Viral Hemorrhagic Fevers: Disease Modeling and Transmission

病毒性出血热：疾病建模和传播

基本信息

批准号：
10272160
负责人：
Heinrich Feldmann
金额：
$ 199.85万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/10272160
关键词：
Acute African Age Andes Virus Animal Model Animals Annual Reports Antibody Therapy Antiviral Agents Arenavirus Biology Borrelia Bunyaviridae Canada Cells Cessation of life Clinical Clinical Trials Clinical Virology Collaborations Competence Containment Crimean-Congo Hemorrhagic Fever Virus Cytomegalovirus DNA Deer Mouse Development Diagnostic Diagnostic tests Disease Disease model Dose Ebola Ebola Hemorrhagic Fever Ebola virus Ecology Effector Cell Electroporation Emerging Communicable Diseases Epidemiology Family suidae Filovirus Fostering Functional disorder Future Gene Expression Gene Expression Profile Glycoproteins Goals Hantavirus Human Immune response Immunologics In Vitro Individual Infection Inflammatory International Kansas Kinetics Lassa virus Lung Macaca Macaca fascicularis Mali Mastomys Membrane Mesocricetus auratus Modeling Molecular Monoclonal Antibodies Mucous Membrane Mus National Institute of Allergy and Infectious Disease Nose Nucleoproteins Oral Order Spirochaetales Organ Outcome Pathogenesis Patients Performance Pharmaceutical Preparations Phase Plasmids Public Health RNA Relapsing Fever Reporting Research Research Activity Respiratory distress Reston Ebola virus Ribavirin Rodent Role Severity of illness Shock Signal Transduction Structure of parenchyma of lung Supportive care System Technology Testing Therapeutic Time Tissues Uganda United States National Institutes of Health Universities Vaccinated Vaccination Vaccine Production Vaccines Vesicular stomatitis Indiana virus Viral Viral Hemorrhagic Fevers Viral Vector Virus Virus Diseases Virus Replication Virus Shedding Wild Type Mouse Work anti-viral efficacy base clinical development cohort design disease transmission field study in vivo innovation mouse model neutralizing antibody nonhuman primate novel vaccines outcome prediction pathogen pathogenic virus prognostic tool respiratory response reverse genetics tool transcriptomics transmission process vaccine candidate vaccine development vector vector-based vaccine virus host interaction

