Influenza and Emerging Infectious Diseases

流感和新发传染病

• 批准号: 8336210
• 负责人: Richard Davey
• 金额: $ 152.82万
• 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/8336210
• 关键词: Affect; Anthrax Attack; Anthrax disease; Anthrax exposure; Anti-influenza Agent; Antibodies; Antiviral Agents; Antiviral resistance; Area Under Curve; Avian Influenza; Birds; Cessation of life; Clinical; Clinical Protocols; Clinical Research; Clinical Research Protocols; Clinical Trials; Clinical Trials Network; Collection; Country; Cytidine Monophosphate; Data Analyses; Department of Defense; Development; Disease; Dose; Double-Blind Method; Double-Stranded RNA; Drug Kinetics; Drug resistance; Drug usage; Emerging Communicable Diseases; Enrollment; Epidemiology; Goals; H1N1 vaccine; Half-Life; Harvest; Hemagglutination; Hospitalization; Human; Immune Sera; Immunocompromised Host; Immunoglobulins; Immunologic Deficiency Syndromes; Immunologics; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; International; Intravenous; Intravenous Immunoglobulins; Knowledge; Laboratories; Licensing; Life; Maps; Measures; Monitor; Multicenter Trials; National Institute of Allergy and Infectious Disease; Nose; Occupational Exposure; Oral; Oseltamivir; 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; Schedule; Serum; Southeastern Asia; Specimen; Staging; Testing; Therapeutic; Time; United States; Vaccines; Veterans; Vietnam; Viral; Viral Genome; aged; anti-influenza; base; cohort; healthy volunteer; improved; influenzavirus; novel; open label; pandemic disease; pathogen; 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 H1N1 strain that emerged in April 2009, as well as the ongoing threat of avian (H5N1) virus. 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 of oseltamvir plus probenecid were analyzed and showed a dose-dependent favorable effect of the latter upon both the trough and area-under-the-curve concentrations of the former. At the schedule of four times daily dosing with probenecid, these parameters were not statistically different from daily dosing of oseltamivir alone, suggesting that probenecid might 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 undertook three 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 has been completed in the affected countries and data analysis is being finalized. The second was a phase I double-blind, placebo-controlled, dose-escalating study to evaluate the relative safety and tolerability of a novel intravenous anti-influenza agent, peramivir, in healthy volunteer subjects. This trial was initiated at the Clinical Center but then largely completed by the sponsor through a Clinical Research Organization. The third 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. H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin. We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 micrograms of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered approximately 28 days apart. 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 have also undertaken a study of a novel nasally-administered 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 nasal Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers received escalating doses of this biologic response modifier to determine its safety when nasally administered as well as to measure both local and systemic immunologic effects of its administration. This trial is currently in the final stages of data analysis. In response to the emergence of a pandemic strain of novel H1N1 influenza A in April 2009, our section undertook additional clinical research efforts to help better characterize and treat infection with this novel new strain. To begin with, protocol 07-I-0229 Influenza in the Immunocompromised Host was revised to allow enrollment and study of normal volunteers in addition to patients with immunodeficiency disorders. A new protocol was also developed to allow serial collection of high-titer anti-H1N1v plasma either from patients recovering from 2009 H1N1 naturally-acquired infection or from recipients of the 2009 H1N1 vaccine. The goal of this protocol 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 2009 H1N1 infection. A treatment trial involving open-label administration of two units of hyperimmune 2009 H1N1 plasma to hospitalized patients with severe influenza has also been launched and is currently open to enrollment on a multicenter basis. We have also launched 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. Finally, we have also continued to contribute to the management and oversight of one domestic and two large international observational protocols for outpatients or hospitalized patients with 2009 H1N1 or other seasonal influenza infection administered under the auspices of DMID or the INSIGHT clinical trials network, respectively. The goal of the latter two large trials is to better characterize the clinical aspects of both 2009 H1N1 and other types of seasonal influenza infection on a global basis, to define predictors of severe disease and/or death, 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, emerging patterns of drug resistance, and other aspects of the evolving pandemic. Lastly, in addition to the clinical trials described above, we 1) continue to monitor on a yearly basis 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) have initiated a clinical research protocol to allow the hospitalization (within NIAID's new Special Clinical Studies Unit), study and treatment of BSL-3/4 laboratory workers potentially exposed to select agents, or of other patients exposed to emerging infectious disease pathogens of public health importance.

