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Molecularly Targeted Vaccines for Anthrax

炭疽分子靶向疫苗

基本信息

批准号：
7187390
负责人：
Kemp Bailey Cease
金额：
$ 101.09万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7187390
关键词：
Adherence Adverse reactions Aerosols Animals Anthrax Vaccines Anthrax disease Antibodies Antibody Formation Antigens Bacillus (bacterium)Bacillus anthracis spore Biological Assay Biological Warfare Biology Blocking Antibodies Breathing Cell Line Cells Complement Dependovirus Development Dose Engineering Epitopes Evaluation Exhibits Freund&apos s Adjuvant Future Generations Human Hybrids Immune Sera Immune response Immunity Immunization Immunologics Immunology In Vitro Individual Infection Intramuscular Knowledge Licensing Molecular Mus Oryctolagus cuniculus Peptides Performance Population Primates Proteins Protocols documentation Route Serum Site Structure System Tandem Repeat Sequences Testing Toxin Treatment Protocols Vaccines Validation Virulent Virus anthrax lethal factor anthrax toxin base design design and construction disorder control edema factor immunogenicity improved in vitro Assay insight interest macrophage neutralizing antibody prevent prototype research study response vaccine evaluation

项目摘要

Inhalation anthrax has emerged as a significant and continuing biowarfare and bioterrofism 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 designed 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 are for the 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.

吸入性炭疽已成为一种重大和持续的生物战和生物恐怖主义威胁。虽然疫苗策略已经基本上控制了动物群体中的这种疾病，但目前的疫苗策略仍然是有效的。被许可用于人类使用的疫苗具有几个缺点，包括显著的不良反应和低免疫原性导致需要多次免疫。炭疽感染的生物学和特别是其毒素的作用已经在分子和细胞水平上被优雅地阐明。这提供了一个独特的机会，合理设计和开发一种改进的疫苗，目前的炭疽以及未来可能遇到的改良形式。在这个项目中，我们将使用大量的知识和洞察力有关炭疽毒素开发分子靶向疫苗，以防止感染后毒素的灾难性影响。基于对晶体结构的仔细分析，序列，以及对所有组分的功能研究，炭疽毒素，我们将开发可溶性蛋白疫苗，直接抗体反应对关键的参与毒素活化、组装和粘附细胞的蛋白质片段。我们将测试这些疫苗这些构建体具有引发强抗体应答的能力以及中和体内毒素活性的能力，体外测定。基于对可溶性蛋白质构建体的响应的分析，将选择的构建体与可溶性蛋白质构建体进行比较。转移到腺相关病毒疫苗平台，用于开发表达疫苗。传统上，此类疫苗表现出更高的免疫原性，特别是AAV产生了非常高的免疫原性。持久的反应。将测试基于AAV的疫苗的免疫原性，并测试其引发免疫应答的能力。毒素中和抗体，以及与可溶性蛋白免疫原一起使用。最后最有希望的可溶性蛋白质和表达形式的构建体将在炭疽孢子中进行测试兔吸入激发研究。这种实验已经在灵长类动物身上得到了广泛的验证以前的实验，也似乎与人类炭疽病最密切相关，保护通过这种方法，我们将开发出有希望的候选炭疽疫苗，针对现有的炭疽菌株以及基于工程的新的和增强的威胁，炭疽的形式。