项目摘要

(A) Study pathogenesis and pathophysiology of high biocontainment viral pathogens utilizing molecular technologies including reverse genetics systems: We continue to optimize mouse models for Crimean-Congo hemorrhagic fever virus (CCHFV) to study pathogenesis, immune responses and develop countermeasures. We defined favipiravir as a potent antiviral against CCHFV infection. Recently, we have established a mouse adapted CCHFV that leads to severe infection in wildtype mice. This will be an extremely valuable tool for future countermeasure development. (Hawman et al.) Using the Collaborative Cross (CC) mouse model of differential Ebola virus disease severity, we identified clinical, virologic, and transcriptomic features distinguishing outcomes. Tolerance is associated with rapid regulated induction of immune responses, including altered quantities of specialized effector cells. Lethal disease results from suppressed early gene expression, followed by uncontrolled inflammatory signaling. Gene expression signatures developed in mice predicted outcome in a cohort of West African Ebola patients demonstrating the potential for developing clinical prognostic tools in mice. (collaboration with A. Rasmussen & I. Lipkin, Columbia University) We have continued to establish a disease model for Reston ebolavirus (RESTV) in a commercial pig breed. Young pigs, ranging in age from 3 7 months, were highly susceptible to oral-nasal inoculation of RESTV. The animals developed acute severe respiratory distress with high but not uniform lethality. Most pigs succumb within a week of infection; some animals recover from severe disease. RESTV replicates mainly in respiratory tissues and virus is shed through mucosal membranes of the oronasal tract. The model will be instrumental for countermeasure development against a potential transboundary pathogen. (Haddock et al. & collaboration with J. Richt, Kansas State University) (B) Study immune responses to infection and vaccination of high containment viral pathogens and develop new vaccine candidates: We have continued to better define the use of VSV -based vaccine vectors against filoviruses. We could show that a single low-dose vaccination with VSV-EBOV protected cynomolgus macaques from lethal Ebola challenge. This work has implications for vaccine production, availability and use during public health response activities. (Marzi et al.) We could show that prior vaccination with VSV-EBOV did not interfere with post exposure antibody treatment, an important clinical aspect in the field for the treatment of recently VSV-EBOV vaccinated individuals. (collaboration with T. Geisbert, UTMB Galveston) Furthermore, we could demonstrate the usefulness of a quadrivalent VSV-based vaccine approach against several filoviruses. (collaboration with T. Geisbert, UTMB Galveston) We report the development and assessment of a DNA-based vaccine for CCHFV in the cynomolgus macaque model. Macaques were vaccinated with a DNA-based vaccine using in vivo electroporation-assisted delivery. The vaccine contained two plasmids encoding the glycoprotein precursor (GPC) and the nucleoprotein (NP) of CCHFV. This is the first evidence of a vaccine that can protect against CCHFV-induced disease in a nonhuman primate model. Clinical development of the vaccine is in progress. (Hawman et al & collaboration with CCHFVaccine Consortium) (C) Study vector/reservoir transmission of high containment viral pathogens using appropriate animal models: We continued to study infection kinetics of Lassa virus in the Mastomys reservoir utilizing a unique colony established here at RML. The animals support virus replication and shedding for several weeks before Lassa virus gets cleared. The model will allow for important transmission studies. (Rosenke et al.). We also developed immunological tools to study host responses in Mastomys. (Tang et al.) A wildlife vaccine project we have isolated and characterized Mastomys-specific cytomegaloviruses. Viral vectors are currently being designed. (Rosenke et al. & collaboration with M. Jarvis, Plymouth University, DARPA PREEMPT project) We also have studied host competency of Mastomys for the African relapsing fever spirochete Borrelia crocidurae. (Rosenke et al.) (D) Utilize in vitro and in vivo systems to study the interactions between viral pathogen or viral components and host cells and develop new antiviral strategies: We utilized the CCHFV Cynomolgus macaque disease model to test for antiviral efficacy of favipiravir. In this model, favipiravir was only of limited benefit compared to the mouse model. Nevertheless, given the bad performance of ribavirin in animal models, we propose to start human trials with favipiravir as the drug seems more potent against CCHFV. (Hawman et al.) We have demonstrated efficacy of monoclonal antibodies against Andes virus (hantavirus) in the Syrian hamster disease model. Neutralizing antibodies against the glycoproteins protected against lethal challenge. This approach can now be considered for clinical trials as there is no other animal model for this hantavirus. (Feldmann et al. & collaboration with F. Krammer, Mount Sinai) We studied the role of supportive care on Ebola virus infection in the lethal cynomolgus macaque model. We found that the animals developed progressive severe organ dysfunction and profound shock preceding death. While the overall impact of supportive care on the observed pathophysiology was limited, we did observe some time-dependent positive responses. (collaboration with J. Strong, Public Health Agency of Canada) (E) Study the epidemiology and ecology of high biocontainment pathogens utilizing newly developed rapid, sensitive and specific diagnostic test systems including those that can be applied under field conditions: Field studies for rodent-borne viruses have been started in the Bitterroot Valley. The initial phase of this project focused on Sin nombre hantavirus in deer mice. We found up to 20% of deer mice positive for SNV RNA in the lungs. We were unable to obtain a SNV isolate from the lungs but could passage SNV from lung tissue into nave deer mice. This is important for local public health as there is potential for human SNV infection. (Williamson et al.) For overseas filed studies, please see Annual Report on Mali ICER and Uganda ICER project.