在这个新项目中所研究的病原体中，最重要的是流感病毒，包括传统季节性流感的药物，新型流感的新型流感菌株，例如2009年4月出现的H1N1菌株，以及持续的Avian（H5N1）病毒的威胁。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及国防部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的有用半衰期，这是主要许可的口腔抗病毒药物（用于治疗美国和其他地方的季节性量表）的主要量身定期的药物，并在美国的量表中进行了适用的量表，并在美国的量表中进行了适用的量表，并且是对AR的适用量表。分析了Oseltamvir Plus Probenecid，并显示后者对前者的低谷和面积浓度的剂量依赖性效果。在每天用probEnecid进行四次剂量的时间表中，这些参数在统计上与单独的oseltamivir的每日给药没有统计学差异，这表明在有限的药物供应情况下，ProbEnecid可能有助于扩展Oseltamivir的供应。 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进行了三项临床试验，重点是人类流感的治疗剂。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。该试验已在受影响的国家完成，数据分析正在敲定。第二个是I期双盲，安慰剂对照，剂量提升的研究，以评估健康志愿者对新型静脉内抗激素剂Peramivir的相对安全性和耐受性。该试验是在临床中心开始的，但随后由赞助商通过临床研究组织完成。 第三次试验是一项II期疫苗剂量发现的试点研究，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。 H5N1禽流感代表了一种发作性的人畜共患病，可能引起大流行，抗病毒药抗性引起了相当大的关注。我们试图在健康志愿者中产生高敏机H5N1抗体，以发展高免疫静脉内免疫球蛋白。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。依次签署了三名二十五名受试者的队列，并接受了90、120或180微克H5N1 A/越南/越南/1203/04疫苗的4剂疫苗，大约相隔约28天。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型鼻水剂进行了研究，对包括流感在内的各种呼吸道病毒。 In this phase I double-blind, placebo-controlled, dose-escalating study to evaluate the safety and tolerability of topical nasal Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers received escalating doses of this biologic response modifier to determine its safety when nasally administered as well as to measure both local and systemic immunologic其管理的影响。该试验目前处于数据分析的最后阶段。 为了响应于2009年4月新型H1N1流感A的大流行菌株的出现，我们的部分进行了额外的临床研究工作，以帮助更好地通过这种新的新菌株来更好地表征和治疗感染。首先，修订了免疫功能低下的宿主中的07-I-0229流感，除了具有免疫缺陷障碍患者外，还允许对正常志愿者进行入学和研究。还制定了一项新方案，以允许从2009年H1N1自然获得感染或2009 H1N1疫苗的接受者中恢复的患者串行收集抗H1N1V血浆。该方案的目的是允许收集一组高敏机抗血清（以等离子体或制造的IVIG产品的形式），然后可以在管理2009 H1N1感染的严重或危及生命的2009 H1N1感染的患者中作为潜在的治疗辅助作用。一项涉及针对住院的严重流感患者的Hypermmune 2009 H1N1血浆开放标签给药的治疗试验，也已发射，目前愿意以多中心为基础入学。我们还启动了两项国际评估的随机多中心试验，1）在处于危险中的三重组合抗激素治疗与单一疗法的病毒学和临床相关性，以及2）使用病毒学评估来衡量奥斯塔米维尔（Oseltamivir）与安慰剂在轻度支配疾病中的影响。最后，我们还继续为分别在DMID或Insight临床临床试验网络的主持下对一项家庭和两种大型国际观察方案进行管理和监督。 The goal of the latter two large trials is to better characterize the clinical aspects of both 2009 H1N1 and other types of seasonal influenza infection on a global basis, to define predictors of severe disease and/or death, 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, emerging patterns of耐药性和不断发展的大流行的其他方面。 最后，除了上述临床试验外，我们1）每年继续监测以前暴露于2001年10月炭疽病攻击的患者的临床和心理状态，以前暴露于炭疽病的临床和心理状态，包括维持开放的临床方案，包括维持可能通过事故或职业经验的临床进行促进的促进临床的临床临床协议，并在临床上进行了临床。研究单位），可能暴露于某些药物的BSL-3/4实验室工人的研究和治疗，或其他暴露于新兴传染病病原体具有公共健康重要性的患者。