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. As part of the US government response to the 2014 Ebola outbreak in West Africa, a series of protocols have been 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. 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. A randomised, double-blind, multicentre phase 2 trial of a combination of oseltamivir, amantadine, and ribavirin versus oseltamivir monotherapy with matching placebo for the treatment of influenza was conducted in 50 sites, consisting of academic medical centre clinics, emergency rooms, and private physician offices in the USA, Thailand, Mexico, Argentina, and Australia. Participants who were aged at least 18 years with influenza and were at increased risk of complications were randomly assigned (1:1) to receive either oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg) combination therapy or oseltamivir monotherapy twice daily for 5 days. Participants were followed for 28 days. The primary endpoint was the percentage of participants with virus detectable by PCR in nasopharyngeal swab at day 3, and was assessed in participants who were randomised, had influenza infection confirmed by the central laboratory on a baseline nasopharyngeal sample, and had received at least one dose of study drug. Secondary endpoints included safety and duration of symptoms. Six hundred and thirty-three participants were randomly assigned to receive combination antiviral therapy (n=316) or monotherapy (n=317). The primary analysis included 394 participants (excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample). Eighty of 200 participants (400%) in the combination group had detectable virus at day 3 compared with 97 of 194 (500%) in the monotherapy group; mean difference 100, 95% CI 02-198, p=0046) . The most common adverse events were gastrointestinal-related disorders, primarily nausea (65 12% of 556 reported adverse events in the combination group vs 63 11% of 585 reported adverse events in the monotherapy group), diarrhoea (56 10% of 556 vs 64 11% of 585), and vomiting (39 7% of 556 vs 23 4% of 585). There was no benefit in multiple clinical secondary endpoints, such as median duration of symptoms (45 days in the combination group vs 40 days in the monotherapy group; p=021). 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. The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. At the time of the 2014-2016 out break two candidates, a recombinant chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z) and a recombinant vesicular stomatitis virus vaccine (rVSVG-ZEBOV-GP) had shown promise in non-human primate models and had entered early phase 1 testing at the NIH Clinical Center and Walter Reed. We conducted a a randomized, placebo-controlled, phase 2 trial of these two experimental vaccines in Liberia to evaluate safety and immunogenicity in a population at risk of Ebola virus infection. A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection-site reactions (in 28.5% of the patients in the ChAd3-EBO-Z group and 30.9% of those in the rVSVG-ZEBOV-GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3-EBO-Z group, in 47 (9.4%) in the rVSVG-ZEBOV-GP group, and in 59 (11.8%) in the placebo group. 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). At 12 months, antibody responses in participants in the ChAd3-EBO-Z group (63.5%) and in those in the rVSVG-ZEBOV-GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons).