Vaccines Against Botulism

肉毒杆菌疫苗

基本信息

批准号：
10630147
负责人：
Joseph T Barbieri
金额：
$ 66.25万
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/10630147
关键词：
Address Animal Model Animals Antibodies Antibody Response Bacterial Toxins Biological Biological Assay Botulinum Toxins Botulism Catalysis Cells Chemicals Clostridium botulinum Collection Developed Countries Developing Countries Development Disease Disease Outbreaks Dose Engineering Enzyme-Linked Immunosorbent Assay Family Funding Future Genetic Genetic Engineering Human Immune response Immunize Immunodominant Epitopes Immunoglobulin G Immunoglobulin M Immunologics Inactivated Vaccines Incidence Informatics Intoxication JTB gene Laboratories Length Licensing 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 botulinum botulinum toxin vaccine cross immunity exposed human population first responder improved nano 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.

肉毒神经毒素（BONT）是一个大蛋白毒素家族，分为七个BONT血清型（A-G）基于对每种BONT血清型的sera的有限保护。 BONT是最有毒的蛋白质以人类而闻名，是肉毒杆菌的认真推动者。目前，没有持牌疫苗针对肉毒杆菌和实验性PENTA型毒素疫苗先前可从CDC获得高危种群在2011年停产。这是有必要开发潜在有效的BONT疫苗反对所有BONT血清型，以保护高危人类免于暴露，包括危害的平民，首先响应者，军队和研究人员。 BONT被组织成参与催化的三个领域（LC）， LC易位（HCN）和接收器结合（HCC）。较早的努力集中于发展重组基于HCC的疫苗要克服化学灭活毒素的缺点，但最近的研究具有表明重组全长Bont疫苗比完成接收器的疫苗更有潜力结合域。此外，ELISA研究将HCN易位域实施为免疫主导在重组全长BONT疫苗接种的小鼠中，域而不是HCC受体结合结构域本地肉毒杆菌毒素挑战。这支持了重组全长无毒的假设突变以使毒素作用的三个独立函数（催化，LC易位和接收器）结合）将改善近代种群的疫苗效力。当前的研究将利用信息信息并评估七个的结构功能对齐肉毒杆菌毒素的血清型，以及细胞生物学分析和抗体的免疫学评估（IgM和IgG）用重组，全长BONT疫苗与化学的反应反应灭活的肉毒杆菌毒素。将测试两种用于肉毒杆菌毒素疫苗的模型：一个高剂量bont 疫苗以快速反应BONT暴露的威胁和低剂量Bont疫苗以进行长期保护反对BONT暴露。低剂量保护的疫苗将被测试与化学灭活小鼠和兔子中的肉毒杆菌毒素。了解细菌毒素的结构功能特性允许生产更安全，更便宜，更易于生产的下一代疫苗，并且与化学灭活的毒素相比，遗传延展性可快速修饰。提出的研究应用为毒素疫苗学方面的这些进展提供了未来的方向。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Critical Analysis of Neuronal Cell and the Mouse Bioassay for Detection of Botulinum Neurotoxins.

神经元细胞的批判性分析和肉毒杆菌神经毒素检测的小鼠生物测定。

DOI：
10.3390/toxins11120713
发表时间：
2019
期刊：
Toxins
影响因子：
4.2
作者：
Pellett,Sabine;Tepp,WilliamH;Johnson,EricA
通讯作者：
Johnson,EricA

Genomic Diversity, Competition, and Toxin Production by Group I and II Clostridium botulinum Strains Used in Food Challenge Studies.

DOI：
10.3390/microorganisms10101895
发表时间：
2022-09-23
期刊：
MICROORGANISMS
影响因子：
4.5
作者：
Bowe, Brooke Kathryn;Wentz, Travis Gwynn;Gregg, Brieana Marie;Tepp, William Howard;Schill, Kristin Marie;Sharma, Shashi;Pellett, Sabine
通讯作者：
Pellett, Sabine

Recent Developments in Vaccine Design: From Live Vaccines to Recombinant Toxin Vaccines.