Development of a novel adjuvanted Th1- and Th17-inducing subunit TB Vaccine
开发新型佐剂 Th1 和 Th17 诱导亚基结核疫苗
基本信息
- 批准号:10576407
- 负责人:
- 金额:$ 48.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdultAerosolsAgonistAntigensBacille Calmette-Guerin vaccinationCellsClinical TrialsCommunicable DiseasesDataDevelopmentDiseaseDrug resistanceDrug resistant Mycobacteria TuberculosisEvaluationFundingFutureGeneticGrantHealthHelper-Inducer T-LymphocyteHumanImmune responseImmunityInbred MouseInbreedingInterferon Type IIInterferonsLeadLicensingLungMacacaMacaca mulattaMediatingModelingMusMycobacterium bovisMycobacterium tuberculosisMycobacterium tuberculosis antigensPharmaceutical PreparationsPhasePhase I Clinical TrialsPopulationPredispositionPreventionProductionPulmonary TuberculosisRecombinantsResistanceRouteSafetyT cell responseT-LymphocyteTLR7 geneTestingTh1 CellsTuberculosisTuberculosis VaccinesVaccine ProductionVaccinesWorkcytokineefficacy evaluationefficacy studyefficacy testingefficacy validationhigh throughput technologyimmunogenicitylead candidatelead optimizationmouse modelmucosal vaccinenonhuman primatenovelpathogenpre-clinicalpreventprotective efficacyrational designresistant strainresponsesafety studysafety testingsingle cell sequencingvaccine candidatevaccine efficacyvaccine evaluationvaccine formulationvaccine immunogenicityvaccine platformvaccine responsevaccine safetyvaccine strategyvaccine-induced immunity
项目摘要
PROJECT SUMMARY
Adjuvants included as a component of a vaccine have a major impact on vaccine efficacy via modulating and
prolonging host immune responses. While vaccines are the most effective way to prevent and control infectious
diseases, many pathogens that significantly impact human health remain without an effective vaccine. For
example, one-fourth of the world’s population is latently infected with Mycobacterium tuberculosis (Mtb), the
causative agent of tuberculosis (TB)1, a leading infectious disease killer in the world. The currently licensed TB
vaccine, M. bovis BCG (BCG) provides variable protective efficacy (0-80%) across the world2-4. In the absence
of clear correlates of protection for TB vaccines, it is imperative that we explore new and effective approaches
to target broad T cell responses for vaccine-induced immunity against TB. In the current proposal, we
hypothesize that use of new adjuvants that drive Th1 responses (UM-1007, a novel TLR7/8 agonist) and Th17
responses (UM-1098, a novel Mincle agonist) will significantly augment vaccine-induced protection against TB.
Thus, during the R61 phase of the proposal, we will optimize the use of these novel Th1- and Th17-inducing
adjuvanted vaccine platforms and conduct proof-of-principle studies including detailed assessment of
immunogenicity, antigen optimization, identification of prime-boost strategies that enhance lung Th1- and Th17-
vaccine responses (Specific Aim 1), and test if these novel Th1- and Th17-inducing TB vaccine candidates will
protect in mouse challenge models of TB (Specific Aim 2). During the R33 phase we will test the optimized
Th1- and Th17-inducing TB candidate vaccines for immunogenicity, safety and protection in an aerosol challenge
model in macaques (Specific Aim 3). We also propose that we will meet the following milestones. R61 phase.
Milestone 1 (Month 12): Antigen selection for an optimized IM vaccine producing a Th1 response (UM-1007:TB)
and a Th17 response (UM-1098:TB). Milestone 2 (Month 18): Identification of the best prime-boost strategy for
a TB vaccine inducing maximal lung Th1 responses (UM-1007:TB) and Th17 responses (UM-1098:TB).
Milestone 3 (Month 33): Testing efficacy of optimized UM-1007:TB and UM-1098:TB candidates against drug
susceptible and drug resistant Mtb and in genetically diverse Mtb-infected mice. Milestone 4 (Month 36):
Submission of R33 transition package. R33 phase. Milestone 5 (Month 60): Immunogenicity, safety and efficacy
studies of optimized UM-1007:TB and UM-1098:TB vaccines in macaques and in-depth characterization of
vaccine-induced immune responses. Milestone 6 (Month 60): Final selection of newly discovered Mtb vaccine.
Thus, the work proposed in this grant will result in a novel, first-of-kind rationally designed Th1- and/or Th17-
inducing TB vaccine for use in humans in the near future.
