Integrated Research Facility at Fort Detrick

德特里克堡综合研究设施

• 批准号: 10914725
• 负责人: Connie Schmaljohn
• 金额: $ 4248.05万
• 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/10914725
• 关键词: 2019-nCoV; Achievement; African Green Monkey; Alveolus; Animal Disease Models; Animals; Attenuated; Bangladesh; Blood Coagulation Disorders; Brain; COVID-19; COVID-19 treatment; Cavia; Chiroptera; Clinical; Clinical Protocols; Clinical Research; Collaborations; Containment; Data; Defective Viruses; Democratic Republic of the Congo; Deposition; Development; Diagnostic; Disease; Ebola virus; Emerging Communicable Diseases; Environment; Equipment; Evaluation; Exposure to; Ferrets; Fibrin; Filovirus; Glycoproteins; Government; Guinea; Hamsters; Hearing Tests; Human; Image; Immune; Immune response; In Vitro; Infectious Diseases Research; Interdisciplinary Study; Intravenous Immunoglobulins; Laboratories; Lassa virus; Lead; Liberia; Lung; MRI Scans; Macaca fascicularis; Macaca mulatta; Marburgvirus; Medical Imaging; Mesocricetus auratus; Methods; Mission; Modeling; Molecular; Monkeypox; Morphology; National Institute of Allergy and Infectious Disease; Neurologic; Nipah Virus; Organ; PET/CT scan; Pathogenesis; Play; Positioning Attribute; Positron-Emission Tomography; Protocols documentation; Pure-Tone Audiometry; Reactive Oxygen Species; Reporter; Research; Research Support; Resolution; Resources; Role; SARS-CoV-2 infection; SARS-CoV-2 variant; Scanning; Serial Magnetic Resonance Imaging; Signal Transduction; Site; Therapeutic antibodies; Time; Training; Transgenic Mice; Tympanometry; United States National Institutes of Health; Virulent; Virus; X-Ray Computed Tomography; aerosolized; brain magnetic resonance imaging; clinical candidate; efficacy evaluation; functional group; human disease; imaging capabilities; imaging system; in vivo; in vivo evaluation; instrument; nonhuman primate; novel; optical imaging; particle; pathogen; pathogenic virus; preclinical imaging; prevent; progressive hearing loss; randomized, clinical trials; research facility; research study; single photon emission computed tomography; small molecule therapeutics; stem cells; tool; transcriptome; vaccine candidate; vector

The Integrated Research Facility - Frederick (IRF-Frederick) plays a central role in U.S. Governments high-containment research on emerging infectious diseases. In FY2023, the IRF-Frederick continued support for COVID-19 research and initiated multiple non-COVID-19 research studies. COVID-19 in vivo research included execution of multiple studies to evaluate the efficacy of therapeutic antibody clinical candidates and defective interfering particles against SARS-CoV-2 in Golden hamsters. COVID-19 hamster studies included analyses of host lung transcriptomes after exposure to 10 different SARS-CoV-2 variants. Efforts have continued in the development of a non-human primate model that recapitulates severe human disease, and an ongoing study involving crab-eating macaques NHP has generated encouraging preliminary results. COVID-19 in vitro research focused on evaluation of potential therapeutic antibodies and human intravenous immunoglobulin for the treatment of SARS-CoV-2 infection. In FY2023, IRF-Frederick utilized its newly developed high-containment audiometry capability to demonstrate progressive hearing loss in rhesus monkeys exposed to Lassa virus (LASV). This achievement marks the first time that tympanometry and pure tone audiometry have been used in high containment for nonclinical evaluations. Additional LASV in vivo evaluations in Hartley guinea pigs showed 100% survival of LASV-exposed animals treated with a small-molecule therapeutic and, in a separate study, 100% protection conferred by a novel live-attenuated LASV vaccine candidate. Multiple other in vivo studies were conducted to characterize disease pathogenesis following exposure to high-consequence pathogens. Using serial Magnetic Resonance Imaging (MRI) scans, reactive oxygen species were characterized in ferrets exposed to Ebola virus (EBOV). Positron Emission Tomography and Computed Tomography (PET-CT) serial scans were used to characterize fibrin deposition and coagulopathy in EBOV-exposed Hartley guinea pigs. The efficacy of a vaccine candidate based on a glycoprotein region conserved across multiple filoviruses was evaluated in Marburg-virus exposed cynomolgus macaques. Additionally, in a study involving African Green Monkeys exposed to large-particle aerosolized Nipah virus (NiV)-Bangladesh, clinical signs, immune responses, and pulmonary and neurological changes were characterized. IRF-Frederick has continued development of its unique advanced medical and pre-clinical imaging capabilities. The imaging team, in collaboration with CIDI partners, has implemented robust analysis workflows to quantify the PET signal in NHP lungs, brain, vasculature, and immune organs and has adapted clinically validated methods to extract quantitative data from morphological and functional brain MRI scans in NHPs. In FY2023, as part of IRF-Fredericks implementation of a multi-year Imaging Equipment Upgrade Plan, two new instruments -- a Mediso Large Field of View Extreme Resolution (LFER) PET/CT scanner; and a Milabs VECTor combined PET, single-photon emission computed tomography (SPECT), CT, and optical imaging system were successfully installed and validated in the Biosafety Level (BSL) 4 laboratory. IRF-Frederick advanced its organ-chip capability, focusing on the implementation and optimization of an alveolus-on-chip and a small-airway-on-chip protocol within BSL-2 and BSL-4 for SARS-CoV-2 and NiV. Other in vitro projects initiated in FY2023 include utilization of bat stem cells and their progeny to investigate the host-viral pathogen interface, development of an EBOV reporter construct for a project aimed at establishing a transgenic mouse for in vivo virus tracking using optical imaging, and determination of molecular mechanisms of filovirus persistence. The IRF-Frederick Clinical Study Support Team (CSST) provided diagnostic and research support for 10 clinical protocols, using IRF-Frederick on-site resources and staff deployments to OCONUS sites. CSST staff engaged with OCONUS partners for training and capability-building activities in Guinea, Liberia, and Democratic Republic of the Congo (DRC). Importantly, the CSST assumed responsibility as the primary lead of the laboratory diagnostics functional group for the Pamoja Tulinde Maisha (PALM) 007: Mpox Randomized Clinical Trial. Eight new projects were initiated in FY2023. IRF-Frederick is engaged in 63 active projects, supporting 79 collaborative partnerships.

