Influenza and Emerging Infectious Diseases

流感和新发传染病

• 批准号: 8946398
• 负责人: Richard Davey
• 金额: $ 205.88万
• 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/8946398
• 关键词: Acute; Address; Affect; Africa; Anthrax Attack; Anthrax disease; Anthrax exposure; Antibodies; Antiviral Agents; Avian Influenza; Birds; Caring; Cessation of life; Childhood; Cities; Clinical; Clinical Protocols; Clinical Research; Clinical Research Protocols; Clinical Trials; Clinical Trials Network; Collaborations; Collection; Communicable Diseases; Coronavirus; Coronavirus Infections; Country; Cytidine Monophosphate; Data Analyses; Department of Defense; Development; Diagnosis; Disease; Disease Outbreaks; Dose; Double-Blind Method; Double-Stranded RNA; Drug Kinetics; Drug resistance; Drug usage; Ebola virus; Emerging Communicable Diseases; Enrollment; Epidemic; Epidemiology; Genomics; Goals; Half-Life; Harvest; Health; Health Personnel; Hemagglutination; Hospitalization; Human; Immune Sera; Immunoglobulins; Immunologics; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H7N9 Subtype; International; Intravenous; Intravenous Immunoglobulins; Knowledge; Laboratories; Legal patent; Licensing; Life; Logistics; Maps; Measures; Mexico; Monitor; Multicenter Trials; National Institute of Allergy and Infectious Disease; Nose; Occupational Exposure; Oral; Oseltamivir; Outcome; Outpatients; Patients; Pattern; Pharmaceutical Preparations; Phase; Pilot Projects; Placebo Control; Placebos; Plasma; Poly ICLC; Population; Populations at Risk; Preparation; Probenecid; Protocols documentation; Public Health; Randomized; Randomized Clinical Trials; Relative (related person); Research; Risk; Safety; Serum; Severe Acute Respiratory Syndrome; Site; Southeastern Asia; Specimen; Testing; Therapeutic; Toxic effect; United States; Vaccines; Veterans; Vietnam; Viral; Viral Genome; Virus; Virus Diseases; aged; anti-influenza; base; clinically relevant; cohort; design; improved; influenzavirus; novel; open label; pandemic disease; pathogen; pilot trial; prevent; psychologic; repository; respiratory; respiratory virus; response; seasonal influenza; treatment trial; volunteer

Foremost among the pathogens under study in this new project is the influenza virus, including the agents of conventional seasonal influenza, novel new strains of influenza A such as the A(H1N1)pdm09 strain that emerged in April 2009, as well as the ongoing threat of avian subtypes such as the H5N1 and H7N9 viruses. Novel means first to better characterize and then to treat infection with these respiratory pathogens using existing or newly developed strategies are a primary focus of this important new project within the Clinical Research Section of the LIR. The first major initiative undertaken in this project was a collaborative protocol undertaken with the Department of Veterans Affairs (DVA) as well as the Department of Defense to determine if novel pharmacokinetic means could be used to extend the useful half-life of oseltamivir, the major licensed oral antiviral drug used to treat seasonal influenza in the United states and elsewhere and also a drug in comparatively short supply on a global scale.The pharmacokinetics proved that probenecid could be useful in extending the supply of oseltamivir in a situation of limited drug supply. The ability of oseltamivir to treat effectively severe cases of seasonal influenza may be limited, and knowledge of its utility in treating human cases of avian influenza is largely anecdotal. For these reasons NIAID launched a portfolio of clinical trials focused on the therapeutics of human influenza. One is a phase II double-blinded, randomized clinical trial conducted within a network of research collaborators in Southeast Asia that compared the relative efficacy of high dose versus standard-dose oseltamivir for the treatment of severe influenza and avian influenza. This trial was completed in the affected countries