Genetically detoxified tetanus toxin for use in vaccines
用于疫苗的基因解毒破伤风毒素
基本信息
- 批准号:10006309
- 负责人:
- 金额:$ 28.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-20 至 2021-09-30
- 项目状态:已结题
- 来源:
- 关键词:Antibody FormationAntigensBacterial ToxinsBindingBiochemistryBiotechnologyCarrier ProteinsCatalysisChemicalsClostridium tetaniConjugate VaccinesDiphtheria ToxinDiphtheria ToxoidDiseaseDisulfidesEconomicsEndotoxinsEngineeringEnvironmentEnzyme-Linked Immunosorbent AssayEscherichia coliFermentationFormaldehydeGenerationsGenetic EngineeringHaemophilus influenzaeHaemophilus influenzae type bImmunizeImmunologic TestsImmunologicsIndustrializationLengthLysineMethodsModernizationMolecular AnalysisMolecular ConformationMusMutateMutationOrganismPhasePolysaccharidesProductionPropertyProteinsProtocols documentationRecombinantsSafetySmall Business Innovation Research GrantSugar PhosphatesSystemTechnologyTetanusTetanus ToxinTetanus ToxoidTetanus VaccineToxinToxoidsVaccinesWisconsinbasecostcross reacting material 197disulfide bondimmunogenicityin vivoinnovationinorganic phosphatemanufacturabilitymanufacturing processmedical schoolsnext generationphase 2 studypolyribitol phosphatepreclinical studypreclinical trialpreventreceptor bindingscale upsmall moleculesuccess
项目摘要
Summary
Tetanus and diphtheria toxoids are highly effective vaccines for preventing diseases. As “carrier proteins”,
tetanus and diphtheria toxoids enhance the immunogenicity of small molecules and polysaccharides. However,
tetanus toxoid (TTxd) represents only 20-70% of the protein in the TTxd vaccine and the TTxd vaccine
contains hundreds of ‘un-intended/contaminant’ clostridial proteins. Purification is often needed prior to TTxd
use a conjugate vaccine carrier. TT is detoxified with formaldehyde, using an over 30-day incubation that
blocks a subset lysines that cannot then be used for conjugation with antigens. Collaborators at the Medical
College of Wisconsin have engineered a full-length, atoxic tetanus toxin (M8TT) with 8 independent mutations
reducing catalysis, translocation, and binding functions. Here, Fina Biosolutions (FinaBio) proposes to develop
and manufacture M8TT in a proprietary engineered E. coli strain that has a unique oxidative environment. This
strain has been used successfully to produce multi-grams/L amounts of CRM197, a mutated form of diphtheria
toxin that has been successfully used as a recombinantly expressed vaccine protein carrier. This proposal
uses recombinant DNA technology, biotechnology, biochemistry and immunological approaches to produce
and test the immunological potency of this next generation conjugate tetanus vaccine platform.
The Specific Aims for Phase I are to: subclone and scale up production and purify > 1 g/L of M8TT at >95%
purity; and to test the immunological properties of M8TT versus conventional TTxd to produce a conjugate of
Hemophilus influenzae subtype b polyribitol phosphate sugar PRP conjugated to M8TT and TTxd to determine
if PRP-TTxd is a more potent conjugate vaccine to PRP and TT than PRP-TTxd. If successful, Phase II
studies will optimize the M8TT manufacturing process to 50 L production scale and characterize the product for
safety and efficacy in pre-clinical trials. In addition, the utility of M8TT as a vaccine carrier protein will be further
explored with additional antigens, including small molecules and other polysaccharides. Ultimately, a superior
tetanus vaccine protein will be commercialized by advancing a 50-year old industrial technology with a new,
modernized, economic, effective, and safe conjugate TT vaccine platform.
