Integrin activator-adjuvanted DNA vaccine against Trypanosoma cruzi infection
整合素激活剂佐剂 DNA 疫苗对抗克氏锥虫感染
基本信息
- 批准号:10544403
- 负责人:
- 金额:$ 99.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-14 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdjuvantAdultAdverse reactionsAllelesAnimal ModelAntibody ResponseAntigen PresentationAntigen-Presenting CellsAntigensApplications GrantsBiodistributionBioinformaticsBiologicalBiological AssayBiological AvailabilityBiological TestingBlood specimenCanis familiarisCell AdhesionCell Adhesion MoleculesCessation of lifeChagas DiseaseChronicClinicalClinical ResearchClinical TrialsCodon NucleotidesCollaborationsCountryCytotoxic T-LymphocytesDNADNA VaccinesDevelopmentDoseDrug KineticsEconomic BurdenEffectivenessEpitopesFemaleFormulationFutureHealth Care CostsHeart failureHumanHypersensitivityImmuneImmune responseImmunityImmunizationImmunoglobulin GImmunotherapyIn VitroInfectionInnate Immune ResponseIntegrinsIntercellular adhesion molecule 1InterruptionIntramuscular InjectionsInvestigationInvestmentsLatin AmericaLeadLigandsLipidsMediatingMemoryModelingMonitorMusMycobacterium tuberculosisOralParasitesPathogenesisPathogenicityPhasePhenotypePlasmaPlayPreparationProductionProductivityRegimenResearchRiskRoleSafetySmall Business Innovation Research GrantStudy SubjectT cell differentiationT cell responseT memory cellT-Cell ActivationT-LymphocyteTestingTherapeuticTissuesTravelTreatment EfficacyTrypanosoma cruziUnited States National Institutes of HealthVaccinationVaccine DesignVaccine ProductionVaccinesVascular Cell Adhesion Molecule-1Workadaptive immunityaluminum sulfatebasecapsulecell motilitychagasic cardiomyopathycommercializationcytokinedesignefficacy evaluationefficacy studyexpression vectorglobal healthimmunogenicityimprovedmalemigrationmouse modelnovelpathogenpre-clinicalpreclinical efficacypreclinical safetypreclinical studyprematureproduct developmentprophylacticprototypereceptorresponsesmall moleculetransmission processvaccine candidatevaccine developmentvaccine efficacyvaccine evaluationvaccine safetyvector
项目摘要
PROJECT SUMMARY/ABSTRACT
Trypanosoma cruzi (Tc) is the causative agent of Chagas disease (CD). With >7 million recorded cases, ~81
million at risk of Tc exposure in Latin America, and large-scale migration from endemic to other countries
including the USA where autochthonous transmission of Tc also occurs, CD remains a global health concern.
Currently no therapies exist to prophylactically treat adults traveling to endemic countries or those who may
already be infected with Tc. The economic burden for chagas cardiomyopathy and heart failure, estimated at
~$10 billion due to healthcare costs and lost productivity by premature deaths, provides a strong rationale for
investment in the development of immune therapies against CD. We have already developed a two-component
DNA vaccine (TcG2/TcG4) for CD and demonstrated preclinical efficacy of this prototype vaccine in controlling
Tc pathogenesis in a mouse model. Vaccine efficacy depends heavily on the induction of a robust TH1 response
for the clearance of intracellular pathogens like Tc. Integrin cell adhesion molecules α4β1 and αLβ2 and their
ligands, VCAM-1 and ICAM-1, respectively, play an essential role in the activation of adaptive immunity.
Prolonged integrin-mediated interactions between T cells and antigen presenting cells (APCs), particularly via
the αLβ2/ICAM-1 axis, are required for effective T cell priming and long-term T cell mediated memory.
