Recombinant Adenovirus Vaccines Against B. anthracis

性状（申请人提供）：炭疽杆菌通过产生致死毒素和水肿毒素两种毒素发挥致病作用。它们中的每一种都是二元毒素，分别由共同的亚基，保护性抗原（PA）和独特的亚基，致死因子（LF）或水肿因子（EF）组成。PA是主要的细菌抗原，免疫系统对其产生保护性应答。炭疽的分子发病机制涉及PA作为七聚体与宿主细胞的结合，随后是LF或EF的结合和复合物的内化。在核内体酸化时，PA的构象变化允许其形成孔，EF或LF通过该孔进入细胞质并引起疾病。只有在感染早期发现，炭疽才能用抗生素治疗。A B。炭疽病疫苗是可用的，其激发阻断PA功能的抗体，但完全免疫需要长时间的注射。有B的威胁。由于炭疽病被用作生物恐怖主义武器，一种更迅速起效的疫苗将使大规模人群的免疫接种更切实可行。人腺病毒是DNA病毒，通常在健康个体中引起轻度、自限性感染。有可能对病毒进行基因工程改造，使其复制能力严重降低，并表达外源蛋白。由于腺病毒在感染抗原呈递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绝佳选择。在本申请中，提出了中试实验以评估开发针对PA的两种类型的重组腺病毒疫苗的可行性。第一种类型是将PA表达为转基因的复制缺陷型病毒，第二种类型是将PA的特异性抗原结构域表达为病毒衣壳的一部分的病毒。这两种疫苗将在B的标准常规模型中进行检测。炭疽感染。如果成功的话，这些初步研究将导致改进的B的发展。炭疽病疫苗，并将建立一个平台，用于针对生物恐怖分子可能使用的其他传染性病原体的类似疫苗。

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.