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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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 comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.

Original languageEnglish
Article numbere1009527
Number of pages24
JournalPLoS Pathogens
Volume17
Issue number5
DOIs
Publication statusPublished - 6 May 2021

Bibliographical note

Funding Information: This work was funded by F. Hoffmann-La Roche (https://www.roche.com/) and Shionogi & Co. Ltd (https://www.shionogi.com/eu/en/) 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.
I have read the journal’s policy and the authors of this manuscript have the
following competing interests: • Keiko Baba, Takashi Hashimoto, Shinya Omoto, Takao Shishido and Takeki Uehara are employees of Shionogi & Co. • Klaus Kuhlbusch, Steffen Wildum and Aeron C Hurt are employees of F. Hoffmann-La Roche. • Neil Collinson and Barry Clinch are employees of Roche Products Ltd. • Wendy Barclay has received honoraria from Roche, Sanofi Pasteur and Seqirus.
• Leo YY Lee has received honoraria from Roche. • Paulina Koszalka, Jie Zhou, Rubaiyea Farrukee, Rebecca Frise, Edin Mifsud, Monica Galiano and Shahjahan Miah have nothing to disclose.

Open Access:This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and
source are credited.

Publisher Copyright: Copyright: © 2021 Lee et al.

Citation: Lee LY, Zhou J, Koszalka P, Frise R, Farrukee R, Baba K, et al. (2021) Evaluating the fitness of PA/I38T-substituted influenza A viruses with reduced baloxavir susceptibility in a competitive mixtures ferret model. PLoS Pathog 17(5): e1009527.

DOI: https://doi.org/10.1371/journal.ppat.1009527

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