Molecularly Targeted Vaccines for Anthrax

炭疽分子靶向疫苗

• 批准号: 6838737
• 负责人: Kemp Bailey Cease
• 金额: $ 63.97万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838737
• 关键词: SDS polyacrylamide gel electrophoresis; adeno associated virus group; aerosols; affinity chromatography; anthrax toxin; anthrax vaccines; antibody neutralization test; antibody specificity; antigen antibody reaction; antigen presentation; bacterial proteins; bacterial toxins; bacterial vaccines; biotechnology; bioterrorism /chemical warfare; cooperative study; drug delivery systems; drug screening /evaluation; enzyme linked immunosorbent assay; green fluorescent proteins; laboratory mouse; laboratory rabbit; neutralizing antibody; nucleic acid sequence; polymerase chain reaction; transfection /expression vector; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Inhalation anthrax has emerged as a significant and continuing biowarfare and bioterrorism threat. Though vaccine strategies have substantially controlled this disease in animal populations, the current vaccine licensed for human use has several shortcomings, including significant adverse reactions and low immunogenicity resulting in the need for multiple immunizations. The biology of anthrax infection and specifically the actions of its toxins have been elegantly elucidated at the molecular and cellular level. This presents a unique opportunity to rationally design and develop an improved vaccine that can counter current anthrax, as well as modified forms that may be encountered in the future. In this project, we will use the substantial body of knowledge and insight available relating to anthrax toxin to develop molecularly targeted vaccines to prevent the catastrophic effects of toxin following infection. Based on careful analysis of the crystal structure, sequence, and functional studies of all components of the anthrax toxins, we will develop soluble protein vaccines that direct antibody responses towards the critical protein segments involved in toxin activation, assembly, and adherence to cells. We will test these vaccine constructs for their ability to elicit strong antibody responses with the ability to neutralize toxin activity in in vitro assays. Based on analysis of responses to the soluble protein constructs, selected constructs will be moved into the adeno-associated virus vaccine platform for development of an expression vaccine. Traditionally such vaccines have exhibited higher immunogenicity, and AAV in particular has yielded very durable responses. The AAV-based vaccines will be tested for immunogenicity and their ability to elicit toxin-neutralizing antibodies, as well as for use in concert with soluble protein immunogens. Finally, the most promising constructs of both soluble protein and expressed forms will be tested in anthrax spore inhalation challenge studies in rabbits. Such experiments have been extensively validated against primate experiments previously and also appear to correlate most closely with human anthrax disease and protection. Through this approach, we will develop promising candidate anthrax vaccines that can protect against currently existing strains of anthrax, as well as new and enhanced threats based on engineered forms of anthrax.

描述（由申请人提供）： 吸入性炭疽已成为一种重大且持续的生物战和生物恐怖主义威胁。尽管疫苗策略已经在动物群体中基本上控制了这种疾病，但目前许可用于人类使用的疫苗存在一些缺点，包括明显的不良反应和低免疫原性，导致需要多次免疫。炭疽感染的生物学，特别是其毒素的作用，已在分子和细胞水平上得到了很好的阐明。这提供了一个独特的机会，可以合理设计和开发一种可以对抗当前炭疽的改良疫苗，以及未来可能遇到的改进形式。在这个项目中，我们将利用与炭疽毒素相关的大量知识和见解来开发分子靶向疫苗，以防止感染后毒素造成的灾难性影响。基于对炭疽毒素所有成分的晶体结构、序列和功能研究的仔细分析，我们将开发可溶性蛋白疫苗，将抗体反应引导至参与毒素激活、组装和细胞粘附的关键蛋白片段。我们将测试这些疫苗构建体引发强烈抗体反应的能力，以及在体外测定中中和毒素活性的能力。根据对可溶性蛋白构建体反应的分析，选定的构建体将被转移到腺相关病毒疫苗平台中以开发表达疫苗。 传统上，此类疫苗表现出较高的免疫原性，尤其是 AAV 产生了非常持久的反应。基于 AAV 的疫苗将测试其免疫原性及其引发毒素中和抗体的能力，以及与可溶性蛋白免疫原协同使用的能力。最后，最有前途的可溶性蛋白质和表达形式的构建体将在兔子的炭疽孢子吸入挑战研究中进行测试。此类实验先前已针对灵长类动物实验进行了广泛验证，并且似乎与人类炭疽疾病和保护密切相关。通过这种方法，我们将开发有前途的候选炭疽疫苗，可以预防目前现有的炭疽菌株，以及基于工程炭疽形式的新的和增强的威胁。