概括
破伤风和白喉类毒素是预防疾病的高效疫苗。作为“载体蛋白”,
破伤风和白喉类毒素增强小分子和多糖的免疫原性。然而,
破伤风类毒素 (TTxd) 仅占 TTxd 疫苗中蛋白质的 20-70%,并且 TTxd 疫苗
含有数百种“非预期/污染”梭菌蛋白。 TTxd 之前通常需要纯化
使用结合疫苗载体。 TT 经过 30 多天的培养,用甲醛进行了解毒,
阻断不能用于与抗原缀合的赖氨酸子集。医学界的合作者
威斯康星大学设计了一种全长无毒破伤风毒素 (M8TT),具有 8 个独立突变
减少催化、易位和结合功能。在这里,菲纳生物解决方案(FinaBio)建议开发
并在具有独特氧化环境的专有工程大肠杆菌菌株中生产 M8TT。这
该菌株已成功用于生产数克/升量的 CRM197(白喉的一种突变形式)
已成功用作重组表达疫苗蛋白载体的毒素。这个提议
采用重组DNA技术、生物技术、生物化学和免疫学方法来生产
并测试下一代破伤风结合疫苗平台的免疫效力。
第一阶段的具体目标是:亚克隆和扩大生产规模,并以 >95% 纯化 > 1 g/L 的 M8TT
纯度;并测试 M8TT 与传统 TTxd 的免疫学特性,以产生
流感嗜血杆菌 b 亚型聚核糖醇磷酸糖 PRP 缀合 M8TT 和 TTxd 进行测定
如果 PRP-TTxd 是比 PRP-TTxd 更有效的 PRP 和 TT 结合疫苗。如果成功的话,第二阶段
研究将优化 M8TT 制造工艺至 50 L 生产规模,并对产品进行表征
临床前试验的安全性和有效性。此外,M8TT作为疫苗载体蛋白的效用也将进一步得到加强。
使用其他抗原进行探索,包括小分子和其他多糖。最终成为一名优秀的
破伤风疫苗蛋白将通过利用新的、有 50 年历史的工业技术来推进,从而实现商业化
现代化、经济、有效、安全的结合TT疫苗平台。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Andrew Lees其他文献
Andrew Lees的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似国自然基金
Neo-antigens暴露对肾移植术后体液性排斥反应的影响及其机制研究
- 批准号:2022J011295
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
- 批准号:30801055
- 批准年份:2008
- 资助金额:19.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Bovine herpesvirus 4 as a vaccine platform for African swine fever virus antigens in pigs
牛疱疹病毒 4 作为猪非洲猪瘟病毒抗原的疫苗平台
- 批准号:
BB/Y006224/1 - 财政年份:2024
- 资助金额:
$ 28.91万 - 项目类别:
Research Grant
A novel vaccine approach combining mosquito salivary antigens and viral antigens to protect against Zika, chikungunya and other arboviral infections.
一种结合蚊子唾液抗原和病毒抗原的新型疫苗方法,可预防寨卡病毒、基孔肯雅热和其他虫媒病毒感染。
- 批准号:
10083718 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Small Business Research Initiative
Uncovering tumor specific antigens and vulnerabilities in ETP-acute lymphoblastic leukemia
揭示 ETP-急性淋巴细胞白血病的肿瘤特异性抗原和脆弱性
- 批准号:
480030 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Operating Grants
Regulation of B cell responses to vaccines by long-term retention of antigens in germinal centres
通过在生发中心长期保留抗原来调节 B 细胞对疫苗的反应
- 批准号:
MR/X009254/1 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Research Grant
Adaptive Discrimination of Risk of Antigens in Immune Memory Dynamics
免疫记忆动态中抗原风险的适应性辨别
- 批准号:
22KJ1758 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Grant-in-Aid for JSPS Fellows
22-ICRAD Call 2 - Improving the diagnosis of tuberculosis in domestic ruminants through the use of new antigens and test platforms
22-ICRAD 呼吁 2 - 通过使用新抗原和测试平台改善家养反刍动物结核病的诊断
- 批准号:
BB/Y000927/1 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Research Grant
Protective immunity elicited by distinct polysaccharide antigens of classical and hypervirulent Klebsiella
经典和高毒力克雷伯氏菌的不同多糖抗原引发的保护性免疫
- 批准号:
10795212 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Integrative proteome analysis to harness humoral immune response against tumor antigens
综合蛋白质组分析利用针对肿瘤抗原的体液免疫反应
- 批准号:
23K18249 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens
功能独特的人类 CD4 T 细胞对新型进化选择的结核分枝杆菌抗原的反应
- 批准号:
10735075 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别:
Targeting T3SA proteins as protective antigens against Yersinia
将 T3SA 蛋白作为针对耶尔森氏菌的保护性抗原
- 批准号:
10645989 - 财政年份:2023
- 资助金额:
$ 28.91万 - 项目类别: