Molecularly Targeted Vaccines for Anthrax

炭疽分子靶向疫苗

• 批准号: 6690634
• 负责人: Kemp Bailey Cease
• 金额: $ 33.98万
• 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/6690634
• 关键词: SDS polyacrylamide gel electrophoresis; adeno associated virus group; aerosols; affinity chromatography; 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）： 吸入炭疽已成为一种持续且持续的生物处理和生物恐怖主义威胁。尽管疫苗策略已在动物种群中基本控制了这种疾病，但当前获得人使用的疫苗有几个缺点，包括严重的不良反应和低免疫原性，导致需要多次免疫。在分子和细胞水平上，已经优雅地阐明了炭疽感染的生物学，特别是其毒素的作用。这为合理设计并开发了可以抵抗当前炭疽的改进的疫苗以及将来可能会遇到的修改形式的疫苗提供了独特的机会。在这个项目中，我们将使用与炭疽毒素有关的大量知识和洞察力，以开发分子靶向疫苗，以防止感染后毒素的灾难性作用。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，这些疫苗将抗体蛋白片段直接抗体蛋白片段直接抗毒素激活，组装，组装和对细胞的粘附。我们将测试这些疫苗构建体的能力，以引起强抗体反应，并在体外测定中中和毒素活性的能力。基于对可溶性蛋白质构建体的反应的分析，选定的构建体将移至与腺相关的病毒疫苗平台中，以开发表达疫苗。 传统上，这种疫苗表现出更高的免疫原性，特别是AAV产生了非常耐用的反应。基于AAV的疫苗将测试免疫原性及其引起毒素中和抗体的能力，并与可溶性蛋白免疫原子一起使用。最后，将在兔子中的炭疽孢子吸入挑战研究中测试可溶性蛋白和表达形式的最有希望的构建体。此类实验以前已经针对灵长类动物实验进行了广泛的验证，并且似乎与人类炭疽病和保护最紧密地相关。通过这种方法，我们将开发有希望的候选炭疽疫苗，以防止当前现有的炭疽病菌株，以及基于工程炭疽形式的新威胁和增强的威胁。