Vaccines Against Botulism

肉毒杆菌疫苗

• 批准号: 10170209
• 负责人: Joseph T Barbieri
• 金额: $ 68.75万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170209
• 关键词: Address; Animal Model; Animals; Antibodies; Antibody Response; Bacterial Toxins; Biological; Biological Assay; Bontoxilysin; Botulinum Toxins; Botulism; Catalysis; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Clostridium botulinum; Collection; Developed Countries; Developing Countries; Development; Disease; Disease Outbreaks; Dose; Engineering; Enzyme-Linked Immunosorbent Assay; Family; Funding; Future; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Engineering; Human; Immune response; Immunize; Immunodominant Epitopes; Immunoglobulin G; Immunoglobulin M; Immunologics; Inactivated Vaccines; Incidence; Informatics; Intoxication; JTB gene; Laboratories; Length; Mediating; Memory; Military Personnel; Modeling; Modification; Mus; Mutate; Mutation; Oryctolagus cuniculus; Pentas; Population; Populations at Risk; Production; Property; Proteins; Recombinants; Research Personnel; Residual state; Risk; Serotyping; Structure; Structure-Activity Relationship; Terrorism; Testing; Toxic effect; Toxin; Toxoids; Translating; Vaccinated; Vaccination; Vaccines; Variant; Zinc; antitoxin; base; botulinum; botulinum toxin type B; botulinum toxin type C; exposed human population; first responder; genetic manipulation; improved; neurotoxin 5; neutralizing antibody; next generation; novel vaccines; potency testing; prevent; prophylactic; receptor binding; response; vaccinology

The botulinum neurotoxins (BoNT) are a large protein toxin family grouped into seven BoNT serotypes (A-G) based upon limited cross protection of -sera against each BoNT serotype. BoNT are the most toxic proteins known for humans and the causative agent of botulism. 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. BoNT are organized into three domains involved in catalysis (LC), LC translocation (HCN), and receptor binding (HCC). Earlier efforts have focused on developing recombinant HCC-based vaccines to overcome the shortcomings of chemically inactivated toxoids, but recent studies have shown that recombinant full-length BoNT vaccines are more potent than vaccines comprising the receptor binding domain. In addition, ELISA studies implicated the HCN translocation domain as the immunodominant domain, not the HCC receptor binding domain, in recombinant full-length BoNT vaccinated mice surviving native botulinum toxin challenge. This supports the hypothesis that a recombinant full-length non-toxic BoNT mutated to inactivate the three independent functions of toxin action (catalysis, LC translocation, and receptor binding) will improve vaccine potency for outbred populations. The current study will utilize informatics and assessment of structure-function alignments of the seven serotypes of botulinum toxin, along with cell biological analysis and immunological assessment of the antibody (IgM and IgG) response of animals immunized with recombinant, full-length BoNT vaccine versus chemically inactivated botulinum toxoid. Two models for botulinum toxin vaccines will be tested: a single high dose BoNT vaccine for rapid response to threats of BoNT exposure and a low dose BoNT vaccine for long term protection against BoNT exposure. The low dose protective vaccine will be tested versus chemically inactivated botulinum toxoid in mice and rabbits. Understanding of the structure-function properties of bacterial toxins allows production of Next Generation vaccines that are safer, less expensive, easier to produce, and genetically malleable for rapid modification than chemically inactivated toxoids. The studies proposed in this application provide future directions for these advances in toxin vaccinology.

肉毒杆菌神经毒素 (BoNT) 是一个大型蛋白质毒素家族，分为七种 BoNT 血清型 (A-G) based upon limited cross protection of -sera against each BoNT serotype. BoNT 是毒性最强的蛋白质 为人类所知，也是肉毒杆菌中毒的病原体。目前，还没有获得许可的疫苗 肉毒杆菌中毒和 CDC 先前提供的用于高危人群的实验性五血清型类毒素疫苗 2011 年停止用于人群。因此，需要开发一种强效且有效的 BoNT 疫苗 首先针对所有 BoNT 血清型，以保护高危人群免受暴露，包括受到伤害的平民 响应者、军队和研究人员。 BoNT 分为参与催化 (LC) 的三个域， LC 易位 (HCN) 和受体结合 (HCC)。早期的努力主要集中在开发重组 基于 HCC 的疫苗克服了化学灭活类毒素的缺点，但最近的研究发现 表明重组全长 BoNT 疫苗比包含该受体的疫苗更有效 结合域。 In addition, ELISA studies implicated the HCN translocation domain as the immunodominant 重组全长 BoNT 疫苗接种的存活小鼠中的结构域，而不是 HCC 受体结合结构域 天然肉毒杆菌毒素挑战。这支持了重组全长无毒 BoNT 的假设 突变使毒素作用的三个独立功能（催化、LC易位和受体）失活 结合）将提高远交种群的疫苗效力。 当前的研究将利用信息学和对七种结构功能对齐的评估 肉毒杆菌毒素的血清型，以及抗体的细胞生物学分析和免疫学评估 使用重组全长 BoNT 疫苗与化学疫苗免疫的动物的（IgM 和 IgG）反应 灭活的肉毒杆菌类毒素。将测试两种肉毒毒素疫苗模型：单一高剂量 BoNT 用于快速应对 BoNT 暴露威胁的疫苗和用于长期保护的低剂量 BoNT 疫苗 对抗 BoNT 暴露。低剂量保护性疫苗将与化学灭活疫苗进行测试 小鼠和兔子体内的肉毒杆菌类毒素。了解细菌毒素的结构功能特性 允许生产更安全、更便宜、更容易生产的下一代疫苗，并且 与化学灭活的类毒素相比，具有遗传可塑性，可以快速修饰。本文提出的研究 application provide future directions for these advances in toxin vaccinology.