Novel means first to better characterize and then to treat infection with major respiratory pathogens using existing or newly developed strategies are a primary focus of this important project within the Clinical Research Section. Beginning with the emergence of the pandemic strain of A(H1N1)pdm09 influenza in April 2009, our section undertook clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. A treatment trial involving open-label administration of two units of hyperimmune plasma to hospitalized patients with severe influenza was launched domestically with the goal of enrolling and studying up to 100 patients on a multicenter basis. In this trial, 98 patients were randomized to receive either hyperimmune plasma plus standard-of-care treatments (investigational arm) or standard-of-care therapy alone (control arm). 67% of plasma participants normalized their respiratory status by Day 28, as compared to 53% of control patients (p=0.069). Overall, while falling short of statistical significance, investigational arm participants had fewer days in the hospital, in the ICU, on mechanical ventilation, and had improved disposition at Day 7. Based upon these highly suggestive trends, the CRS then designed and helped launch a follow-up multicenter trial of hyperimmune plasma in hospitalized patients that is currently recruiting. In this latest trial, enrolled patients with severe influenza A infection are being randomized in a double-blind manner to receive either high-titer (hyperimmune) plasma or a low-titer (control) plasma in addition to standard-of-care treatments. As a separate trial through the INSIGHT clinical trials network we have also helped design and implement an international multi-center randomized, double-blind study of hyperimmune IVIG plus standard-of-care versus standard-of-care alone in hospitalized patients with severe influenza. This ongoing clinical outcome trial was preceded by successful completion of a multi-center pilot trial in 31 patients through domestic US sites within the INSIGHT network that showed that administration of IVIG to hospitalized patients or outpatients was safe, significantly boosted HAI titers against the infecting influenza A subtypes, and could be conducted at clinical sites while maintaining the blind. We have also been conducting 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. The section has also recently completed a safety and pharmacokinetic study in normal volunteers of a novel antisense compound, AVI-7100, that has strong in vitro activity against influenza. Administration of AVI-7100 appears to be both safe and well tolerated. We also continue to provide scientific and logistical support to the Mexico infectious diseases network La Red, a multi-site collaboration with the Mexico Ministry of Health. One of the most recent initiative through La Red has been an ongoing study of the licensed antiparasitic drug nitazoxanide as a potential antiviral medication in patients presenting with influenza-like illness. In addition to the ongoing interventional trials mentioned above, we have also continued to contribute to the management and oversight of three large international observational protocols for outpatients or hospitalized patients with seasonal influenza infection administered under the auspices of the INSIGHT clinical trials network. In the realm of biodefense-related initiatives, we continue to 1) monitor yearly the clinical and psychological status of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attacks, and 2) continue to enroll patients on a protocol designed to permit diagnosis and characterization of patients presenting with unusual, previously undiagnosed infectious or inflammatory conditions. The Special Clinical Studies Unit (SCSU) was one of three special high containment patient care units within the US called upon to hospitalize and provide care to medically-evacuated HCWs exposed to or infected with Ebola virus in 2014-15. Two HCWs with needlestick exposures to Ebola virus in Sierra Leone that were treated with experimental VSVG-ZEBOV vaccine administration en route back to the United States, and two HCWs with documented Ebola virus infection, were treated in the SCSU over the course of the West African outbreak. In concert with WRAIR, we successfully completed a phase 1 randomized, double-blind dose-escalating safety and immunogenicity trial of (VSVG-ZEBOV) vaccine in a prime-boost strategy in late 2014 and early 2015. This study established the safety parameters of the experimental vaccine as well as provided comparative immunogenicity data on the three different dosing levels tested. In Fall 2016 NIAID also launched a pre-exposure vaccination protocol called PREPARE utilizing VSVG-ZEBOV vaccine to immunize HCWs, BSL-4 Laboratory staff, and other at-risk personnel against Ebola virus infection. The protocol features randomization to a homologous booster immunization at month 18 to determine whether the booster further augments antibody levels induced by the primary immunization. The section authored and implemented the only multicenter randomized controlled safety and efficacy study of putative MCMs in the treatment of patients with confirmed Ebola infection during the current crisis. The first investigational countermeasure to be studied in this ongoing was a triple monoclonal antibody product called ZMappTM. Although the goal was to enroll a total of 200 patients, the trial was terminated in early January 2016 due to the extinction of new cases of Ebola in the affected countries. By that time a total of 71 evaluable patients had been enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Within this cohort there were a total of 21 deaths, for an overall case fatality rate of 29.6%: 13/35 (37.1%) in the oSOC alone arm versus 8/36 (22.2%) in the ZMappTM-containing arm. The observed posterior probability that ZMappTM plus oSOC was superior to oSOC alone was 91.2%, falling short of the predefined threshold of 97.5% required to establish efficacy, but these data suggested at least the possibility of a potential beneficial effect of ZMappTM had it been possible to complete full accrual. Finally, in order to develop a potential MCM against Middle East Respiratory Syndrome (MERS) virus, in summer 2016 we launched a phase 1, randomized double-blind, placebo-controlled, single ascending dose safety, tolerability, and pharmacokinetics study of a novel product called SAB-301 consisting of human polyclonal IgG raised in transchromosomic cattle immunized with the causative agent of MERS.

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Fischer 2nd, William A; Vetter, Pauline; Bausch, Daniel G et al. (2018) Ebola virus disease: an update on post-exposure prophylaxis. Lancet Infect Dis 18:e183-e192
Beigel, John H; Voell, Jocelyn; Muñoz, Paula et al. (2018) Safety, tolerability, and pharmacokinetics of radavirsen (AVI-7100), an antisense oligonucleotide targeting influenza a M1/M2 translation. Br J Clin Pharmacol 84:25-34
Pett, Sarah L; Kunisaki, Ken M; Wentworth, Deborah et al. (2018) Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study. Open Forum Infect Dis 5:ofx228
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Beigel, John H; Voell, Jocelyn; Kumar, Parag et al. (2018) Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study. Lancet Infect Dis 18:410-418
Davey Jr, Richard T; Nordwall, Jacquie; Proschan, Michael A et al. (2017) Trial of ZMapp for Ebola Virus Infection. N Engl J Med 376:700-701
Beigel, John H; Tebas, Pablo; Elie-Turenne, Marie-Carmelle et al. (2017) Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med 5:500-511
Barnes, Kayla G; Kindrachuk, Jason; Lin, Aaron E et al. (2017) Evidence of Ebola Virus Replication and High Concentration in Semen of a Patient During Recovery. Clin Infect Dis :
Kash, John C; Walters, Kathie-Anne; Kindrachuk, Jason et al. (2017) Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease. Sci Transl Med 9:

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