Pre-Exposure Prophylaxis Against Francisella tularensis
针对土拉弗朗西斯菌的暴露前预防
基本信息
- 批准号:8840491
- 负责人:
- 金额:$ 70.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-01 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AntibioticsAntigensAttenuatedAttenuated Live Virus VaccineAwarenessBCG VaccineBiologicalBioterrorismCategoriesCellsChildChimeric ProteinsCollaborationsDevelopmentDiagnosisDiseaseDisease OutbreaksDoseFrancisella tularensisFutureGenerationsGoalsGrantHealthHospitalizationHumanImmune responseImmunityImmunocompromised HostIn VitroIndividualIntramuscularLaboratoriesLearningLicensingLifeMediatingMedicalMilitary PersonnelMorbidity - disease rateMusOralParentsPatientsPersonsPopulationProphylactic treatmentProteinsPublic HealthRecombinant ProteinsRecombinantsRiskRouteSafetyTestingTimeToxic effectTuberculosisTuberculosis VaccinesTularemiaVaccinesVirulentaerosolizedbaseemergency service responderimmunogenicimmunogenicitymacrophagemortalitymouse modelmutantnoveloverexpressionpathogenpromoterprotein expressionprototyperBCGresistant strainsuccessvaccine developmentvaccine efficacyvaccine evaluationvaccine safetyvectorweapons
项目摘要
DESCRIPTION (provided by applicant): Francisella tularensis (Ft) causes tularemia, a serious and potentially fatal disease. Because Ft has an extraordinarily high infectivity, causes high morbidity and mortality, is relatively easily cultured and dispersed, and has previously been weaponized, it is classified as a Category A potential agent of bioterrorism. As post- exposure prophylaxis is not a practical public health alternative for countering an outbreak of pneumonic tularemia, a safe and effective pre-exposure vaccine is needed. The goal of this application is a safer and more potent vaccine against aerosolized Ft than the current unlicensed, toxic, and insufficiently effective vaccine (LVS). Our strategy is to utilize a live attenuated recombinant homologous vector - an attenuated form of the LVS vaccine (this parent vaccine has already been tested in humans) - to overexpress highly immunoprotective Ft proteins such as IglC, previously demonstrated in this laboratory to enhance protective immunity against aerosolized Ft. The proposed 2nd generation recombinant LVS (rLVS¿capB) vaccine will be safer than LVS because the proposed vector already has been demonstrated to be >10,000 times more attenuated than LVS and yet induce strong cell-mediated and humoral immune responses. The proposed 2nd generation rLVS¿capB vaccine will be more potent than LVS because it will overexpress large amounts of highly immunoprotective Ft proteins via novel promoters. This strategy for a tularemia vaccine mimics that used successfully in this laboratory to develop the first vaccines against tuberculosis that are safer and more potent than the current BCG vaccine; one of these tuberculosis vaccines has already demonstrated safety and enhanced immunogenicity in human trials. In this application, to accomplish our goal of a vaccine against tularemia that is safer and more potent than LVS, we propose to build upon our preliminary success with 1st generation rLVS¿capB vaccines by constructing the aforementioned new 2nd generation rLVS¿capB vaccines and testing them systematically for stability; protein expression extracellularly and intracellularly; safety; immunogenicity; and near-term and long- term efficacy against lethal Ft challenge in a mouse model. At the same time we shall determine optimal mucosal and systemic routes for administration. By the completion of this project, we anticipate having a vaccine that is substantially safer and more potent than LVS and suitable for testing in humans. While the focus of our grant is on a tularemia vaccine, our approach is applicable to vaccines against intracellular pathogens in general. Thus, lessons learned and strategies developed during the development of a successful tularemia vaccine are likely to be broadly applicable.
