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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.

肉毒杆菌神经毒素（BoNT）是一个庞大的蛋白毒素家族，分为七个血清型（A-G）这是基于抗BoNT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和肉毒杆菌中毒的病原体。目前，还没有获得许可的疫苗，肉毒杆菌中毒和实验性五血清型类毒素疫苗以前可从疾病预防控制中心的风险人口在2011年停止。因此，需要开发一种有效的BoNT疫苗。针对所有BoNT血清型，以保护处于危险中的人免受暴露，包括处于危险中的平民，首先救援人员、军方和研究人员。BoNT被组织成三个参与催化（LC）的结构域， LC易位（HCN）和受体结合（HCC）。早期的努力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，但最近的研究表明，显示重组全长BoNT疫苗比包含受体的疫苗更有效结合域此外，ELISA研究暗示HCN易位结构域作为免疫显性蛋白，在重组全长BoNT疫苗接种的小鼠中，天然肉毒杆菌毒素挑战。这支持了重组全长无毒BoNT 突变以抑制毒素作用的三个独立功能（催化、LC易位和受体），结合）将提高远系繁殖群体的疫苗效力。目前的研究将利用信息学和评估的结构功能比对的七个肉毒杆菌毒素的血清型，沿着细胞生物学分析和抗体的免疫学评估 (IgM和IgG）应答的动物进行免疫接种的重组全长BoNT疫苗与化学免疫接种的动物相比，灭活的肉毒杆菌类毒素。将测试两种肉毒杆菌毒素疫苗模型：单次高剂量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疫苗对抗肉毒杆菌毒素将对低剂量保护性疫苗与化学灭活疫苗进行对比试验肉毒杆菌类毒素在小鼠和兔子中的作用。对细菌毒素结构-功能特性的理解允许生产更安全、更便宜、更容易生产的下一代疫苗，与化学灭活的类毒素相比，具有遗传可塑性，可进行快速修饰。本报告中提出的研究应用为毒素疫苗学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）

Botulinum neurotoxins A, B, C, E, and F preferentially enter cultured human motor neurons compared to other cultured human neuronal populations.

DOI：
10.1002/1873-3468.13508
发表时间：
2019-09
期刊：
FEBS letters
影响因子：
3.5
作者：
Pellett S;Tepp WH;Johnson EA
通讯作者：
Johnson EA

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

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

DOI：
10.3390/toxins15090563
发表时间：
2023-09-08
期刊：
Toxins
影响因子：
4.2
作者：
Gupta S;Pellett S
通讯作者：
Pellett S

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

Light Chain Diversity among the Botulinum Neurotoxins.

肉毒神经毒素之间的轻链多样性。