Pathogenesis, Treatment and Prevention of Emerging Infectious Diseases

新发传染病的发病机制、治疗和预防

• 批准号: 10021335
• 负责人: H. Clifford Lane
• 金额: $ 26.46万
• 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/10021335
• 关键词: Abdomen; Adult; Africa; Anthrax Attack; Anthrax disease; Antibodies; Antibody Response; Antiviral Agents; Area; Arthralgia; Bladder Control; Characteristics; Chest; Clinical; Clinical Data; Clinical Trials; Cohort Studies; Complement; Conduct Clinical Trials; Democratic Republic of the Congo; Detection; Development; Diagnostic; Disease; Disease Outbreaks; Drug usage; Ebola Hemorrhagic Fever; Ebola Vaccines; Ebola virus; Emerging Communicable Diseases; Enrollment; Evaluation; Event; Fatigue; Government; Headache; Incidence; Increased frequency of micturition; Infection; Influenza; Inhalation; International; Intravenous Immunoglobulins; Investigational Therapies; Liberia; Longterm Follow-up; Memory Loss; Monoclonal Antibodies; Morbidity - disease rate; Musculoskeletal; Myalgia; Neurologic; Oseltamivir; Participant; Pathogenesis; Patients; Phase II Clinical Trials; Placebos; Plasma; Prevalence; Prevention; Protocols documentation; RNA; Randomized; Randomized Controlled Trials; Reporting; Research; Respiratory Tract Diseases; Respiratory Tract Infections; Role; Safety; Sampling; Seminal fluid; Series; Serological; Severe Acute Respiratory Syndrome; Survivors; Symptoms; Testing; Time; Treatment Protocols; United States National Institutes of Health; Uveitis; Vaccines; Virus Diseases; Virus Shedding; Zaire Ebola virus; chemotherapeutic agent; cohort; follow-up; improved; mortality; novel strategies; novel therapeutics; pandemic disease; placebo group; pre-clinical; prevent; response; therapy development; trial comparing; vaccine efficacy; vaccine safety; volunteer

Research in this project is currently focused on four areas. These are characterization of the survivors of the anthrax attacks of 2001; characterization of emerging respiratory infections including SARS and influenza; development of novel therapies for influenza; and evaluation of experimental vaccines and treatments for Ebola virus as well as characterizing the long-term sequelae of Ebola virus infection. The anthrax study has enrolled a cohort of volunteers who are currently undergoing an extensive diagnostic evaluation. To be ready to deal with emerging infectious diseases of the respiratory tract, an international protocol is in place to systematically study patients presenting with an influenza-like illness. This protocol has been complemented by the development of treatment protocols that study either hyperimmune plasma, intravenous immunoglobulin or a combination of antiviral chemotherapeutic agents. Influenza causes substantial morbidity and mortality despite available treatments. At present there are several drugs used to treat influenza however they are of modest efficacy. Pre-clinical data suggest that combining antivirals might be more effective than single agents. Although combination treatment showed a significant decrease in viral shedding at day 3 relative to monotherapy, this difference was not associated with improved clinical benefit. Current studies are looking at the role of oseltamivir in patients with mild disease and the role of intravenous immunoglobulin in patients with severe disease. As part of the US government response to the 2014 Ebola outbreak in West Africa, a series of protocols were initiated at the NIH Clinical Center and in West Africa to study the pathogenesis, treatment, long-term sequelae and prevention of Ebola virus disease. These include studies of the monoclonal antibody cocktail ZMapp, the candidate rVSV, ChAd3 and hAD26/MVA platform Ebola vaccines, the experimental antiviral GS-5734 (remdesivir) and an observational cohort study of survivors of Ebola virus disease. As part of the response to the 2018 Ebola outbreak in the Democratic Republic of the Congo a randomized controlled trial comparing ZMapp to mAb114, REGN-EB3 or remdesivir was initiated. The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. A randomized, placebo-controlled, phase 2 trial of ChAd3-EBO-Z group and rVSVG-ZEBOV-GP group enrolled and randomized 1500 adults. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3-EBO-Z group and in 83.7% of those in the rVSVG-ZEBOV-GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). Long-term follow up of this cohort continues. In order to determine the long-term sequelae of Ebola virus infection, a total of 1145 EBOV survivors and 2785 close contacts (controls) were enrolled in an observational cohort study. Eleven percent of survivors and 13% of contacts had a serologic status that was discordant with the assigned group suggesting that some survivors may have been misdiagnosed as having Ebola virus disease and some contacts may have had undiagnosed infection. Among the antibody-positive survivors and antibody-negative contacts, six symptoms were reported significantly more often among survivors than among controls: urinary frequency (14.7% vs. 3.4%), headache (47.6% vs. 35.6%), fatigue (18.4% vs. 6.3%), muscle pain (23.1% vs. 10.1%), memory loss (29.2% vs. 4.8%), and joint pain (47.5% vs. 17.5%). On examination, more survivors than controls had abnormal abdominal, chest, neurologic, and musculoskeletal findings and uveitis. Other than uveitis (prevalence at enrollment, 26.4% vs. 12.1%; at year 1, 33.3% vs. 15.4%), the prevalence of these conditions declined during follow-up in both groups. EBOV RNA was detected in semen samples from 30% of the survivors tested, with a maximum time from illness to detection of 40 months.

