Vaccines Against Botulism

肉毒杆菌疫苗

基本信息

批准号：
10434672
负责人：
Joseph T Barbieri
金额：
$ 67.07万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434672
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 cross immunity exposed human population first responder genetic manipulation improved neurotoxin 5 neutralizing antibody next generation novel vaccines potency testing prevent prophylactic receptor binding response vaccine strategy vaccinology

项目摘要

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) 基于 α 血清对每种 BoNT 血清型的有限交叉保护，BoNT 是毒性最强的蛋白质。人类已知的肉毒杆菌毒素，目前还没有获得许可的疫苗。肉毒杆菌中毒和疾病预防控制中心先前为高危人群提供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、军队和研究人员被组织成涉及催化（LC）的三个领域， LC 易位 (HCN) 和受体结合 (HCC) 早期的工作重点是开发重组。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此外，ELISA 研究表明 HCN 易位结构域是免疫显性的。存活的重组全长 BoNT 小鼠中的结构域，而不是 HCC 受体结合结构域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 疫苗将针对低剂量保护性疫苗与化学灭活疫苗进行测试。小鼠和兔子中的肉毒杆菌类毒素的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，该类毒素具有遗传可塑性，可快速修饰。应用为毒素疫苗学的这些进展提供了未来方向。