Pathogenesis, Treatment and Prevention of Emerging Infectious Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

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.