Vaccines Against Botulism
肉毒杆菌疫苗
基本信息
- 批准号:10630147
- 负责人:
- 金额:$ 66.25万
- 依托单位:
- 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:
- 关键词:AddressAnimal ModelAnimalsAntibodiesAntibody ResponseBacterial ToxinsBiologicalBiological AssayBotulinum ToxinsBotulismCatalysisCellsChemicalsClostridium botulinumCollectionDeveloped CountriesDeveloping CountriesDevelopmentDiseaseDisease OutbreaksDoseEngineeringEnzyme-Linked Immunosorbent AssayFamilyFundingFutureGeneticGenetic EngineeringHumanImmune responseImmunizeImmunodominant EpitopesImmunoglobulin GImmunoglobulin MImmunologicsInactivated VaccinesIncidenceInformaticsIntoxicationJTB geneLaboratoriesLengthLicensingMediatingMemoryMilitary PersonnelModelingModificationMusMutateMutationOryctolagus cuniculusPentasPopulationPopulations at RiskProductionPropertyProteinsRecombinantsResearch PersonnelResidual stateRiskSerotypingStructureStructure-Activity RelationshipTerrorismTestingToxic effectToxinToxoidsTranslatingVaccinatedVaccinationVaccinesVariantZincantitoxinbotulinumbotulinum toxin vaccinecross immunityexposed human populationfirst responderimprovednanoneutralizing antibodynext generationnovel vaccinespotency testingpreventprophylacticreceptor bindingresponsevaccine strategyvaccinology
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:
- 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:
- 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:
- 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.
- DOI:10.3390/toxins15090563
- 发表时间:2023-09-08
- 期刊:
- 影响因子:4.2
- 作者:Gupta S;Pellett S
- 通讯作者:Pellett S
Light Chain Diversity among the Botulinum Neurotoxins.
肉毒神经毒素之间的轻链多样性。
- DOI:10.3390/toxins10070268
- 发表时间:2018-07-02
- 期刊:
- 影响因子:4.2
- 作者:Gardner AP;Barbieri JT
- 通讯作者:Barbieri JT
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Joseph T Barbieri其他文献
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{{ truncateString('Joseph T Barbieri', 18)}}的其他基金
Characteristics of Botulinum Neurotoxins that determine potency
决定效力的肉毒杆菌神经毒素的特征
- 批准号:
10539300 - 财政年份:2019
- 资助金额:
$ 66.25万 - 项目类别:
Characteristics of Botulinum Neurotoxins that determine potency
决定效力的肉毒杆菌神经毒素的特征
- 批准号:
10326384 - 财政年份:2019
- 资助金额:
$ 66.25万 - 项目类别:
Therapeutic Delivery Platforms against Botulism
针对肉毒杆菌中毒的治疗递送平台
- 批准号:
8366528 - 财政年份:2012
- 资助金额:
$ 66.25万 - 项目类别:
Therapeutic Delivery Platforms against Botulism
针对肉毒杆菌中毒的治疗递送平台
- 批准号:
8468641 - 财政年份:2012
- 资助金额:
$ 66.25万 - 项目类别:
Characterization of botulinum neurotoxin A subtypes
肉毒杆菌神经毒素 A 亚型的表征
- 批准号:
9542546 - 财政年份:2012
- 资助金额:
$ 66.25万 - 项目类别:
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