项目摘要
作为疫苗组分包括的佐剂通过调节和调节免疫原性对疫苗效力具有重大影响。
延长宿主免疫反应。虽然疫苗是预防和控制传染病的最有效方法,
尽管有许多病原体严重影响人类健康,但仍然没有有效的疫苗。为
例如,世界上四分之一的人口潜伏感染结核分枝杆菌(Mtb),
结核病(TB)1的病原体,结核病是世界上主要的传染病杀手。目前获得许可的TB
vaccine,M.牛卡介苗(BCG)在世界各地提供不同的保护效力(0-80%)2 -4。在没有
鉴于结核病疫苗保护作用的明显相关性,我们必须探索新的有效方法
靶向广泛的T细胞反应,用于疫苗诱导的抗结核免疫。在目前的提案中,我们
假设使用驱动Th 1应答新佐剂(UM-1007,一种新的TLR 7/8激动剂)和Th 17
应答(UM-1098,一种新型Mincle激动剂)将显著增强疫苗诱导的抗TB保护。
因此,在该提案的R61阶段,我们将优化这些新的Th 1-和Th 17-诱导因子的使用。
佐剂疫苗平台,并进行原理验证研究,包括详细评估
免疫原性、抗原优化、增强肺Th 1-和Th 17-的初免-加强策略的鉴定
疫苗反应(具体目标1),并测试这些新的Th 1和Th 17诱导结核病候选疫苗是否
在小鼠结核病攻击模型中保护(具体目标2)。在R33阶段,我们将测试优化的
在气溶胶激发中用于免疫原性、安全性和保护的Th 1和Th 17诱导的TB候选疫苗
猕猴模型(具体目标3)。我们还提议,我们将实现以下里程碑。R61阶段。
里程碑1(第12个月):产生Th 1应答的优化IM疫苗的抗原选择(UM-1007:TB)
和Th 17应答(UM-1098:TB)。里程碑2(第18个月):确定最佳预充-加强策略,
诱导最大肺Th 1应答(UM-1007:TB)和Th 17应答(UM-1098:TB)的TB疫苗。
里程碑3(第33个月):测试优化的UM-1007:TB和UM-1098:TB候选药物对药物的疗效
易感和耐药结核分枝杆菌和遗传多样性结核分枝杆菌感染的小鼠。里程碑4(第36个月):
提交R33过渡包。R33阶段。里程碑5(第60个月):免疫原性、安全性和疗效
优化的UM-1007:TB和UM-1098:TB疫苗在猕猴中的研究以及
疫苗诱导的免疫反应。里程碑6(第60个月):最终选择新发现的结核分枝杆菌疫苗。
因此,这项资助中提出的工作将产生一种新颖的,第一种合理设计的Th 1-和/或Th 17-
诱导结核病疫苗在不久的将来用于人类。
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)
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Jay T. Evans其他文献
Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529
氨烷基氨基葡萄糖胺 4-磷酸盐 (AGP) 的免疫刺激活性:RC-524 和 RC-529 诱导保护性先天免疫反应
- DOI:
10.1177/09680519020080061501 - 发表时间:
2002 - 期刊:
- 影响因子:0
- 作者:
J. Baldridge;C. Cluff;Jay T. Evans;M. Lacy;J. Stephens;V. Brookshire;Rong Wang;J. Ward;Y. Yorgensen;D. Persing;David A. Johnson - 通讯作者:
David A. Johnson
A novel cationic liposome-formulated toll like receptor (TLR) 7/8 agonist enhances the efficacy of a vaccine against fentanyl toxicity
一种新型阳离子脂质体配制的Toll样受体(TLR)7/8激动剂提高了一种针对芬太尼毒性的疫苗的效力
- DOI:
10.1016/j.jconrel.2025.113901 - 发表时间:
2025-08-10 - 期刊:
- 影响因子:11.500
- 作者:
Fatima A. Hamid;Nguyet-Minh Nguyen Le;Daihyun Song;Hardik Amin;Linda Hicks;Sophia Bird;Karthik Siram;Brooke Hoppe;Borries Demeler;Jay T. Evans;David J. Burkhart;Marco Pravetoni - 通讯作者:
Marco Pravetoni
Toll-like receptor 4 agonists as vaccine adjuvants
Toll 样受体 4 激动剂作为疫苗佐剂
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:0
- 作者:
D. Persing;P. Mcgowan;Jay T. Evans;C. Cuff;S. Mossman;David A. Johnson;J. Baldridge - 通讯作者:
J. Baldridge
6,6'-Aryl trehalose analogs as potential Mincle ligands.
6,6-芳基海藻糖类似物作为潜在的 Mincle 配体。
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:3.5
- 作者:
O. Rasheed;George Ettenger;C. Buhl;R. Child;Shannon M Miller;Jay T. Evans;K. Ryter - 通讯作者:
K. Ryter
Encapsulation of the lipidated TLR7/8 agonist INI-4001 into ionic liposomes impacts H7 influenza antigen-specific immune responses
- DOI:
10.1007/s13346-025-01917-6 - 发表时间:
2025-07-14 - 期刊:
- 影响因子:5.500
- 作者:
Fatemeh Mehradnia;Hardik Amin;Maria E. Ferrini;Haley Partlow;Timothy Borgogna;Soma Shekar Dachavaram;Kendal T. Ryter;Hélène G. Bazin;Jay T. Evans;David J. Burkhart;Blair DeBuysscher;Walid M. Abdelwahab - 通讯作者:
Walid M. Abdelwahab
Jay T. Evans的其他文献
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