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（由应用提供）：肉毒杆菌神经毒素（BONT）是人类闻名的最具毒性蛋白，也是肉毒杆菌症的严重毒剂。 BONT被组织成涉及催化（LC），易位（HCT）和受体结合（HCR）的三个结构域。现在有八个BONT血清型（A-H）基于对每种BONT血清型的cross型保护有限的保护。目前，在2011年，尚无针对肉毒杆菌病的持牌疫苗，并且先前从CDC上获得的实验性五型毒素毒素疫苗在2011年停用。这需要开发潜在有效的bont疫苗，以防止所有Bont bott疫苗，以防止所有Bont bont Serotypes，以保护所有的血清型，以保护危险的人类免受海平面的暴露，包括Harmisians in Harmean in Harmean，包括Harmeans，第一位征服者，以及第一批响应者，以及第一个响应者，以及响应者。几种生成新的BONT疫苗的方法尚未产生疫苗产品。通过Barbieri和Johnson Laboratore之间的合作而开发的两种已发表的针对肉毒杆菌的疫苗方法包括一种HCR亚基疫苗，该疫苗受到了七个BONT血清型保护的挑战，以及一种全长的Atoxic Bont（M-Bont）疫苗，该疫苗受到保护，该疫苗受到防止BONT/A BONT/A BONT挑战。 HCR是大量生产的稳定产品，是无毒的，而不是受调节的剂，因此，这项研究的目标是优化HCR和M-Bont疫苗平台，以生成泛滥的受保护疫苗，以抗食源和吸入肉毒杆菌。假设是，与毒素疫苗相比，已经突变以消除细胞结合和催化活性的天然BONT或HCR衍生物将提高对所有BONT血清型的疫苗效力，同时增强安全性并减少疫苗副作用。具体目标将利用Barbieri和Johnson实验室的完整研究专业知识。该目标将使用小鼠挑战模型来设计一种泛孔血清型保护疫苗，以防止肉毒杆菌。优化的疫苗将在肉毒杆菌症中的食物和吸入模型中测试预付款。这些研究将产生针对肉毒杆菌病的下一代疫苗，以及快速响应BONT变体的策略。