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.

该项目的研究目前集中在四个领域。 这些是 2001 年炭疽袭击幸存者的特征；新出现的呼吸道感染（包括 SARS 和流感）的特征；开发流感新疗法；埃博拉病毒实验疫苗和治疗的评估以及埃博拉病毒感染的长期后遗症的特征。 炭疽研究招募了一批志愿者，目前正在进行广泛的诊断评估。 为了做好应对新出现的呼吸道传染病的准备，制定了一项国际方案来系统地研究患有流感样疾病的患者。 研究超免疫血浆、静脉注射免疫球蛋白或抗病毒化疗药物组合的治疗方案的开发补充了该方案。尽管有可用的治疗方法，流感仍会导致严重的发病率和死亡率。目前有多种药物用于治疗流感，但疗效有限。 临床前数据表明，联合抗病毒药物可能比单一药物更有效。 尽管联合治疗相对于单一疗法在第 3 天的病毒脱落量显着减少，但这种差异与临床获益的改善无关。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注射免疫球蛋白在重度疾病患者中的作用。 作为美国政府应对 2014 年西非埃博拉疫情的一部分，NIH 临床中心和西非启动了一系列方案，研究埃博拉病毒病的发病机制、治疗、长期后遗症和预防。 其中包括单克隆抗体混合物 ZMapp、候选 rVSV、ChAd3 和 hAD26/MVA 平台埃博拉疫苗、实验性抗病毒药物 GS-5734（瑞德西韦）的研究以及埃博拉病毒病幸存者的观察性队列研究。 作为应对 2018 年刚果民主共和国埃博拉疫情的一部分，启动了一项比较 ZMapp 与 mAb114、REGN-EB3 或瑞德西韦的随机对照试验。 当利比里亚埃博拉病毒病（EVD）发病率达到高峰时，预防埃博拉病毒病（EVD）的疫苗的安全性和有效性尚不清楚。 ChAd3-EBO-Z 组和 rVSVG-ZEBOV-GP 组的一项随机、安慰剂对照 2 期试验随机招募了 1500 名成年人。 1 个月时，ChAd3-EBO-Z 组的 70.8% 的参与者和 rVSVG-ZEBOV-GP 组的 83.7% 的参与者出现了抗体反应，而安慰剂组的这一比例为 2.8%（P两次比较均 <0.001）。对这一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，共有1145名埃博拉病毒幸存者和2785名密切接触者（对照）参加了一项观察性队列研究。 11% 的幸存者和 13% 的接触者的血清学状态与指定组不一致，这表明一些幸存者可能被误诊为患有埃博拉病毒病，而一些接触者可能患有未确诊的感染。 在抗体阳性幸存者和抗体阴性接触者中，幸存者报告的六种症状明显多于对照组：尿频（14.7% vs. 3.4%）、头痛（47.6% vs. 35.6%）、疲劳（18.4%）与 6.3%）、肌肉疼痛（23.1% 对 10.1%）、记忆丧失（29.2% 对 4.8%）以及关节疼痛（47.5% 对比 17.5%）。检查时，与对照组相比，更多的幸存者出现腹部、胸部、神经系统和肌肉骨骼异常以及葡萄膜炎。除了葡萄膜炎（入组时的患病率分别为 26.4% 和 12.1%；第一年时的患病率分别为 33.3% 和 15.4%），在随访期间，两组这些疾病的患病率均有所下降。 30% 的受检幸存者的精液样本中检测到了 EBOV RNA，从患病到检测的最长时间为 40 个月。