弗雷德里克综合研究机构(IRF-Frederick)在美国政府对新发传染病的高遏制研究中发挥着核心作用。在2023财年，国际扶轮基金会-弗雷德里克继续支持新冠肺炎研究，并发起了多项非新冠肺炎研究。 新冠肺炎的体内研究包括在金黄地鼠开展多项研究，以评估治疗性抗体、临床候选药物和缺陷干扰颗粒对SARS-CoV-2的疗效。新冠肺炎仓鼠的研究包括对接触10种不同SARS-CoV-2变种后宿主肺转录本的分析。继续努力开发一种概括人类严重疾病的非人类灵长类动物模型，正在进行的一项关于食蟹猕猴的研究产生了令人鼓舞的初步结果。新冠肺炎的体外研究重点是评价潜在的治疗性抗体和人静脉注射免疫球蛋白治疗SARS-CoV-2感染的效果。 在2023财年，IRF-Frederick利用其新开发的高包容测听能力，证明了暴露于Lassa病毒(LASV)的恒河猴进行性听力损失。这一成果标志着鼓室导纳和纯音测听首次被用于非临床评估的高安全性。在哈特利豚鼠身上进行的其他LASV体内评估显示，接受小分子治疗的LASV暴露动物的存活率为100%，在另一项单独的研究中，由一种新型减毒LASV候选疫苗提供的100%保护。 还进行了多项其他体内研究，以确定暴露于高后果病原体后的疾病发病机制。使用系列磁共振成像(MRI)扫描，对暴露于埃博拉病毒(EBOV)的雪貂进行了活性氧物种的表征。用正电子发射断层扫描和计算机断层扫描(PET-CT)对暴露于EBOV的Hartley豚鼠的纤维蛋白沉积和凝血障碍进行了研究。基于多种丝状病毒之间保守的糖蛋白区域的候选疫苗在暴露于马尔堡病毒的食蟹猴中进行了有效性评估。此外，在一项涉及接触孟加拉国大颗粒雾化尼帕病毒(Nipah Virus，NIV)的非洲绿猴的研究中，对临床体征、免疫反应以及肺部和神经变化进行了表征。 IRF-Frederick继续发展其独特的先进医疗和临床前成像能力。成像团队与CIDI合作伙伴合作，实施了强大的分析工作流程，以量化NHP肺、脑、血管和免疫器官中的PET信号，并采用了经过临床验证的方法，从NHP的形态和功能脑MRI扫描中提取定量数据。在2023财年，作为IRF-Fredericks实施的多年成像设备升级计划的一部分，两台新仪器--Mediso大视场极限分辨率(LFER)PET/CT扫描仪和Milabs矢量组合PET、单光子发射计算机断层扫描(SPECT)、CT和光学成像系统--在生物安全级别(BSL)4实验室成功安装和验证。 IRF-Frederick提高了其器官芯片能力，重点实施和优化了针对SARS-CoV-2和NIV的BSL-2和BSL-4中的芯片上肺泡和小气道芯片协议。2023财年启动的其他体外项目包括利用蝙蝠干细胞及其后代调查宿主-病毒病原体界面，为一个旨在建立转基因小鼠的项目开发EBOV报告结构，用于使用光学成像进行体内病毒跟踪，以及确定丝状病毒持续的分子机制。 IRF-Frederick临床研究支持团队(CSST)利用IRF-Frederick现场资源和人员部署到OCONUS站点，为10个临床方案提供诊断和研究支持。CSST工作人员与OCONUS合作伙伴在几内亚、利比里亚和刚果民主共和国开展培训和能力建设活动。重要的是，CSST承担了Pamoja Tulinde Maisha(Palm)007：MPOX随机临床试验实验室诊断职能组的主要领导责任。 2023财年启动了八个新项目。IRF-Frederick参与了63个积极项目，支持79个合作伙伴关系。