Vaccines Against Botulism

肉毒杆菌疫苗

• 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
• 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

 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(申请人提供)：肉毒杆菌神经毒素(BONT)是已知的对人类最有毒的蛋白质，也是肉毒杆菌中毒的病原体。BoNTs分为催化(LC)、易位(HCT)和受体结合(HCR)三个结构域。根据血清对每种BONT血清型的有限交叉血清型保护，目前有八种BONT血清型(A-H)。目前，没有获得许可的肉毒杆菌中毒疫苗，疾控中心以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，有必要开发一种针对所有BONT血清型的有效且有效的BONT疫苗，以保护高危人群免受接触，包括处于危险中的平民、急救人员、军方和研究人员。生产新的BONT疫苗的几种方法还没有产生疫苗产品。通过Barbieri和Johnson实验室的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HCR亚单位疫苗，它可以防止七种BONT血清型的挑战，以及一种全长无毒BONT(M-BONT)疫苗，它可以防止BONT/A挑战。HCRS是大量生产的稳定产品，无毒，不受选择剂监管，从而使产品开发变得简单明了。这项研究的目标是优化HCR和M-BONT疫苗平台，以产生针对食源性和吸入性肉毒杆菌中毒的PAN-BONT保护性疫苗。假说是，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，同时提高安全性并减少疫苗副作用。具体的目标将利用Barbieri和Johnson实验室的互补研究专业知识。AIMS将使用小鼠挑战模型设计一种针对肉毒杆菌中毒的泛邦特血清型保护性疫苗。优化后的疫苗将在肉毒杆菌中毒的食源性和吸入性模型中进行效力测试。这些研究将生产针对肉毒杆菌中毒的下一代疫苗，以及对BoNT变种的释放做出快速反应的策略。