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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.

吸入性炭疽病已成为一种重大的、持续的生物武器和生物毒害威胁。尽管疫苗策略在很大程度上控制了动物种群中的这种疾病，但目前的授权人类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进行多次免疫。炭疽病感染的生物学和具体地说，其毒素的作用已在分子和细胞水平上得到了优雅的阐明。这提供了一个独特的机会，可以合理地设计和开发一种可以对抗目前的炭疽病以及今后可能遇到的改良形式。在这个项目中，我们将使用与炭疽毒素相关的大量知识和见解开发分子靶向疫苗，以防止毒素在感染后的灾难性影响。基于对所有成分的晶体结构、序列和功能的仔细分析炭疽毒素，我们将开发可溶性蛋白疫苗，将抗体反应定向到关键的参与毒素激活、组装和与细胞黏附的蛋白质片段。我们将对这些疫苗进行测试构建其能够诱导强大的抗体反应并中和体内毒素活性的载体体外试验。基于对可溶蛋白质构建物的响应分析，选定的构建物将是进入腺相关病毒疫苗平台，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已经产生了非常持久的反应。以AAV为基础的疫苗将接受免疫原性测试，并用于诱导毒素中和抗体，以及与可溶性蛋白免疫原结合使用。最后，最有希望的可溶性蛋白质和表达形式的构建将在炭疽孢子中进行测试在兔身上进行的吸入性挑战研究。这样的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和保护。通过这种方法，我们将开发出有希望的候选炭疽疫苗，这种疫苗可以预防针对当前存在的炭疽菌株以及基于工程设计的新的和增强的威胁各种形式的炭疽病。