and showed no survival benefit to double-dose treatment. An additional trial was a phase II vaccine dose-finding pilot study for the development of an anti-influenza A (H5N1) intravenous hyper-immune globulin preparation of potential utility in the treatment of human cases of avian influenza. We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-microg, 120-microg, and 180-microg cohorts were compared. However, the results did suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses, even if there was no apparent benefit to increasing the dose of the vaccine. In addition to these trials, we also undertook a study of a novel agent with potential antiviral activity against a variety of respiratory viruses, including influenza. In this phase I double-blind, placebo-controlled, dose-escalating study to evaluate the safety and tolerability of topical Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers received escalating doses of this biologic response modifier through nasal administration. Although there were no consistent local or systemic immunologic effects that emerged, the product was both safe and well tolerated topically. Beginning with the emergence of the pandemic strain of A(H1N1)pdm09 influenza in April 2009, our section also undertook additional clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. A protocol was developed to allow serial collection of high-titer anti-influenza plasma either from patients recovering from naturally-acquired infection or from recipients of the trivalent vaccine. The purpose is to allow harvesting of a pool of high-titer antisera (in the form of either plasma or a manufactured IVIG product) that could then be tested as a potential therapeutic adjunct in the management of patients with severe or life-threatening influenza infection. A treatment trial involving open-label administration of two units of hyperimmune plasma to hospitalized patients with severe influenza was launched domestically with the goal of enrolling and studying 100 patients on a multicenter basis. Most recently we have also designed an international multi-center randomized, double-blind study of hyperimmune IVIG plus standard-of-care versus standard-of-care alone in hospitalized patients with severe influenza. This clinical outcome trial was preceded by completion of a multi-center pilot trial in 31 patients through the INSIGHT network addressing the safety, pharmacokinetics, and logistics of administering hyperimmune IVIG to patents with acute influenza. We have also been conducting two randomized multicenter trials internationally evaluating 1) the virologic and clinical correlation of triple combination anti-influenza treatment versus monotherapy in at-risk populations, and 2) the use of virologic assessments in measuring the effects of oseltamivir versus placebo in mild outpatient disease. More recently we have also initiated a safety and pharmacokinetic study in normal volunteers of single and then multiple doses of a novel antisense compound, AVI-7100, that has activity against influenza. Recruitment into the single dose phase has been completed and data analyses are ongoing. We continue to provide scientific and logistical support to the Mexico infectious diseases network La Red, a multi-site collaboration with the Mexico Ministry of Health designed to promote sustainability and capacity to continue clinically relevant and high-quality research on emerging infectious diseases. The five sites in Mexico City include two pediatric sites. Finally, we have also continued to contribute to the management and oversight of three large international observational protocols for outpatients or hospitalized patients with seasonal influenza infection administered under the auspices of the INSIGHT clinical trials network. The goal of these trials is to better characterize the clinical aspects of seasonal influenza infection on a global basis, to define