Optimization and Advanced Proof-of-Concept Studies of a Listeria-vectored Multi-Antigenic Vaccine against Tuberculosis

李斯特菌载体多抗原结核疫苗的优化和高级概念验证研究

基本信息

项目摘要

PROJECT SUMMARY Tuberculosis (TB) is one of the world's most important diseases, and a safe and effective vaccine against the causative agent Mycobacterium tuberculosis (Mtb) that is more potent than the currently available only partially effective M. bovis strain Bacille Calmette-Guérin (BCG) vaccine is sorely needed. It is generally acknowledged that both an improved replacement vaccine for BCG and a potent heterologous booster vaccine are needed in the fight against TB. The purpose of this project is to optimize and conduct advanced proof-of-concept studies in small animals and non-human primates (NHP) of a second-generation heterologous multiantigenic recombinant attenuated Listeria monocytogenes-vectored vaccine against TB. Live attenuated recombinant Listeria monocytogenes (rLm) vaccines offer major advantages over other approaches to booster vaccines, including protein in adjuvant and virus-vectored vaccines, in terms of cost, ease of manufacture, immunogenicity and efficacy. In preliminary studies, we have identified an improved multi-deletional Listeria vector (Lm ΔactA ΔinlB prfA*) and demonstrated that rLm vaccines expressing four key immunoprotective Mtb proteins (rLmMtb4Ag) substantially augment protective immunity when used as a heterologous booster vaccine in a prime-boost vaccination strategy against Mtb aerosol challenge in mice and guinea pigs. Moreover, delivering the immunoprotective Mtb protein via a first generation rLm vector was more efficacious than delivering it via a recombinant viral vector or administering it with a potent adjuvant. The goal of this application is to optimize expression of an Lm-vectored vaccine expressing 4 Mtb antigens; expand its antigen repertoire to six antigens to increase its potency; and to evaluate the optimized final lead rLm vaccine candidate for safety, immunogenicity and efficacy as a standalone vaccine and as a heterologous booster vaccine to BCG-primed animals in mouse, guinea pig, and non-human primate (NHP) models of pulmonary TB. We shall accomplish this goal by: a) Optimizing the protein expression cassette of rLmMtb4Ag vaccine; systematically evaluating additional novel Mtb antigens for immunogenicity and efficacy in mice, selecting the top two antigens, and subsequently constructing a rLmMtb6Ag lead vaccine candidate; b) Conducting comprehensive proof-of-concept studies of the optimized rLmMtb6Ag lead vaccine candidate for safety, immunogenicity, and efficacy as standalone and heterologous booster vaccine in the mouse model of pulmonary TB; c) Conducting selected proof-of-concept studies of the lead rLmMtb6Ag vaccine as a standa- lone and heterologous booster vaccine for safety, immunogenicity and efficacy in a guinea pig model of pulmonary TB; and d) as Aeras requires proof-of-concept in NHP for a vaccine to enter preclinical develop- ment, evaluating the lead rLmMtb6Ag candidate as a standalone vaccine for safety, immunogenicity and efficacy in a NHP model of pulmonary TB in collaboration with Aeras, Bioqual, and Tulane National Primate Research Centre.
项目总结

项目成果

期刊论文数量(1)
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会议论文数量(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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 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:
    $ 120.07万
  • 项目类别:

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术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
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