Novel Vaccines for Anthrax Prevention

描述（申请人提供）：炭疽是由炭疽芽孢杆菌引起的高致死率疾病。目前，它作为一种生物恐怖主义武器引起了人们的关注。炭疽芽孢杆菌的三组分毒素是主要的致病性介质。它由保护性抗原（PA）、致死性因子（LF）和水肿因子（EF）组成。虽然已知对PA的抗体反应可以保护炭疽，但目前还没有一种适合预防吸入性炭疽（最致命的形式）的疫苗可供大规模实际使用。我们假设，可能有可能将PA的特定结构域设计到流感病毒的血凝素糖蛋白（HA）中，并且含有这种嵌合HAs的流感疫苗株可能对这两种疾病提供保护性免疫。一个优点是，流感疫苗每年都大规模生产，因此，只要重组病毒生长得相当好，大规模免疫接种程序就不会出现问题。这种方法的另一个优点与流感作为全身和粘膜免疫的强诱导剂的特性有关，因此，可能增强对PA的中和抗体反应，并提供对吸入性炭疽的保护。因此，我们建议生成HA- pa嵌合蛋白，评估其提供HA受体结合和膜融合功能的能力，并通过反向遗传学生成含有最合适构建体的病毒。然后在小鼠中分析这些病毒诱导适当的抗ha和抗pa免疫反应的能力。

DESCRIPTION (provided by applicant): Anthrax is a highly lethal disease caused by Bacillus anthracis. Currently it poses a major concern as a bioterrorist weapon. The three-component toxin of Bacillus anthracis is the principle mediator of pathogenicity. It consists of the protective antigen (PA), the lethal factor (LF), and the edema factor (EF). Although antibody responses to the PA are known to protect anthrax, a suitable vaccine for prevention of inhalation anthrax, the most lethal form, is not currently available for large-scale practical use. We hypothesize that it might be possible to engineer particular domains of the PA into the hemagglutinin glycoprotein (HA) of influenza virus, and that vaccine strains of influenza containing such chimeric HAs might provide protective immunity against both diseases. One advantage is that influenza vaccines are produced in large scale on an annual basis, so mass immunization procedures would not be problematic provided the recombinant viruses grow reasonably well. Another advantage of this approach relates to the properties of influenza as a strong inducer of both systemic and mucosal immunity, and as such, might enhance the neutralizing antibody responses to PA and provide protection against inhalation anthrax. As such, we propose to generate chimeric HA-PA proteins, assess their capacity to provide HA receptor binding and membrane fusion functions, and generate viruses containing the most suitable constructs by reverse genetics. These viruses will then be analyzed in mice for their ability to induce appropriate anti-HA and anti-PA immune responses.