Assessing the efficacy of BCG vaccination in a pre-clinical model of SARS-CoV-2 infection

评估 BCG 疫苗接种在 SARS-CoV-2 感染临床前模型中的功效

• 批准号: 10272292
• 负责人: Alan Sher
• 金额: $ 2.86万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272292
• 关键词: 2019-nCoV; Adult; Alveolar Macrophages; Amendment; Animals; Bacillus; COVID-19; Cancer Patient; Child; Childhood; Clinical Trials; Communities; Core Facility; Correlative Study; Country; Data; Disease; Environment; Epigenetic Process; Ethics; Experimental Animal Model; Flow Cytometry; Generations; Gold; Grant; Hematopoiesis; Host resistance; Human; Immunization; Incidence; Infant; Infection; Innate Immune System; Intravenous; K-18 conjugate; Lead; Long-Term Effects; Lung; Malignant neoplasm of urinary bladder; Measures; Metabolic; Modeling; Mus; Mycobacterium tuberculosis; Myelogenous; Myeloid Cells; Phenotype; Plaque Assay; Population; Positioning Attribute; Pre-Clinical Model; Preclinical Testing; Predisposition; Preparation; Progress Reports; Protocols documentation; Public Health; Publishing; Reagent; Reporting; Resistance; Route; Safety; Source; Structure of parenchyma of lung; Test Result; Time; Transgenic Mice; Tuberculosis; Vaccinated; Vaccination; Vaccines; Vero Cells; Viral; Viremia; Virus; Yellow Fever Vaccine; anti-tumor immune response; cohort; design; efficacy testing; epidemiology study; experience; experimental study; interest; mortality; mouse model; novel coronavirus; pathogen; prevent; programs; standard care; tumor; vaccine trial

The bacillus Calmette-Gurin (BCG) vaccine has been widely used to protect against disseminated tuberculosis in infants and children since the 1930s, and is currently included in the national vaccine programme in over 150 countries. In addition to providing some protection against tuberculosis, BCG vaccination is associated with lower all-cause mortality in infants and is reported to reduce viremia following a yellow fever vaccine challenge in adults. BCG has also proved successful in stimulating anti-tumor immune responses in cancer patients and is considered to be the gold-standard treatment for bladder cancer. Together, these observations provide evidence for beneficial non-specific effects of BCG in humans, which have been attributed to epigenetic and metabolic re-programming of the innate immune system, as well as the re-direction of haematopoiesis towards the rapid generation of protective myeloid cells. Given the reported non-specific protection afforded by BCG vaccination, it has been hypothesised that BCG may offer some protection against the novel coronavirus, SARS-CoV-2. A number of epidemiologic studies have reported an association between mass BCG vaccination and lower incidence of SARS-CoV-2 infection as well as mortality from COVID-19. These preliminary correlative studies have been the subject of much debate within the scientific community, with a number of published reports finding no positive correlation between BCG vaccination status and susceptibility to SARS-CoV-2 infection. Nonetheless, significant interest has been generated in the public health and scientific arenas, and at least eighteen clinical trials have been registered on clinicaltrials.gov (as of August 14th, 2020) aiming to formally test the efficacy of BCG vaccination in protecting against SARS-CoV-2 infection and mortality in adults. Our own unpublished data (see accompanying report AI001044-13) demonstrates that BCG immunization, particularly when administered via the intravenous (i.v.) route, profoundly alters the composition and phenotype of the pulmonary myeloid compartment, creating an environment that restricts the ability of Mycobacterium tuberculosis to gain entry into the lung parenchyma. These changes include a prolonged depleion of alveolar macrophages. In this study, we will assess the efficacy of BCG vaccination in the K18-hACE2 transgenic mouse model of SARS-CoV-2 infection (and other virus susceptible murine models when available), with the aim of providing pre-clinical testing results prior to the release of the human vaccine trial data. At the same time, we will specifically examine whether the pulmonary myeloid changes we have documented in i.v. BCG vaccinated mice impact on SARS-CoV-2 infection and disease . Our current experience with murine BCG vaccination models places us in the position to rapidly generate such data and to interrogate potential mechanisms behind any observed protection. As this project was initiated in the Spring and to this date we do not have the facilities fully in place to perform SARS-COV2 animal challenges and measure viral titers, we can only report the progress made on our preparations and first steps. These are summarized as follows: 1) All required safety and ethical approvals have been applied for and granted including the necessary amendments to our animal study protocols. 2) K18-hACE2 animals have been sourced and purchased for this study. BCG vaccination has been performed on the initial cohorts so that we can assess long term effects of this bacterial exposure. 3) SARS-CoV-2 isolates have been sourced and viral stocks are currently being generated for this project by the COVID-19 core facility and we have been provided Vero cells for viral plaque assays by our RML colleagues. 4) Flow cytometry reagents have been purchased and panel design and optimization experiments have been performed.

