Journal article

Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model

Leo YY Lee, Jie Zhou, Paulina Koszalka, Rebecca Frise, Rubaiyea Farrukee, Keiko Baba, Shahjahan Miah, Takao Shishido, Monica Galiano, Takashi Hashimoto, Shinya Omoto, Takeki Uehara, Edin J Mifsud, Neil Collinson, Klaus Kuhlbusch, Barry Clinch, Steffen Wildum, Wendy S Barclay, Aeron C Hurt



Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but com..

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Funding Acknowledgements

This work was funded by F. Hoffmann-La Roche ( and Shionogi & Co. Ltd ( who both played a role in the study design, data collection and analysis, decision to publish and preparation of the manuscript. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health, who had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.