Accelerating Influenza Research: Vaccines, Antivirals, Immunomodulators and Monoclonal Antibodies. The Manufacture of a New Wild-Type H3N2 Virus for the Human Viral Challenge Model

• Published in: PloS one Vol. 11; no. 1; p. e0145902
• Main Authors: Fullen, Daniel J, Noulin, Nicolas, Catchpole, Andrew, Fathi, Hosnieh, Murray, Edward J, Mann, Alex, Eze, Kingsley, Balaratnam, Ganesh, Borley, Daryl W, Gilbert, Anthony, Lambkin-Williams, Rob
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.01.2016; Public Library of Science (PLoS)
• Subjects: Adult; Animals; Antibodies, Monoclonal - immunology; Antibodies, Viral - immunology; Antiviral agents; Antiviral Agents - chemistry; Antiviral drugs; Disease control; Double-Blind Method; Drug dosages; Female; Ferrets; Forecasts and trends; Gene expression; Healthy Volunteers; Humans; Immunization; Immunomodulation; Immunomodulators; Infections; Infectious diseases; Influenza; Influenza A Virus, H3N2 Subtype - genetics; Influenza Vaccines - chemistry; Influenza Vaccines - therapeutic use; Influenza viruses; Influenza, Human - prevention & control; Influenza, Human - virology; Inoculum; London; Male; Medical research; Middle Aged; Monoclonal antibodies; Morbidity; Mortality; Pathology; Polymerase Chain Reaction; Studies; Vaccines; Viral infections; Virus Shedding; Viruses; Young Adult; London; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0145902

Influenza and its associated diseases are a major cause of morbidity and mortality. The United States Advisory Committee on Immunization Practices recommends influenza vaccination for everyone over 6 months of age. The failure of the flu vaccine in 2014-2015 demonstrates the need for a model that allows the rapid development of novel antivirals, universal/intra-seasonal vaccines, immunomodulators, monoclonal antibodies and other novel treatments. To this end we manufactured a new H3N2 influenza virus in compliance with Good Manufacturing Practice for use in the Human Viral Challenge Model. We chose an H3N2 influenza subtype, rather than H1N1, given that this strain has the most substantial impact in terms of morbidity or mortality annually as described by the Centre for Disease Control. We first subjected the virus batch to rigorous adventitious agent testing, confirmed the virus to be wild-type by Sanger sequencing and determined the virus titres appropriate for human use via the established ferret model. We built on our previous experience with other H3N2 and H1N1 viruses to develop this unique model. We conducted an initial safety and characterisation study in healthy adult volunteers, utilising our unique clinical quarantine facility in London, UK. In this study we demonstrated this new influenza (H3N2) challenge virus to be both safe and pathogenic with an appropriate level of disease in volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we established the minimum infectious titre required to achieve reproducible disease whilst ensuring a sensitive model that can be translated to design of subsequent field based studies. ClinicalTrials.gov NCT02525055.