自1930年代以来，该芽孢杆菌Calmette-gurin（BCG）疫苗已被广泛用于预防婴儿和儿童的肺结核病，目前已包括在150多个国家 /地区的国家疫苗计划中。除了提供针对结核病的保护外，BCG疫苗接种还与婴儿全因死亡率降低有关，据报道，在成年人的黄热病疫苗攻击后，疫苗会降低病毒血症。 BCG还被证明在刺激癌症患者的抗肿瘤免疫反应方面成功，被认为是膀胱癌的金标准治疗方法。总之，这些观察结果为BCG在人类中的有益非特异性作用提供了证据，这归因于先天性免疫系统的表观遗传和代谢重新编程，以及对造成造血的重新指导，以迅速产生保护性髓样细胞。 鉴于BCG疫苗接种提供的据报道的非特异性保护，已经假设BCG可以对新型冠状病毒SARS-COV-2提供一些保护。许多流行病学研究报道了质量BCG疫苗接种与SARS-COV-2感染的较低发生率以及Covid-19的死亡率之间存在关联。这些初步的相关研究一直是科学界众多争论的主题，许多已发表的报告发现BCG疫苗接种状态与SARS-COV-2感染的易感性之间没有正相关。尽管如此，在公共卫生和科学领域已经产生了重大兴趣，并且在临床过程中至少进行了18项临床试验。 我们自己未发表的数据（请参阅随附的报告AI001044-13）表明，BCG免疫，尤其是通过静脉内（i.v.）途径进行管理时，会深刻地改变了肺髓样链状的组成和表型，从而创造了一个限制Mycobacterium tuberculsis的能力，从而限制了Tuberculculsis的能力。这些变化包括长时间的肺泡巨噬细胞脱落。在这项研究中，我们将评估BCG疫苗接种在SARS-COV-2感染的K18-HACE2转基因小鼠模型中（以及其他病毒易感的鼠模型），目的是在释放人疫苗试验数据之前提供临时测试结果。同时，我们将专门检查我们在静脉注射中记录的肺髓样变化是否变化。 BCG接种小鼠对SARS-COV-2感染和疾病的影响。我们目前在Murine BCG疫苗接种模型中的经验使我们有能力快速生成此类数据并审问任何观察到的保护背后的潜在机制。 由于该项目是在春季开始的，到目前为止，我们还没有充分的设施来执行SARS-COV2动物挑战并测量病毒滴度，因此我们只能报告在准备和第一步中取得的进展。这些总结如下： 1）所有必需的安全和道德批准都已申请并批准，包括我们动物研究方案的必要修订。 2）K18-HACE2动物已用于本研究并购买。 BCG疫苗接种已在初始队列上进行，因此我们可以评估这种细菌暴露的长期影响。 3）COVID-19核心设施目前正在为该项目生成SARS-COV-2分离株，并正在为我们的RML同事提供病毒斑块测定法。 4）已经购买了流式细胞仪试剂，并进行了面板设计和优化实验。