的亚基、保护性抗原(PA)和一个独特的亚基--致死因子(LF)或水肿因子(EF)组成。PA是主要的细菌抗原，免疫系统对其进行保护性反应。炭疽病的分子致病机制包括PA作为七聚体与宿主细胞结合，然后与LF或EF结合，并使复合体内化。在内体酸化时，PA的构象变化允许它形成一个孔，EF或LF通过这个孔进入细胞质并导致疾病。炭疽病只有在感染的早期被发现时，才能用抗生素治疗。一种炭疽杆菌疫苗可以产生抗体来阻断PA功能，但完全免疫需要长时间的注射。随着炭疽杆菌被用作生物恐怖主义武器的威胁，一种更快速有效的疫苗将使大规模人群免疫更可行。人类腺病毒是一种DNA病毒，通常会在健康人中引起轻微的自限性感染。对病毒进行基因改造，使其复制能力和表达外来蛋白的能力严重下降是可能的。由于腺病毒在感染抗原提呈细胞和诱导免疫方面非常有效，这些特性使其成为疫苗载体的理想选择。在目前的应用中，建议进行中试实验，以评估开发两种针对PA的重组腺病毒疫苗的可行性。第一种类型是将PA作为转基因表达的复制缺陷病毒，第二种将是将PA的特定抗原域作为病毒衣壳的一部分表达的病毒。这两种疫苗都将在炭疽杆菌感染的标准常规模型中进行测试。如果成功，这些初步研究将导致改进的炭疽杆菌疫苗的开发，并将为针对可能被生物恐怖分子使用的其他传染病病原体的类似疫苗建立一个平台。

DESCRIPTION (provided by applicant): Bacillus anthracis exerts its pathogenic effects through the production of two toxins, lethal toxin and edema toxin. Each of these is a binary toxin consisting of a common subunit, protective antigen (PA), and a unique subunit, lethal factor (LF) or edema factor (EF), respectively. PA is the major bacterial antigen against which the immune system mounts a protective response. The molecular pathogenesis of anthrax involves binding of PA as a heptamer to the host cell, followed by binding of LF or EF and internalization of the complex. Upon endosome acidification, a conformational change in PA allows it to form a pore through which EF or LF enters the cytoplasm and causes disease. Anthrax is treatable with antibiotics only if the infection is identified early in its course. A B. anthracis vaccine is available which elicits antibodies that block PA function, but full immunity requires a long series of injections. With the threat of B. anthracis being used as a bioterrorism weapon, a more rapid-acting vaccine would make immunization of large populations more practicable. Human adenoviruses are DNA viruses that generally cause mild, self-limiting infections in healthy individuals. It is possible to genetically engineer the virus such that its ability to replicate is severely reduced, and to express foreign proteins. As adenovirus is very efficient at infecting antigen presenting cells and inducing immunity, these characteristics make it an excellent choice as a vaccine vector. In the present application, pilot experiments are proposed to assess the feasibility of developing two types of recombinant adenovirus vaccines against PA. The first type will be a replication defective virus that expresses PA as a transgene, and the second will be a virus that expresses specific antigenic domains of PA as part of the virus capsid. Both these vaccines will be tested in a standard routine model of B. anthracis infection. If successful, these initial studies will lead to the development of an improved B. anthracis vaccine, and will establish a platform for similar vaccines against other infectious agents that might be used by bioterrorists.