Characterisation of a wild-type influenza (A/H1N1) virus strain as an experimental challenge agent in humans
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RESEARCH
Open Access
Characterisation of a wild-type influenza (A/H1N1) virus strain as an experimental challenge agent in humans Jeannette M Watson1, James N Francis1*, Sofie Mesens2, Gabriel A Faiman1, Jill Makin3, Peter Patriarca4, John J Treanor5, Bertrand Georges1 and Campbell J Bunce1
Abstract Background: Human challenge models using respiratory viruses such as influenza are increasingly utilised in the development of novel vaccines and anti-viral modalities and can provide preliminary evidence of protection before evaluation in field trials. We describe the results of a clinical study characterising an A/H1N1 influenza challenge virus in humans. Methods: The challenge agent, influenza A/California/2009 (H1N1), was manufactured under cGMP conditions and characterised in accordance with regulatory guidelines. A dose-ascending open-label clinical study was conducted in 29 healthy young adults screened sero-negative to the challenge strain. Subjects were intranasally inoculated with three increasing doses of virus and physician-reported signs, subjected-reported symptoms, viral shedding and immunological responses were monitored. Results: A dose-dependent increase in clinical signs and symptoms was observed with 75% of subjects developing laboratory-confirmed illness at the highest inoculum (3.5 × 106 TCID50). At the highest dose, physician or subjectreported signs of infection were classified as mild (all subjects), moderate (50%) and severe (16%) with peak symptoms recorded four days after infection. Clinical signs were correlated with nasal mucus weight (P < .001) and subject-reported symptoms (P < .001). Geometric mean peak viral shedding was log10 5.16 TCID50 and occurred three days after inoculation with a median duration of five days. The safety profile was such that physiological responses to viral infection were mainly restricted to the upper airways but were not of such severity to be of clinical concern. Conclusions: A highly characterised wild-type Influenza A/California/2009 (H1N1) virus manufactured for clinical use was shown to induce a good infectivity profile in human volunteers. This clinical challenge model can be used for evaluating potential efficacy of vaccines and anti-viral therapeutics. Trial registration: NCT02014870 Keywords: Influenza A/H1N1 virus, Challenge agent, Vaccine, Clinical trial
Background Influenza A is a major global health concern with seasonal influenza epidemics affecting 5 to 15% of the population, resulting in severe illness in 3 to 5 million patients and approximately 250,000 to 500,000 deaths per year [1]. Hospitalisation and deaths mainly occur * Correspondence: [email protected] 1 Immune Targeting Systems Ltd, London BioScience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK Full list of author information is available at the end of the article
in high-risk groups, in particular children younger than age two, adults age 65 or older, and people of any age with certain medical conditions, such as chronic heart, lung, kidney, liver,
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