目前，该项目的研究集中在四个领域。 这些是2001年炭疽袭击的幸存者的表征；包括SARS和流感在内的新兴呼吸道感染的表征；发展流感的新疗法；以及评估埃博拉病毒的实验疫苗和治疗方法，并表征了埃博拉病毒感染的长期后遗症。 炭疽研究已经招募了一群志愿者，他们目前正在接受广泛的诊断评估。 为了准备应对呼吸道新兴的传染病，制定了一种国际方案，可以系统地研究出现类似流感的疾病的患者。 该方案与研究过度免疫性血浆，静脉免疫球蛋白或抗病毒化学治疗剂组合的治疗方案的制定相辅相成。尽管有可用的治疗，但流感仍会引起大量的发病率和死亡率。目前，有几种药物用于治疗流感，但是它们具有适度的功效。 临床前数据表明，结合抗病毒药可能比单一药物更有效。 尽管组合治疗在第3天相对于单一疗法的病毒脱落显着下降，但这种差异与临床益处的改善无关。目前的研究正在研究奥司他韦在轻度疾病患者中的作用以及静脉免疫球蛋白在严重疾病患者中的作用。 作为美国政府对2014年西非埃博拉病毒爆发的反应的一部分，在NIH临床中心和西非启动了一系列方案，以研究发病机理，治疗，长期后遗症和预防埃博拉病毒疾病。 其中包括对单克隆抗体鸡尾酒ZMAPP，候选RVSV，CHAD3和HAD26/MVA平台埃博拉疫苗的研究，实验性抗病毒药GS-5734（Remdesivir）（Remdesivir）以及观察性的埃博拉病毒疾病生存者研究。 作为对刚果民主共和国2018年埃博拉疫情的回应的一部分，将ZMAPP与MAB114的随机对照试验进行了比较，REGN-EB3或REMDESIVIR启动了。 疫苗预防埃博拉病毒疾病（EVD）的安全性和功效何时在利比里亚达到EVD峰值时，尚不清楚。 CHAD3-EBO-Z组和RVSVG-ZEBOV-GP组的随机，安慰剂对照，2阶段试验，招募了和随机的1500名成年人。 到1个月，在CHAD3-EBO-Z组中有70.8％的参与者以及RVSVG-ZEBOV-GP组中的83.7％的参与者发生了抗体反应，相比之下，安慰剂组中的2.8％（这两种比较p <0.001）。该队列的长期随访仍在继续。 为了确定埃博拉病毒感染的长期后遗症，总共有1145名EBOV幸存者和2785个密切接触（对照组）参与了一项观测队列研究。 11％的幸存者和13％的接触状态与指定的组不一致，这表明某些幸存者可能被误诊为患有埃博拉病毒病，并且某些接触可能没有诊断出感染。 Among the antibody-positive survivors and antibody-negative contacts, six symptoms were reported significantly more often among survivors than among controls: urinary frequency (14.7% vs. 3.4%), headache (47.6% vs. 35.6%), fatigue (18.4% vs. 6.3%), muscle pain (23.1% vs. 10.1%), memory loss (29.2% vs. 4.8%), and joint pain （47.5％比17.5％）。经检查，幸存者多于对照组的腹部，胸部，神经系统和肌肉骨骼发现和葡萄膜炎。除葡萄膜炎（入学率流行，26.4％vs. 12.1％；在第1年，33.3％比15.4％），两组随访期间这些疾病的患病率下降。 在30％的幸存者的精液样本中检测到EBOV RNA，从疾病到40个月的检测最长的时间。