（a）利用包括反向遗传学系统在内的分子技术的高生物内养病毒病原体的高生物内养病毒病原体的发病机理和病理生理学：我们继续优化Crimean-Congo出血热病毒（CCHFV）的小鼠模型，以研究发病机理，免疫反应并发展对策。我们将Favipiravir定义为针对CCHFV感染的有效抗病毒药。最近，我们建立了一种小鼠适应的CCHFV，导致野生型小鼠的严重感染。这将是未来对策开发的极其有价值的工具。（Hawman等人）使用差异埃博拉病毒疾病严重程度的协作横杂交（CC）小鼠模型，我们确定了区分结局的临床，病毒和转录组特征。耐受性与免疫反应的快速调节诱导有关，包括改变量的专用效应细胞。致命疾病是由抑制早期基因表达的抑制作用，随后是不受控制的炎症信号传导。在小鼠中开发的基因表达信号预测了西非埃博拉病人队列的结果，证明了在小鼠中开发临床预后工具的潜力。（与哥伦比亚大学的A. Rasmussen＆I。Lipkin合作）我们继续在商业猪品种中建立雷斯顿埃博拉病毒（RESTV）的疾病模型。年轻的猪的年龄从3个月7个月不等，非常容易受到RESTV的口腔鼻接种。这些动物出现了急性严重的呼吸窘迫，具有较高但不均匀的致死性。大多数猪在感染后一周内屈服；一些动物从严重疾病中恢复过来。 RESTV主要在呼吸道组织中复制，病毒是通过Ororanasal道的粘膜膜脱落的。该模型将有助于与潜在的跨性病原体的对策发展。（Haddock等人与堪萨斯州立大学的J. Richt合作）（b）研究对高关闭病毒病原体感染和疫苗接种的免疫反应，并发展出新的疫苗候选者：我们继续更好地定义使用基于VSV的疫苗媒介对FILOVIRES的使用。我们可以证明，一种低剂量的疫苗接种vsv-ebov保护了cynomolgus猕猴免受致命的埃博拉挑战。这项工作对公共卫生反应活动中的疫苗生产，可用性和使用有影响。（Marzi等人）我们可以证明，先前使用VSV-EBOV疫苗接种不会干扰暴露后抗体治疗，这是该领域的重要临床方面，用于治疗最近VSV-EBOV疫苗接种的个体。（与T. Geisbert合作，UTMB Galveston）此外，我们可以证明基于二价VSV的疫苗方法对几种丝状病毒的有用性。（与T. Geisbert合作，UTMB Galveston）我们报告了CCHFV的基于DNA的疫苗在Cynomolgus猕猴模型中的开发和评估。使用体内电穿孔辅助输送，用基于DNA的疫苗接种猕猴。该疫苗包含两个编码糖蛋白前体（GPC）和CCHFV的核蛋白（NP）的质粒。这是可以在非人类灵长类动物模型中预防CCHFV诱导的疾病的第一个证据。疫苗的临床发育正在进行中。（Hawman等人与CCHFVACCINE财团的合作）（c）使用适当的动物模型研究载体/储层传播高容器病毒病原体：我们继续利用RML建立的独特菌落研究在乳腺储层中LASSA病毒的感染动力学。在清除Lassa病毒之前，这些动物支持病毒复制和脱落数周。该模型将允许进行重要的传输研究。（Rosenke等）。我们还开发了免疫学工具来研究肥大中的宿主反应。（Tang等人）我们的野生动植物疫苗项目我们已经孤立并表征了乳腺特异性巨细胞病毒。目前正在设计病毒矢量。（Rosenke等人与M. Jarvis合作，DARPA抢占项目）我们还研究了Mastomys的宿主能力，以实现非洲复发性发烧螺旋体渗透性Crocidurae。（Rosenke等）（d）利用体外和体内系统来研究病毒病原体或病毒成分与宿主细胞之间的相互作用，并制定新的抗病毒药策略：我们利用CCHFV Cynomolgus猕猴疾病模型来测试favipiravir的抗病毒功效。在此模型中，与小鼠模型相比，Favipiravir仅具有有限的好处。然而，鉴于利巴韦林在动物模型中的表现不佳，我们建议用favipiravir进行人体试验，因为该药物对CCHFV似乎更有效。（Hawman等人）我们已经证明了叙利亚仓鼠疾病模型中针对安第斯山脉病毒（汉塔病毒）的单克隆抗体的功效。对抗致命挑战的糖蛋白中和抗体中和抗体。现在可以考虑这种方法进行临床试验，因为该汉坦病毒没有其他动物模型。（Feldmann等人与F. Krammer，Sinai Mount合作）我们研究了支持性护理对埃博拉病毒感染的作用，在致命的囊肿模型中。我们发现，动物发生了严重的器官功能障碍和死亡前的深刻冲击。尽管支持护理对观察到的病理生理学的总体影响有限，但我们确实观察到了一些时间依赖的阳性反应。（与加拿大公共卫生机构J. Strong合作）（e）研究了利用新开发的快速，敏感和特定的诊断测试系统的高生物培养病原体的流行病学和生态学，包括可以在现场条件下应用的测试系统：啮齿动物传播病毒的现场研究已经开始在Bitterroot山谷中。该项目的初始阶段集中于鹿小鼠中的罪恶nombre hantavirus。我们发现多达20％的鹿小鼠在肺中呈SNV RNA阳性。我们无法从肺部获得SNV分离株，但可以从肺组织中通过SNV进入中神中的鹿小鼠。这对当地的公共卫生很重要，因为有可能引起人类SNV感染。（Williamson等人）有关海外申请的研究，请参阅有关马里·icer和乌干达ICER项目的年度报告。