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

PLoS Pathog. 2021 May 6;17(5):e1009527. doi: 10.1371/journal.ppat.1009527. eCollection 2021 May.

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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antiviral Agents / pharmacology*
  • Dibenzothiepins / pharmacology*
  • Disease Models, Animal*
  • Drug Resistance, Viral*
  • Female
  • Ferrets
  • Influenza A virus / drug effects
  • Influenza A virus / genetics*
  • Influenza A virus / isolation & purification
  • Male
  • Morpholines / pharmacology*
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / virology
  • Pyridones / pharmacology*
  • Triazines / pharmacology*
  • Virus Replication*

Substances

  • Antiviral Agents
  • Dibenzothiepins
  • Morpholines
  • Pyridones
  • Triazines
  • baloxavir

Grants and funding

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.