predictors of severe disease and/or death including host genomics, to sequence and compare viral genomes on a geographic and epidemiologic basis, and to develop a repository of clinical research specimens potentially of great value in helping map viral antigenic drift, identifying emerging patterns of drug resistance, and characterizing other aspects of the evolving pandemic. Most recently these protocols have been modified to also permit enrollment of patients diagnosed with novel coronavirus infections such as that due to the MERS-CoV agent. Lastly, in addition to the clinical trials described above, we continue to 1) monitor yearly the clinical and psychologic status of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attacks, including maintaining an open clinical protocol for the study of additional anthrax exposures that may occur through accidental or occupational exposures, and 2) support a clinical research protocol to allow the hospitalization (within the Clinical Center's Special Clinical Studies Unit) and treatment of BSL-3/4 laboratory workers potentially exposed to select agents, or of other patients exposed to emerging infectious diseases of public health importance. This latter protocol will also permit us to hospitalize and provide care for health care workers potentially exposed to, or infected with, Ebola virus as a result of deployment to regions of West Africa presently suffering from an unprecedented outbreak of Ebola virus infection. At the Clinical Center we have also initiated plans to undertake one or more phase 1 safety/toxicity studies of investigational vaccines or MCMs with putative activity against Ebola virus.

该新项目研究的病原体中最重要的是流感病毒，包括传统季节性流感的病原体、新型甲型流感病毒株，例如 2009 年 4 月出现的 A(H1N1)pdm09 病毒株，以及持续存在的威胁禽亚型，如 H5N1 和 H7N9 病毒。新颖的方法是首先更好地表征这些呼吸道病原体的感染，然后使用现有或新开发的策略治疗这些呼吸道病原体的感染，这是 LIR 临床研究部门这一重要新项目的主要焦点。该项目的第一个重大举措是与退伍军人事务部 (DVA) 以及国防部签订了一项合作协议，以确定是否可以使用新的药代动力学方法来延长奥司他韦的有效半衰期，奥司他韦是主要的药物在美国和其他地方用于治疗季节性流感的许可口服抗病毒药物，也是全球范围内供应相对短缺的药物。药代动力学证明丙磺舒可用于在以下情况下延长奥司他韦的供应：药品供应有限。 奥司他韦有效治疗严重季节性流感病例的能力可能有限，并且对其在治疗人类禽流感病例中的效用的了解很大程度上是传闻。出于这些原因，NIAID 启动了一系列专注于人类流感治疗的临床试验。其中一项是在东南亚的研究合作者网络中进行的一项 II 期双盲随机临床试验，该试验比较了高剂量与标准剂量奥司他韦治疗严重流感和禽流感的相对疗效。这项试验在受影响的国家完成，结果表明双剂量治疗没有生存获益。另一项试验是一项 II 期疫苗剂量探索试点研究，旨在开发抗甲型流感 (H5N1) 静脉注射超免疫球蛋白制剂，该制剂可用于治疗人类禽流感病例。我们进行了一项剂量递增、非盲法临床试验，涉及 75 名年龄在 18-59 岁之间的受试者。当比较 90 微克、120 微克和 180 微克队列时，没有观察到血清血凝抑制抗体几何平均滴度 (GMT) 出现统计学上显着的剂量相关增加。然而，结果确实表明，与较少剂量产生的 GMT 相比，第三剂和第四剂 H5N1 A/Vietnam/1203/04 疫苗可能会导致更高的血凝抑制和微中和 GMT，即使没有明显的益处增加疫苗的剂量。除了这些试验之外，我们还开展了一项针对多种呼吸道病毒（包括流感病毒）具有潜在抗病毒活性的新型药物的研究。在这项旨在评估局部 Poly-ICLC（聚肌苷酸和聚胞苷酸的合成 dsRNA 链）安全性和耐受性的 I 期双盲、安慰剂对照、剂量递增研究中，正常志愿者接受了递增剂量的这种生物制剂通过鼻腔给药的反应调节剂。尽管没有出现一致的局部或全身免疫效应，但该产品既安全又具有良好的局部耐受性。 自 2009 年 4 月出现 A(H1N1)pdm09 流感大流行毒株开始，我们科室还开展了额外的临床研究工作，以帮助更好地表征和治疗新型流感亚型和季节性流感亚型的感染。 开发了一种方案，允许从自然获得性感染恢复的患者或三价疫苗的接受者中连续收集高滴度抗流感血浆。目的是收集高滴度抗血清（以血浆或制造的 IVIG 产品的形式），然后将其作为治疗严重或危及生命的流感感染患者的潜在治疗辅助剂进行测试。国内开展了一项针对重症流感住院患者开放标签给予两单位超免疫血浆的治疗试验，目标是多中心入组和研究100名患者。最近，我们还设计了一项国际多中心随机、双盲研究，对住院的严重流感患者进行超免疫 IVIG 加标准护理与单独标准护理的研究。在这项临床结果试验之前，通过 INSIGHT 网络完成了对 31 名患者进行的多中心试点试验，解决了急性流感患者注射超免疫 IVIG 的安全性、药代动力学和后勤问题。我们还在国际上进行了两项随机多中心试验，评估 1) 三联抗流感治疗与单药治疗在高危人群中的病毒学和临床相关性，以及 2) 使用病毒学评估来衡量奥司他韦与安慰剂的效果轻症门诊。最近，我们还在正常志愿者中启动了一项安全性和药代动力学研究，研究了一种新型反义化合物 AVI-7100，该化合物具有抗流感活性，然后是单剂量和多剂量。单剂量阶段的招募已经完成，数据分析正在进行中。我们继续为墨西哥传染病网络 La Red 提供科学和后勤支持，该网络是与墨西哥卫生部的多站点合作，旨在促进可持续性和能力，以继续对新兴传染病进行临床相关和高质量的研究。墨西哥城的五个站点包括两个儿科站点。最后，我们还继续为在 INSIGHT 临床试验网络的支持下管理和监督针对季节性流感感染的门诊或住院患者的三个大型国际观察方案做出贡献。这些试验的目标是更好地描述全球季节性流感感染的临床特征，定义严重疾病和/或死亡的预测因素，包括宿主基因组学，在地理和流行病学基础上对病毒基因组进行测序和比较，并开发一个临床研究样本库，在帮助绘制病毒抗原漂移、识别新出现的耐药模式以及描述不断演变的流行病的其他方面方面可能具有巨大价值。最近，这些方案进行了修改，允许招募被诊断患有新型冠状病毒感染（例如中东呼吸综合征冠状病毒感染）的患者。 最后，除了上述临床试验外，我们继续 1) 每年监测部分因 2001 年 10 月炭疽袭击而暴露于炭疽的患者的临床和心理状态，包括维持开放的临床方案研究可能因意外或职业接触而发生的额外炭疽接触，以及 2) 支持临床研究方案，以允许住院治疗（在临床中心的特殊临床研究单位内）和治疗BSL-3/4 实验室工作人员可能接触过特定病原体，或接触过具有公共卫生重要性的新发传染病的其他患者。后一项协议还将允许我们为因部署到目前遭受前所未有的埃博拉病毒感染爆发的西非地区而可能接触或感染埃博拉病毒的医护人员住院并提供护理。在临床中心，我们还启动了计划，对具有抗埃博拉病毒活性的研究疫苗或 MCM 进行一项或多项一期安全/毒性研究。