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.

在这个新项目中所研究的病原体中的最重要的是流感病毒，包括传统的季节性流感，新型流感的新型流感菌株，例如2009年4月出现的A（H1N1）PDM09菌株，以及诸如H5N1和H7n1和H7n9 nivers的持续威胁。新颖的意思是首先要更好地表征并使用这些呼吸道病原体使用现有或新开发的策略来治疗感染，这是LIR临床研究部分中这个重要新项目的主要重点。该项目中采取的第一个主要举措是与退伍军人事务部（DVA）进行的合作协议以及国防部，以确定是否可以使用新颖的药代动力学手段来扩展奥斯塔米维尔有用的半衰期，这是主要的抗病毒药物（用于治疗季节性的药物）和在美国的季节性量表，并在美国和量表中进行了较短的量表，并在美国的季节性量表中进行了适用的量表。在药物供应有限的情况下，ProbEnecid对于扩展Oseltamivir的供应可能很有用。 奥斯塔米维尔（Oseltamivir）有效治疗季节性流感病例的严重病例的能力可能受到限制，并且对治疗人类禽流感病例的效用的了解在很大程度上是轶事。由于这些原因，NIAID推出了一项临床试验的组合，该试验集中在人类流感的治疗中。一种是在东南亚的研究合作者网络中进行的II期双盲，随机临床试验，比较了高剂量与标准剂量oseltamivir的相对功效，以治疗严重的流感和禽流感。该试验在受影响的国家完成，没有对双剂量治疗的生存益处。一项额外的试验是一项II期疫苗剂量调查试验研究，用于开发抗激素ZA A（H5N1）静脉内超免疫球蛋白在治疗人类禽流感病例中潜在效用的静脉内高免疫蛋白制备。我们进行了一项剂量提升，未盲的临床试验，涉及75名18-59岁的受试者。当比较90-Microg，120-Microg和180-Microg群体时，观察到血清血凝抑制抗体的几何平均滴度（GMT）的统计学意义增加。然而，结果确实表明，与剂量较少的GMT相比，H5N1 A/越南/1203/04疫苗的第三剂量可能会导致更高的血凝抑制和微中性化GMT，即使没有明显增加疫苗剂量的好处，GMT也没有剂量。除了这些试验外，我们还对具有潜在的抗病毒活性的新药物进行了针对各种呼吸道病毒的新型药物，包括流感病毒。在这一阶段，双盲，安慰剂对照，剂量升级的研究，以评估局部局部多体性局部（合成DSRNA链）的安全性和耐受性，正常志愿者接受了这种生物响应响应剂量通过NASAL管理的升级剂量的升级剂量。尽管没有出现的局部或全身免疫效应一致，但该产品既安全又宽容。 从2009年4月的A（H1N1）PDM09流感的大流行菌株的出现开始，我们的部分还进行了额外的临床研究工作，以帮助更好地通过流感的新颖和季节性亚型来更好地表征和治疗感染。 制定了一项方案，以允许从自然感染的患者或三价疫苗的接受者中恢复的患者的高细胞抗发炎血浆。目的是允许收集一组抗血清（以等离子体或制成的IVIG产品的形式），然后可以作为潜在的治疗辅助物测试，以治疗严重或威胁生命的流感感染患者。在国内发射了一项针对住院的严重流感患者的两个单位高免疫血浆的开放标签给药的治疗试验，其目的是在多中心招募和研究100名患者。最近，我们还设计了一项国际多中心随机，双盲IVIG的双盲研究，在住院的严重流感患者中，与单独的护理标准相对于护理标准的护理和护理标准。在这项临床结果试验之前，通过解决急性流感的专利的安全性，药代动力学的洞察力，药代动力学和物流，完成了31名患者的多中心试验试验。我们还一直在进行两项在国际评估的随机多中心试验中，以评估1）三合一组合抗炎性治疗的病毒学和临床相关性与处于高危人群中的单一疗法的病毒学和临床相关性，以及2）使用病毒学评估在轻度支撑疾病中的oseltamivir versus antus bethsbo的影响中使用病毒学评估。最近，我们还对单个单一的正常志愿者进行了安全和药代动力学研究，然后多种剂量的一种新型的反义化合物AVI-7100，具有针对流感的活性。招募单剂量阶段已经完成，并且正在进行数据分析。我们继续为墨西哥传染病网络La Red提供科学和后勤支持，这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，以继续在临床上相关和高质量的有关新兴的传染病。墨西哥城的五个地点包括两个儿科地点。最后，我们还继续为在Insight临床试验网络的主持下管理的三种大型国际观察方案的管理和监督，用于门诊或住院治疗患者。 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不断发展的大流行的各个方面。最近，这些方案已被修改，还允许入学被诊断为新型冠状病毒感染的患者，例如由于MERS-COV剂而导致的冠状病毒感染。 最后，除了上述临床试验外，我们继续进行1）监测一年一度的先前暴露于2001年10月炭疽病攻击的患者的临床和心理状况BSL-3/4实验室工人可能会接触某些特工或其他患有新兴的公共健康重要性传染病的患者。后一种方案还将允许我们住院并为可能接触或感染埃博拉病毒的医护人员医疗服务人员部署到西非地区目前患有前所未有的埃博拉病毒感染爆发。在临床中心，我们还启动了对研究性疫苗或MCMS进行一项或多项针对埃博拉病毒的活动活动的1次安全/毒性研究的计划。