Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility

PLoS Pathog. 2020 Jun 18;16(6):e1008592. doi: 10.1371/journal.ppat.1008592. eCollection 2020 Jun.

Abstract

The neuraminidase (NA) inhibitor (NAI) oseltamivir (OST) is the most widely used influenza antiviral drug. Several NA amino acid substitutions are reported to reduce viral susceptibility to OST in in vitro assays. However, whether there is a correlation between the level of reduction in susceptibility in vitro and the efficacy of OST against these viruses in vivo is not well understood. In this study, a ferret model was utilised to evaluate OST efficacy against circulating influenza A and B viruses with a range of in vitro generated 50% inhibitory concentrations (IC50) values for OST. OST efficacy against an A(H1N1)pdm09 and an A(H1N1)pdm09 virus with the H275Y substitution in neuraminidase was also tested in the macaque model. The results from this study showed that OST had a significant impact on virological parameters compared to placebo treatment of ferrets infected with wild-type influenza A viruses with normal IC50 values (~1 nM). However, this efficacy was lower against wild-type influenza B and other viruses with higher IC50 values. Differing pathogenicity of the viruses made evaluation of clinical parameters difficult, although some effect of OST in reducing clinical signs was observed with influenza A(H1N1) and A(H1N1)pdm09 (H275Y) viruses. Viral titres in macaques were too low to draw conclusive results. Analysis of the ferret data revealed a correlation between IC50 and OST efficacy in reducing viral shedding but highlighted that the current WHO guidelines/criteria for defining normal, reduced or highly reduced inhibition in influenza B viruses based on in vitro data are not well aligned with the low in vivo OST efficacy observed for both wild-type influenza B viruses and those with reduced OST susceptibility.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Female
  • Ferrets
  • Influenza A Virus, H1N1 Subtype* / genetics
  • Influenza A Virus, H1N1 Subtype* / metabolism
  • Influenza A Virus, H3N2 Subtype* / genetics
  • Influenza A Virus, H3N2 Subtype* / metabolism
  • Influenza B virus* / genetics
  • Influenza B virus* / metabolism
  • Macaca fascicularis
  • Macrolides
  • Male
  • Mutation, Missense
  • Neuraminidase / genetics
  • Neuraminidase / metabolism
  • Orthomyxoviridae Infections* / drug therapy
  • Orthomyxoviridae Infections* / genetics
  • Orthomyxoviridae Infections* / metabolism
  • Orthomyxoviridae Infections* / pathology
  • Oseltamivir* / pharmacology

Substances

  • Macrolides
  • Neuraminidase
  • Oseltamivir
  • viranamycin A

Grants and funding

The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. We further acknowledge the NHMRC-A*STAR grant (APP1055793) for supporting this research work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.