Development of a Self Inactivating, Highly Effective TB Vaccine

开发一种自灭活高效结核疫苗

基本信息

批准号：
10549744
负责人：
SABINE EHRT
金额：
$ 78.61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-06 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549744
关键词：
Address Adolescence Adult Aerosols Amino Acids Animal Model Antibiotic Resistance Attenuated Attenuated Vaccines BCG Live Bacille Calmette-Guerin vaccination Biosynthetic Proteins Birth CD8-Positive T-Lymphocytes Cause of Death Cessation of life Child Childhood Collaborations Country Data Development Disease Doxycycline Enzymes Generations Genetic Goals HIV Infections Human Immune Immune response Immunity Immunocompromised Host Immunology In Vitro Individual Infant Infection Infectious Agent Intravenous Kinetics Licensing Lung diseases Lung infections Macaca Macaca mulatta Mediating Modeling Molecular Morbidity - disease rate Mus Mycobacterium bovis Mycobacterium tuberculosis NIH Vaccine Research Center Newborn Infant PET/CT scan Persons Pilot Projects Population Preclinical Testing Predisposition Proteins Publishing Pulmonary Tuberculosis Recording of previous events Repression Route SIV Safety Suicide Technology Testing Time Toxin Trimethoprim Tuberculosis Tuberculosis Vaccines Vaccinated Vaccination Vaccinee Vaccines X-Ray Computed Tomography design experience genetic approach high risk immunogenicity in vivo innovation intravenous administration mortality mouse model mycobacterial nonhuman primate novel vaccines safety testing

项目摘要

Abstract Tuberculosis remains a major cause of morbidity and mortality worldwide, and is the leading cause of death due to a single infectious agent, Mycobacterium tuberculosis. Most countries still vaccinate newborns with the only licensed vaccine against tuberculosis, Bacille Calmette Guerin (BCG) an attenuated version of Mycobacterium bovis. The vaccine was developed over a century ago and, although widely used, has limited efficacy. BCG delivered intradermally (ID) does provide protection against the worst manifestations of tuberculosis in infants but has variable (0-80%) protection against pulmonary TB. Our recent data in non-human primates (rhesus macaques) demonstrate that BCG delivered by the intravenous (IV) route provides sterilizing or near sterilizing protection in 90% of macaques (>10,000 fold reduction in bacterial burden overall), while ID BCG provides little protection in this model. However, delivery of even an attenuated live vaccine poses potential safety issues, particularly in immune compromised subjects. In this proposal, we aim to construct BCG strains that are self-inactivating, using several innovative molecular approaches. Such strains would persist only for a short time in vivo, and would likely die by different mechanisms. We will construct and characterize the BCG self-inactivating strains in vitro (Aim 1), assess persistence and immunogenicity in a murine model, and then determine persistence, immunogenicity and protection of a subset of BCG strains in a susceptible non-human primate model (rhesus macaques). Published data indicate that the robust protection seen by IV BCG in macaques is not recapitulated in mice, which necessitates testing in macaques. We will use sophisticated technology for construction of strains, assessment of immune responses and bacterial burden, and PET CT imaging for tracking protection. This proposal builds on the experience of the Multi-PI team in mycobacterial genetics, immunology, and animal models, with the goal of developing a safer TB vaccine for IV delivery.

抽象的结核病仍然是全世界发病和死亡的主要原因，并且是主要疾病死亡原因是单一传染源——结核分枝杆菌。大多数国家仍然为新生儿接种唯一获得许可的结核病疫苗卡介苗 (BCG) 牛分枝杆菌的减毒版本。该疫苗的开发经过了一个世纪前，尽管广泛使用，但功效有限。卡介苗皮内注射 (ID) 确实可以预防婴儿结核病最严重的表现，但针对肺结核的可变（0-80%）保护。我们最近在非人类灵长类动物中的数据（恒河猴）证明通过静脉 (IV) 途径输送的 BCG 可以提供对 90% 的猕猴提供灭菌或接近灭菌保护（细菌减少超过 10,000 倍）总体负担），而 ID BCG 在此模型中提供的保护很少。然而，即使交付减毒活疫苗会带来潜在的安全问题，特别是在免疫受损的情况下科目。在本提案中，我们的目标是构建自我失活的 BCG 菌株，使用几种创新的分子方法。这种压力只会持续很短的时间体内，并且可能会通过不同的机制死亡。我们将构建并表征 BCG 体外自失活菌株（目标 1），评估小鼠体内的持久性和免疫原性模型，然后确定 BCG 子集的持久性、免疫原性和保护作用易感非人类灵长类动物模型（恒河猴）中的菌株。公布的数据表明 IV BCG 在猕猴中观察到的强大保护作用在小鼠中并未重现，这需要在猕猴身上进行测试。我们将利用先进的技术来建造菌株、免疫反应和细菌负荷评估以及 PET CT 成像跟踪保护。该提案建立在 Multi-PI 团队在分枝杆菌领域的经验基础上遗传学、免疫学和动物模型，目标是开发一种更安全的静脉注射结核疫苗送货。