185-New Developments in Respiratory Viruses
Thursday, Sep 12, 2013, 3:00 PM - 5:30 PM
V-1471a - Validation of a Wild-Type Influenza A Human Challenge Model: H1N1pdMIST, A 2009 H1N1(pdm) Dose Finding IND Study
Meeting Room 113
Thursday, Sep 12, 2013, 4:45 PM - 5:00 PM
influenza A ; Influenza vaccine ; Influenza A viruses
M. J. Memoli
, L. Czajkowski, S. Reed, R. Athota, T. Bristol, K. Proudfoot, J. Taubenberger; NIH, Bethesda, MD
M. J. Memoli,
Despite extensive research since 1918, many questions regarding influenza pathogenesis remain unanswered. With the emergence of the 2009 H1N1 and novel strains such as H7N9 and H3N2v, the challenge to reduce the impact from influenza remains. Experimental animal studies have significant limitations, as do studies of natural infection in humans. Human influenza challenge studies offer a unique opportunity to investigate aspects of influenza including correlates of protection, host susceptibility, biomarkers, and efficacy of novel therapeutics/vaccines. These studies have not been performed in the U.S. in over a decade, limiting our capability to study this important virus and develop countermeasures. We have completed the first wild-type influenza A challenge study under an IND, and the only challenge ever performed with the 2009 H1N1(pdm) virus. This dose finding study represents the first step to reintializing these important studies and large scale development of this model both for H1N1(pdm) as well as seasonal and emerging influenza viruses.
Healthy volunteers were admitted to an isolation unit at the NIH for a minimum 9 days. A reverse genetics, cell-based, GMP produced, wild-type 2009 H1N1(pdm) virus was administered intranasally with a mucosal atomizer. Escalating doses were given until a dose was reached that produced disease in
60% of volunteers with an HAI titer of
1:40. Clinical and lab testing to evaluate pathogenesis, immune correlates of protection, biomarkers, immune response, and intrahost viral evolution were performed. Patients were followed for two months.
A dose of 10
TCID50 caused mild to moderate influenza (defined as nasal shedding plus symptoms) in 69% of individuals; meeting our initial goal of
60%. Exploration of biomarkers, correlates of protection, and intrahost evolution in these participants is described.
We have successfully validated the only healthy volunteer influenza challenge model in the world using a GMP-produced wild-type virus under an IND. This unique clinical program can be applied to advance the field of influenza research allowing for numerous important studies of influenza pathogenesis, validation of animal models, and rapid, efficient, and cost-effective evaluation of efficacy of both novel vaccines and therapeutics.
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