Augmenting cell adhesion may facilitate T cell priming and subsequent immune responses. 7HP349 is a clinical-
stage, first-in-concept, oral, small-molecule, positive allosteric activator of α4β1 and αLβ2 integrins, which could
facilitate endogenous integrin ligand-receptor engagement, promote cell adhesion, and improve T helper function
and the effectiveness of CD vaccination. We have demonstrated that 7HP349 augments the effectiveness of the
prototype TcG2/TcG4 DNA vaccine in a mouse model of CD. Additionally, 7HP349 has a favorable preclinical
safety and pharmacokinetic profile, and was found to be safe and well tolerated in a Phase 1 clinical study in
healthy male subjects. In this SBIR grant application, we propose to develop a vaccination regimen for CD
consisting of a bicistronic DNA vaccine (BCV)-adjuvant combination with 7HP349 or another integrin activator,
7HP577, demonstrate preclinical efficacy and safety of the BCV-adjuvant combination, and manufacture clinical
grade cGMP BCV and adjuvant to support a Phase I/IIa clinical study to assess the safety and tolerability of the
vaccine-adjuvant combination, and thereafter to evaluate its immunogenicity in humans. The proposed studies
will allow the development of a novel vaccination regimen to prophylactically treat Tc infection and CD.
项目摘要/摘要
克氏锥虫是恰加斯病的病原体。有记录的案例达700万例,约81例
在拉丁美洲有100万人面临接触TC的风险,以及从地方病流行到其他国家的大规模移民
包括美国在内,在那里也发生了原地传播的TC,CD仍然是一个全球卫生问题。
目前还没有预防性的疗法来治疗去流行国家旅行的成年人或那些可能
已经感染了TC。查加斯心肌病和心力衰竭的经济负担估计为
约100亿美元,原因是医疗成本和过早死亡造成的生产力损失,为
投资开发针对CD的免疫疗法。我们已经开发了一种由两个组件组成的
CD DNA疫苗(TcG2/TcG4)及其临床前控制效果
TC在小鼠模型中的发病机制。疫苗的效力在很大程度上依赖于诱导强大的TH1反应
用于清除像TC这样的细胞内病原体。整合素细胞黏附分子α-4-β-1和α-L-β-2及其表达
配体VCAM-1和ICAM-1分别在获得性免疫的激活中发挥重要作用。
整合素介导长时间T细胞和抗原提呈细胞(APC)之间的相互作用,特别是通过
αL ICAM-2/β-1轴是有效的T细胞启动和长期T细胞介导的记忆所必需的。
增强细胞黏附可能有助于T细胞的启动和随后的免疫反应。7HP349是一种临床-
阶段,概念第一,口服,小分子,阳性变构激活剂α4β1和αLβ2整合素,可以
促进内源性整合素配体受体结合,促进细胞黏附,改善辅助性T细胞功能
以及CD疫苗接种的效果。我们已经证明,7HP349增强了
CD小鼠模型中TcG2/TcG4 DNA疫苗的原型研究此外,7HP349具有良好的临床前
安全性和药代动力学特征,在#年的一项1期临床研究中发现该药是安全和耐受性良好的
健康的男性受试者。在这项SBIR赠款申请中,我们建议开发一种CD疫苗接种方案
由双顺反子DNA疫苗(BCV)佐剂与7HP349或另一整合素激活剂组成,
7HP577,展示BCV-佐剂组合的临床前有效性和安全性,并制造临床
分级cGMP BCV和佐剂以支持I/IIa期临床研究,以评估
疫苗-佐剂组合,然后评估其在人体内的免疫原性。建议进行的研究
这将使一种新的疫苗接种方案得以开发,以预防性地治疗TC感染和CD。
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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Siddhartha De其他文献
Siddhartha De的其他文献
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{{ truncateString('Siddhartha De', 18)}}的其他基金
7HP349, an oral integrin activator to augment effectiveness of pre-exposure influenza vaccination
7HP349,一种口服整合素激活剂,可增强暴露前流感疫苗接种的有效性
- 批准号:
10693536 - 财政年份:2023
- 资助金额:
$ 99.93万 - 项目类别:
Integrin activator-adjuvanted DNA vaccine against Trypanosoma cruzi infection
整合素激活剂佐剂 DNA 疫苗对抗克氏锥虫感染
- 批准号:
10665082 - 财政年份:2022
- 资助金额:
$ 99.93万 - 项目类别:
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