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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。