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

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 (IC 50) 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 IC 50 values (~1 nM). However, this efficacy was lower against wild-type influenza B and other viruses with higher IC 50 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 IC 50 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.

Antiviral Activity of Probenecid and Oseltamivir on Influenza Virus Replication

“…Probenecid reduced the viral load better than oseltamivir for both treatments. To determine the effect of drug resistance on the antiviral activity profile, A549 cells were infected with oseltamivir-resistant A/Mississippi/3/2001 H275Y [36]. The A549 cells were prophylactically treated with probenecid or oseltamivir.…”

Influenza antivirals and animal models

“…Prophylactic treatment with oseltamivir was administered against pdmH1N1 with reduced susceptibility to oseltamivir (NA H274Y) resulting in decreased virus shedding. However, the best outcome was seen in the group challenge with the oseltamivir‐sensitive pdmH1N1 strain [167]. Oseltamivir and peramivir were also effective in decreasing the burden associated with the HPAI H5N6 virus, whereas amantadine did not exhibit antiviral activity [31].…”

Vaccination with Deglycosylated Modified Hemagglutinin Broadly Protects against Influenza Virus Infection in Mice and Ferrets

“…The potential of vaccination with a deglycosylated modified HA construct to induce a protective immune response was further evaluated in ferrets, a more sensitive animal model for influenza virus infection [25][26][27]. Ferrets were immunized with doses of 30 µg HA fg , HA mg , and HA ug , and sera were collected on day 14 after boost immunization (Figure 4A).…”