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

• 批准号: 10308053
• 负责人: MARCUS AARON HORWITZ
• 金额: $ 120.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308053
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Aerosols; Affect; Amino Acid Substitution; Animals; Antigens; Attenuated; BCG Live; BCG Vaccine; Bioterrorism; Cavia; Clinical Research; Collaborations; DNA cassette; Development; Disease; Dose; ELF3 gene; Evaluation; Francisella tularensis; Generations; Glycoproteins; Goals; Human; Immune response; Immunity; Immunization; Immunize; Laboratories; Lead; Listeria; Listeria monocytogenes; Modeling; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Patients; Persons; Planet Earth; Primates; Proteins; Public Health; Pulmonary Tuberculosis; Recombinants; Research; Risk; Route; Safety; System; Testing; Tuberculosis; Tuberculosis Vaccines; Tularemia; Vaccinated; Vaccines; Virulence; Virulent; Virus; booster vaccine; cancer cell; cost; early childhood; efficacy study; fight against; guinea pig model; immunogenicity; improved; lead candidate; macrophage; mouse model; nonhuman primate; novel; pathogen; pathogenic bacteria; preclinical development; protein expression; recombinant viral vector; secretory protein; vaccination strategy; vaccine candidate; vaccine immunogenicity; vaccine safety; vector; vector vaccine

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.

项目概要 结核病（TB）是世界上最重要的疾病之一，也是预防结核病的安全有效的疫苗 病原体结核分枝杆菌（Mtb）比目前仅部分有效的 迫切需要有效的牛分枝杆菌卡介苗（BCG）疫苗。这是普遍公认的 需要改进的卡介苗替代疫苗和有效的异源加强疫苗 与结核病的斗争。该项目的目的是优化并进行高级概念验证研究 在小动物和非人灵长类动物 (NHP) 中发现第二代异源多抗原 重组减毒单核细胞增多性李斯特菌载体抗结核疫苗。 重组单核细胞增生李斯特菌 (rLm) 减毒活疫苗与其他疫苗相比具有主要优势 加强疫苗的方法，包括佐剂中的蛋白质和病毒载体疫苗，在成本方面， 易于制造、免疫原性和功效。在初步研究中，我们已经确定了一种改进的 多缺失李斯特菌载体 (Lm ΔactA ΔinlB prfA*) 并证明 rLm 疫苗表达四个关键 免疫保护性 Mtb 蛋白 (rLmMtb4Ag) 用作免疫保护剂时可显着增强保护性免疫力 异源加强疫苗在小鼠和小鼠中针对 Mtb 气溶胶攻击的初免加强疫苗接种策略 豚鼠。此外，通过第一代 rLm 载体递送免疫保护性 Mtb 蛋白更有效。 比通过重组病毒载体递送或与有效佐剂一起施用更有效。 此应用的目标是优化表达 4 Mtb 的 Lm 载体疫苗的表达 抗原；将其抗原库扩展到六种抗原以增加其效力；并评估优化后的 作为独立疫苗和作为替代疫苗，其安全性、免疫原性和有效性的最终主要候选疫苗 针对小鼠、豚鼠和非人类灵长类动物 (NHP) 的 BCG 免疫动物的异源加强疫苗 肺结核模型。我们将通过以下方式实现这一目标： a) 优化蛋白质表达盒 rLmMtb4Ag 疫苗；系统地评估其他新型 Mtb 抗原的免疫原性和功效 小鼠，选择前两种抗原，随后构建 rLmMtb6Ag 候选疫苗； b) 对优化的 rLmMtb6Ag 主要候选疫苗进行全面的概念验证研究 作为独立和异源加强疫苗在小鼠模型中的安全性、免疫原性和功效 肺结核； c) 对领先的 rLmMtb6Ag 疫苗进行选定的概念验证研究作为标准 单独和异源加强疫苗在豚鼠模型中的安全性、免疫原性和有效性 肺结核； d) 由于 Aeras 需要在 NHP 中进行概念验证，以便疫苗进入临床前开发阶段 评估主要的 rLmMtb6Ag 候选药物作为独立疫苗的安全性、免疫原性和 与 Aeras、Bioqual 和 Tulane National Primate 合作，在 NHP 肺结核模型中的疗效 研究中心。