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

Autoři: Rubaiyea Farrukee aff001;  Celeste Ming-Kay Tai aff001;  Ding Yuan Oh aff001;  Danielle E. Anderson aff004;  Vithiagaran Gunalan aff005;  Martin Hibberd aff006;  Gary Yuk-Fai Lau aff004;  Ian G. Barr aff001;  Veronika von Messling aff004;  Sebastian Maurer-Stroh aff005;  Aeron C. Hurt aff001
Působiště autorů: WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia aff001;  Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia aff002;  School of Health and Life Sciences, Federation University, Churchill, Victoria, Australia aff003;  Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore aff004;  Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, Singapore aff005;  Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore aff006;  Veterinary Medicine Division, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany aff007;  National Public Health Laboratories, National Centre for Infectious Diseases, Ministry of Health, Singapore aff008;  Department of Biological Sciences, National University Singapore, Singapore aff009
Vyšlo v časopise: Utilising animal models to evaluate oseltamivir efficacy against influenza A and B viruses with reduced in vitro susceptibility. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008592
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008592


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.

Klíčová slova:

Ferrets – H1N1 – Influenza – Influenza A virus – Influenza B virus – Influenza viruses – Macaque – Viral release


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