描述(由申请方提供):土拉热弗朗西丝菌(Ft)引起土拉菌血症,这是一种严重且可能致命的疾病。由于Ft具有非常高的传染性,导致高发病率和死亡率,相对容易培养和传播,并且以前已被武器化,因此被列为A类生物恐怖主义潜在制剂。由于暴露后预防不是对抗肺炎土拉菌病爆发的实用公共卫生替代方案,因此需要安全有效的暴露前疫苗。本申请的目标是一种比目前未经许可的、有毒的、有效性不足的疫苗(LVS)更安全、更有效的雾化Ft疫苗。 我们的策略是利用活的减毒重组同源载体-LVS疫苗的减毒形式(这种亲本疫苗已经在人体中进行了测试)-来过表达高度免疫保护性的Ft蛋白,例如IglC,其先前在本实验室中被证明可以增强针对雾化Ft的保护性免疫。所提出的第二代重组LVS(rLVS <$capB)疫苗将比LVS更安全,因为所提出的载体已经被证明比LVS减毒> 10,000倍,并且还诱导强烈的细胞介导的和体液免疫应答。拟议的第二代rLVS capB疫苗将比LVS更有效,因为它将通过新型启动子过表达大量高度免疫保护性的Ft蛋白。这种兔热病疫苗的策略模仿了在该实验室成功使用的策略,以开发出第一种比目前的BCG疫苗更安全和更有效的结核病疫苗;其中一种结核病疫苗已经在人体试验中证明了安全性和增强的免疫原性。 在本申请中,为了实现我们的目标,即获得比LVS更安全和更有效的抗兔热病疫苗,我们建议通过构建上述新的第二代rLVS <$capB疫苗并系统地测试它们的稳定性、细胞外和细胞内的蛋白表达、安全性、免疫原性、以及在小鼠模型中对致死性Ft攻击的近期和长期功效。同时,我们将确定最佳的粘膜和全身给药途径。通过这个项目的完成,我们预计有一个疫苗,大大安全和更有效的比LVS和适合在人类中测试。 虽然我们资助的重点是兔热病疫苗,但我们的方法一般适用于针对细胞内病原体的疫苗。因此,在开发成功的兔热病疫苗过程中吸取的经验教训和制定的策略可能会广泛适用。
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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MARCUS AARON HORWITZ其他文献
MARCUS AARON HORWITZ的其他文献
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{{ truncateString('MARCUS AARON HORWITZ', 18)}}的其他基金
Development of a novel TB vaccine safer and more effective than BCG based on a precisely controlled replication-limited Mycobacterium tuberculosis engineered for optimal in vivo growth and clearance
基于精确控制的复制限制结核分枝杆菌,开发出比卡介苗更安全、更有效的新型结核疫苗,该疫苗经过精心设计,可实现最佳的体内生长和清除
- 批准号:
10115911 - 财政年份:2021
- 资助金额:
$ 70.67万 - 项目类别:
Development of a novel TB vaccine safer and more effective than BCG based on a precisely controlled replication-limited Mycobacterium tuberculosis engineered for optimal in vivo growth and clearance
基于精确控制的复制限制结核分枝杆菌,开发出比卡介苗更安全、更有效的新型结核疫苗,该疫苗经过精心设计,可实现最佳的体内生长和清除
- 批准号:
10372028 - 财政年份:2021
- 资助金额:
$ 70.67万 - 项目类别:
Development of a novel TB vaccine safer and more effective than BCG based on a precisely controlled replication-limited Mycobacterium tuberculosis engineered for optimal in vivo growth and clearance
基于精确控制的复制限制结核分枝杆菌,开发出比卡介苗更安全、更有效的新型结核疫苗,该疫苗经过精心设计,可实现最佳的体内生长和清除
- 批准号:
10570976 - 财政年份:2021
- 资助金额:
$ 70.67万 - 项目类别:
Composition, Atomic Structure and Function of the Francisella Type 6 Secretion System, a Distinct Subtype Essential for Phagosomal Escape, Intracellular Replication, and Virulence
弗朗西斯菌 6 型分泌系统的组成、原子结构和功能,这是吞噬体逃逸、细胞内复制和毒力所必需的独特亚型
- 批准号:
10462669 - 财政年份:2020
- 资助金额:
$ 70.67万 - 项目类别:
Composition, Atomic Structure and Function of the Francisella Type 6 Secretion System, a Distinct Subtype Essential for Phagosomal Escape, Intracellular Replication, and Virulence
弗朗西斯菌 6 型分泌系统的组成、原子结构和功能,这是吞噬体逃逸、细胞内复制和毒力所必需的独特亚型
- 批准号:
10120412 - 财政年份:2020
- 资助金额:
$ 70.67万 - 项目类别:
Composition, Atomic Structure and Function of the Francisella Type 6 Secretion System, a Distinct Subtype Essential for Phagosomal Escape, Intracellular Replication, and Virulence
弗朗西斯菌 6 型分泌系统的组成、原子结构和功能,这是吞噬体逃逸、细胞内复制和毒力所必需的独特亚型
- 批准号:
10685383 - 财政年份:2020
- 资助金额:
$ 70.67万 - 项目类别:
Composition, Atomic Structure and Function of the Francisella Type 6 Secretion System, a Distinct Subtype Essential for Phagosomal Escape, Intracellular Replication, and Virulence
弗朗西斯菌 6 型分泌系统的组成、原子结构和功能,这是吞噬体逃逸、细胞内复制和毒力所必需的独特亚型
- 批准号:
10267736 - 财政年份:2020
- 资助金额:
$ 70.67万 - 项目类别:
Development of a Safe and Potent Vaccine Against Melioidosis using the LVS dcapB Vector Platform
使用 LVS dcapB 载体平台开发安全有效的类鼻疽疫苗
- 批准号:
10837445 - 财政年份:2019
- 资助金额:
$ 70.67万 - 项目类别:
Development of a Safe and Potent Vaccine Against Melioidosis using the LVS dcapB Vector Platform
使用 LVS dcapB 载体平台开发安全有效的类鼻疽疫苗
- 批准号:
10308602 - 财政年份:2019
- 资助金额:
$ 70.67万 - 项目类别:
Development of a Safe and Potent Vaccine Against Melioidosis using the LVS dcapB Vector Platform
使用 LVS dcapB 载体平台开发安全有效的类鼻疽疫苗
- 批准号:
9815937 - 财政年份:2019
- 资助金额:
$ 70.67万 - 项目类别:
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