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 H1N1 strain that emerged in April 2009, as well as the ongoing threat of avian (H5N1) virus. 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 of oseltamvir plus probenecid were analyzed and showed a dose-dependent favorable effect of the latter upon both the trough and area-under-the-curve concentrations of the former. At the schedule of four times daily dosing with probenecid, these parameters were not statistically different from daily dosing of oseltamivir alone, suggesting that probenecid might 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 undertook three 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 has been completed in the affected countries and data analysis is being finalized. The second was a phase I double-blind, placebo-controlled, dose-escalating study to evaluate the relative safety and tolerability of a novel intravenous anti-influenza agent, peramivir, in healthy volunteer subjects. This trial was initiated at the Clinical Center but then largely completed by the sponsor through a Clinical Research Organization. The third 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. H5N1 avian influenza represents an episodic zoonotic disease with the potential to cause a pandemic, and antiviral resistance is of considerable concern. We sought to generate high-titer H5N1 antibodies in healthy volunteers for the purpose of developing hyperimmune intravenous immunoglobulin. We conducted a dose-escalating, unblinded clinical trial involving 75 subjects aged 18-59 years. Three cohorts of twenty-five subjects were enrolled sequentially and received 90, 120, or 180 micrograms of H5N1 A/Vietnam/1203/04 vaccine in 4 doses administered approximately 28 days apart. 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 have also undertaken a study of a novel nasally-administered 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 nasal Poly-ICLC (synthetic dsRNA strands of poly-inosinic and poly-cytidylic acids), normal volunteers received escalating doses of this biologic response modifier to determine its safety when nasally administered as well as to measure both local and systemic immunologic effects of its administration. This trial is currently in the final stages of data analysis. In response to the emergence of a pandemic strain of novel H1N1 influenza A in April 2009, our section undertook additional clinical research efforts to help better characterize and treat infection with this novel new strain. To begin with, protocol 07-I-0229 Influenza in the Immunocompromised Host was revised to allow enrollment and study of normal volunteers in addition to patients with immunodeficiency disorders. A new protocol was also developed to allow serial collection of high-titer anti-H1N1v plasma either from patients recovering from 2009 H1N1 naturally-acquired infection or from recipients of the 2009 H1N1 vaccine. The goal of this protocol 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 2009 H1N1 infection. A treatment trial involving open-label administration of two units of hyperimmune 2009 H1N1 plasma to hospitalized patients with severe influenza has also been launched and is currently open to enrollment on a multicenter basis. We have also launched 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. Finally, we have also continued to contribute to the management and oversight of one domestic and two large international observational protocols for outpatients or hospitalized patients with 2009 H1N1 or other seasonal influenza infection administered under the auspices of DMID or the INSIGHT clinical trials network, respectively. The goal of the latter two large trials is to better characterize the clinical aspects of both 2009 H1N1 and other types of seasonal influenza infection on a global basis, to define predictors of severe disease and/or death, 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, emerging patterns of drug resistance, and other aspects of the evolving pandemic. Lastly, in addition to the clinical trials described above, we 1) continue to monitor on a yearly basis 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) have initiated a clinical research protocol to allow the hospitalization (within NIAID's new Special Clinical Studies Unit), study and treatment of BSL-3/4 laboratory workers potentially exposed to select agents, or of other patients exposed to emerging infectious disease pathogens of public health importance.
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