Preventing TB with intravenous BCG in SIV-infected macaques

在感染 SIV 的猕猴中静脉注射卡介苗预防结核病

• 批准号: 10401493
• 负责人: Charles A. Scanga
• 金额: $ 79.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-05 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10401493
• 关键词: ATAC-seq; Adult; Animals; Anti-Retroviral Agents; Antimycobacterial Agents; Attenuated; BCG Live; Bronchoscopes; Chest; Childhood; Chronic; Clinical Trials; Collaborations; Country; Data; Development; Disease; Dose; Drug resistance in tuberculosis; Ensure; Epigenetic Process; Exhibits; Flow Cytometry; Genus Mycobacterium; Goals; HIV; HIV Infections; HIV/TB; Immune; Immunity; Immunocompromised Host; Immunologics; Individual; Infant; Infection; Intention; Intervention; Intravenous; Learning; Lung diseases; Macaca; Macaca fascicularis; Macaca mulatta; Mediating; Modeling; Monkeys; Mycobacterium bovis; Mycobacterium tuberculosis; Newborn Infant; Pathogenicity; Persons; Pharmaceutical Preparations; Population; Pulmonary Tuberculosis; Recording of previous events; Regimen; Rhesus; Risk; Risk Factors; Route; SIV; Safety; Sampling; Serology; Signal Transduction; System; Technology; Testing; Time; Training; Tuberculosis; Tuberculosis Vaccines; United States; Vaccinated; Vaccination; Vaccines; Virulent; Virus Diseases; Vulnerable Populations; aerosolized; antiretroviral therapy; co-infection; global health; immunogenic; improved; insight; mortality; multidisciplinary; mycobacterial; nonhuman primate; prevent; single-cell RNA sequencing; tuberculosis immunity; vaccination against tuberculosis; vaccination strategy

PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is the most common cause of mortality in HIV+ individuals. Although antiretroviral and antimycobacterial drugs have reduced the burden of TB in the HIV+ population, they are incompletely effective against this global health burden. The only available TB vaccine is the live attenuated mycobacterium Bacillus Calmette-Guerin (BCG) that is given intradermally to infants. While this provides substantial protection against non-pulmonary TB in childhood, it has little impact on pulmonary TB rates in adults. However, we have shown recently that BCG delivered intravenously (BCG IV) conferred dramatic protection from TB in SIV-negative macaques. Dr. Scanga conducted a preliminary study of BCG IV in his macaque model of HIV/Mtb co-infection. Animals infected with pathogenic SIV for several months that were then co-infected with virulent Mtb exhibited more severe TB than did similarly-infected SIV-naïve animals. In their preliminary study, vaccination of SIV+ macaques with BCG IV induced immunity that parallels that seen in SIV-naïve rhesus and conferred dramatic protection from TB in 6/7 animals. Furthermore, there were no signs of disseminated BCG. This unprecedented protection from TB in SIV+ animals provides exciting evidence that BCG IV can be safe, immunogenic, and protective in NHP with chronic SIV infection While these data are provocative, there is still much to learn about the mechanisms by which BCG IV provides such striking protection. In this R01 proposal, we will extend these exciting results to refine the ability of BCG IV to protect SIV+ macaques from infection with Mtb. Most importantly, we will use comprehensive immunologic approaches, both biased and unbiased, to determine the immune correlates and mechanisms of BCG IV-mediated protection against TB in the context of pre-existing SIV. This will demonstrate that it may indeed be possible to protect persons infected with HIV from TB and will guide the development of TB vaccine approaches that can protect this highly vulnerable population. The team we have assembled includes experts in the field of TB, vaccines, and the cutting-edge technologies that will allow us to understand better the remarkable protection of SIV+ animals with BCG IV. We already have an established collaborative relationship and ensures successful completion of this very exciting study.

项目总结 由结核分枝杆菌(Mtb)引起的结核病(TB)是HIV+患者最常见的死亡原因 个人。尽管抗逆转录病毒和抗分枝杆菌药物减轻了HIV+人群中结核病的负担 对于人口来说，它们对这一全球健康负担并不完全有效。唯一可用的结核病疫苗是 给婴儿皮内注射的活的卡介苗(卡介苗)。而当 这为儿童时期的非肺结核病提供了实质性的保护，对肺结核病几乎没有影响。 成人的房价。然而，我们最近已经表明，卡介苗静脉注射(BCG IV)具有戏剧性的效果 SIV阴性猕猴对结核病的保护。 斯坎加博士在他的艾滋病毒/结核分枝杆菌混合感染猕猴模型中进行了卡介苗IV的初步研究。动物 感染致病性SIV几个月后与强毒结核分枝杆菌混合感染的患者表现出更多 严重的结核病比同样感染SIV的幼稚动物更严重。在他们的初步研究中，SIV+猕猴的疫苗接种 卡介苗IV诱导的免疫力与SIV天真恒河猴相似，并获得了戏剧性的保护 在6/7的动物身上发现了结核病。此外，没有播散性卡介苗的迹象。这是前所未有的 SIV+动物对结核病的保护提供了令人兴奋的证据，表明卡介苗IV可以是安全的，免疫原性的， NHP慢性SIV感染的防护 虽然这些数据具有挑衅性，但关于卡介苗IV提供的机制仍有许多需要了解 如此引人注目的保护。在这份R01提案中，我们将扩展这些令人兴奋的结果，以提炼BCG的能力 IV保护SIV+猕猴免受结核分枝杆菌感染最重要的是，我们将使用全面的 免疫学方法，既有偏见的，也有无偏见的，以确定免疫相关性和机制 在先前存在的SIV的背景下，对卡介苗IV介导的结核病预防进行评估。这将证明它 可能确实有可能保护艾滋病毒感染者免受结核病的侵袭，并将指导结核病的发展 能够保护这一高度脆弱人群的疫苗方法。 我们组建的团队包括结核病、疫苗和尖端技术领域的专家 这将使我们更好地了解卡介苗IV对SIV+动物的显著保护。我们已经 建立了合作关系，并确保成功完成这项非常令人兴奋的研究。