Vaccines Against Botulism

肉毒杆菌疫苗

基本信息

批准号：
9109536
负责人：
Joseph T Barbieri
金额：
$ 60万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9109536
关键词：
Adverse effects Amino Acids Bacterial Proteins Bacteriology Binding Biochemistry Bioterrorism Bontoxilysin Botulinum Toxin Type A Botulism Breathing C-terminal Catalysis Cells Cellular biology Centers for Disease Control and Prevention (U.S.)Clostridium botulinum Collaborations Cytosol Engineering Epitopes Escherichia coli Gangliosides Generations Goals Gold Health Human Immune Immune response Intoxication Laboratories Length Licensing Light Link Military Personnel Modeling Molecular Biology Mus Mutagenesis Mutate Mutation N-terminal Neurons Notification Pentas Pichia Populations at Risk Post-Translational Protein Processing Proteins Publishing Recombinants Recording of previous events Regulation Research Research Personnel Risk Safety Serotyping Serum Solubility Structure Subunit Vaccines Testing Toxin Toxoids Vaccination Vaccines Variant base botulinum toxin type B disulfide bond emergency service responder exposed human population foodborne ganglioside receptor improved in vivo mouse model neutralizing vaccine novel vaccines potency testing product development receptor binding response structural biology vaccine development weapons

项目摘要

DESCRIPTION (provided by applicant): The botulinum neurotoxins (BoNT) are the most toxic proteins known for humans and the causative agent of botulism. BoNTs are organized into three domains that are involved in catalysis (LC), translocation (HCT), and receptor binding (HCR). There are now eight BoNT serotypes (A-H) based upon limited cross serotype protection of -sera against each BoNT serotype. Currently, there is no licensed vaccine against botulism and the experimental penta-serotype toxoid vaccine previously available from the CDC for at-risk populations was discontinued in 2011. Thus, there is a need to develop a potent and effective BoNT vaccine against all BoNT serotypes to protect at-risk humans from exposure, including civilians in harm's way, first responders, the military, and researchers. Several approaches to generate new BoNT vaccines have not yielded a vaccine product. Two published vaccine approaches against botulism developed through collaborations between the Barbieri and Johnson laboratories include an HCR subunit vaccine that protected against challenge by the seven BoNT serotypes, and a full-length, atoxic BoNT (M-BoNT) vaccine that protected against BoNT/A challenge. HCRs are stable products made in large quantity, are nontoxic and not Select Agent regulated, thus making product development straightforward. The goal of this study is to optimize the HCR and M-BoNT vaccine platforms towards the generation of a pan-BoNT protective vaccine against foodborne and inhalation botulism. The hypothesis is that native BoNT or HCR derivatives that have been mutated to eliminate cell binding and catalytic activity will improve vaccine potency against all BoNT serotypes compared to toxoid vaccines, while enhancing safety and reducing vaccine side effects. The specific aims will utilize the complementary research expertise of both the Barbieri and Johnson laboratories. The aims will engineer a pan-BoNT serotype protective vaccine against botulism, using the mouse challenge model. Optimized vaccines will be tested for potency in food borne- and inhalation- models of botulism. These studies will produce the next generation vaccine against botulism and a strategy for rapid response to the release of BoNT variants.

描述（由申请人提供）：肉毒杆菌神经毒素 (BoNT) 是已知对人类毒性最强的蛋白质，肉毒杆菌中毒的病原体分为三个结构域，涉及催化 (LC)、易位 (HCT) 和受体。基于 α 血清针对每种 BoNT 的有限交叉血清型保护，现在有八种 BoNT 血清型 (A-H)。目前，还没有获得许可的针对肉毒杆菌中毒的疫苗，并且 CDC 先前为高危人群提供的实验性五血清型类毒素疫苗已于 2011 年停止使用。因此，需要开发一种针对所有肉毒杆菌中毒的强效且有效的 BoNT 疫苗。用于保护高危人群（包括处于危险中的平民、急救人员、军队和研究人员）免受暴露的 BoNT 血清型几种生产新 BoNT 疫苗的方法尚未产生疫苗。 Barbieri 和 Johnson 实验室合作开发的两种已发表的针对肉毒杆菌中毒的疫苗方法包括一种可抵御七种 BoNT 血清型攻击的 HCR 亚单位疫苗，以及一种可抵御 BoNT 的全长无毒 BoNT (M-BoNT) 疫苗。 /挑战。HCR 是大量生产的稳定产品，无毒且不受 Select Agent 监管，因此本研究的目标是优化 HCR 和 M-BoNT 疫苗平台。针对食源性和吸入性肉毒中毒的泛 BoNT 保护性疫苗的产生假设是，与类毒素疫苗相比，经过突变以消除细胞结合和催化活性的天然 BoNT 或 HCR 衍生物将提高针对所有 BoNT 血清型的疫苗效力。提高安全性并减少疫苗副作用的具体目标将利用 Barbieri 和 Johnson 实验室的互补研究专业知识，设计一种针对多种 BoNT 血清型的保护性疫苗。优化的疫苗将在食源性和吸入性肉毒中毒模型中进行效力测试，这些研究将产生下一代针对肉毒中毒的疫苗以及对 BoNT 变体释放的快速反应策略。