Foremost among the pathogens under study in this new project is the influenza virus, including the agents of conventional seasonal influenza, novel new strains of influenza A such as the A(H1N1)pdm09 strain that emerged in April 2009, as well as the ongoing threat of avian subtypes such as the H5N1 and H7N9 viruses. Novel means first to better characterize and then to treat infection with these respiratory pathogens using existing or newly developed strategies are a primary focus of this important new project within the Clinical Research Section of the LIR. The first major initiative undertaken in this project was a collaborative protocol undertaken with the Department of Veterans Affairs (DVA) as well as the Department of Defense to determine if novel pharmacokinetic means could be used to extend the useful half-life of oseltamivir, the major licensed oral antiviral drug used to treat seasonal influenza in the United states and elsewhere and also a drug in comparatively short supply on a global scale.The pharmacokinetics proved that probenecid could be useful in extending the supply of oseltamivir in a situation of limited drug supply. The ability of oseltamivir to treat effectively severe cases of seasonal influenza may be limited, and knowledge of its utility in treating human cases of avian influenza is largely anecdotal. For these reasons NIAID launched a portfolio of clinical trials focused on the therapeutics of human influenza. One is a phase II double-blinded, randomized clinical trial conducted within a network of research collaborators in Southeast Asia that compared the relative efficacy of high dose versus standard-dose oseltamivir for the treatment of severe influenza and avian influenza. This trial was completed in the affected countries and showed no survival benefit to double-dose treatment. An additional trial was a phase II vaccine dose-finding pilot study for the development of an anti-influenza A (H5N1) intravenous hyper-immune globulin preparation of potential utility in the treatment of human cases of avian influenza. We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. No statistically significant dose-related increases in the geometric mean titers (GMTs) of serum hemagglutination inhibition antibody were observed when the 90-microg, 120-microg, and 180-microg cohorts were compared. However, the results did suggest that a third and fourth dose of the H5N1 A/Vietnam/1203/04 vaccine may result in higher hemagglutination inhibition and microneutralization GMTs, compared with the GMTs resulting from fewer doses, even if there was no apparent benefit to increasing the dose of the vaccine. In addition to these trials, we also undertook a study of a novel agent with potential antiviral activity against a variety of respiratory viruses, including influenza. In this phase I double-blind, placebo-controlled, dose-escalating study to evaluate the safety and tolerability of topical Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers received escalating doses of this biologic response modifier through nasal administration. Although there were no consistent local or systemic immunologic effects that emerged, the product was both safe and well tolerated topically. Beginning with the emergence of the pandemic strain of A(H1N1)pdm09 influenza in April 2009, our section also undertook additional clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. A protocol was developed to allow serial collection of high-titer anti-influenza plasma either from patients recovering from naturally-acquired infection or from recipients of the trivalent vaccine. The purpose is to allow harvesting of a pool of high-titer antisera (in the form of either plasma or a manufactured IVIG product) that could then be tested as a potential therapeutic adjunct in the management of patients with severe or life-threatening influenza infection. 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 100 patients on a multicenter basis. Most recently we have also designed 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 clinical outcome trial was preceded by completion of a multi-center pilot trial in 31 patients through the INSIGHT network addressing the safety, pharmacokinetics, and logistics of administering hyperimmune IVIG to patents with acute influenza. 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. More recently we have also initiated a safety and pharmacokinetic study in normal volunteers of single and then multiple doses of a novel antisense compound, AVI-7100, that has activity against influenza. Recruitment into the single dose phase has been completed and data analyses are ongoing. We 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 designed to promote sustainability and capacity to continue clinically relevant and high-quality research on emerging infectious diseases. The five sites in Mexico City include two pediatric sites. Finally, 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. The goal of these trials is to better characterize the clinical aspects of seasonal influenza infection on a global basis, to define predictors of severe disease and/or death including host genomics, to sequence and compare viral genomes on a geographic and epidemiologic basis, and to develop a repository of clinical research specimens potentially of great value in helping map viral antigenic drift, identifying emerging patterns of drug resistance, and characterizing other aspects of the evolving pandemic. Most recently these protocols have been modified to also permit enrollment of patients diagnosed with novel coronavirus infections such as that due to the MERS-CoV agent. Lastly, in addition to the clinical trials described above, we continue to 1) monitor yearly the clinical and psychologic status of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attacks, including maintaining an open clinical protocol for the study of additional anthrax exposures that may occur through accidental or occupational exposures, and 2) support a clinical research protocol to allow the hospitalization (within the Clinical Center's Special Clinical Studies Unit) and treatment of BSL-3/4 laboratory workers potentially exposed to select agents, or of other patients exposed to emerging infectious diseases of public health importance. This latter protocol will also permit us to hospitalize and provide care for health care workers potentially exposed to, or infected with, Ebola virus as a result of deployment to regions of West Africa presently suffering from an unprecedented outbreak of Ebola virus infection. At the Clinical Center we have also initiated plans to undertake one or more phase 1 safety/toxicity studies of investigational vaccines or MCMs with putative activity against Ebola virus.
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