Abrupt rise in Oseltamivir resistance in Catalonia, Spain - fall 2025
#19,189
For the past 3 years we've been following sporadic reports of `reduced susceptibility' of the seasonal H1N1 flu virus to the antiviral drug oseltamivir (aka `Tamiflu') around the globe (see EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024).
While concerning, these reports indicated reduced inhibition - not complete failure - and its incidence has been modest; typically in the low single digits.The main culprit in all of this has been an increase in the S247N mutation (often combined with I223V), which can reduce the effectiveness of oseltamivir 7 to 16 fold.
Less common, but far more impactful, is the H275Y mutation, which can effectively render oseltamivir useless. This was the cause of the `Tamiflu failure' of 2008, which temporarily forced the CDC to change their flu treatment guidelines.
Luckily, the arrival of a new, and still susceptible pandemic H1N1 virus in 2009 granted oseltamivir an unexpected reprieve, but since then we've kept a close eye out for any genetic changes that could affect its effectiveness.
Last summer, in Virus Research: A 15-year Study of Neuraminidase Mutations and the Increasing of S247N Mutation in Spain, we looked at a study that found a sharp increase in detections of the S247N mutation beginning in 2024.
Over the 2025-2026 flu season we've continued to see scattered reports of resistance, including Taiwan's CDC reported that 6.5% of the H1N1 viruses characterized in 2025 showed signs of oseltamivir resistance, and China: National Influenza Center Reporting Increased Oseltamivir Resistance in Seasonal H1N1.Highlights• In a landscape of a very narrow arsenal of influenza antivirals, resistance mutations are a significant threat.• Resistance mutations were present in 0.5-5% in A and B influenza viruses during the last 15 years.• However, S247N resistance mutation in the NA gene sharply increased during 2023-2024 season.• While this mutation does not confer strong resistance by itself, their fixation could increase the risk of resistance in the future if other resistance mutations appears or get fixed together with it
Four A(H1N1)pdm09 viruses had NA-H275Y amino acid substitution conferring highly reduced inhibition by oseltamivir and peramivir. Ten A(H1N1)pdm09 viruses had amino acid substitutions NA-I223V and NA-S247N and showed reduced inhibition by oseltamivir. Two B viruses had amino acid substitution NA- M464T and showed reduced inhibition by peramivir.
Nine A(H1N1)pdm09 viruses had NA-H275Y amino acid substitution conferring highly reduced inhibition by oseltamivir and peramivir. Nineteen A(H1N1)pdm09 viruses had amino acid substitutions NA-I223V and NA-S247N and showed reduced inhibition by oseltamivir. One A(H1N1)pdm09 virus had amino acid substitutions NA-I223T and NA-S247N and showed reduced inhibition by oseltamivir. Two A(H3N2) viruses had amino acid substitution NA-E119V conferring highly reduced inhibition by oseltamivir. Three B viruses had amino acid substitution NA-M464T and showed reduced inhibition by peramivir.
While the number of S247N+I223V mutations remains low (2.1%), this is more than a 35-fold increase over the previous year, making this a trend well worth following.
The incidence of the far more impactful H275Y mutation (1%) remains about average, but there are concerns that the stacking of H275Y with either I223V or S247N could greatly enhance its impact.
None of this is to suggest we are on the verge of another antiviral crisis, only that we continue to see some concerning trends. And given the gaps in global influenza surveillance and reporting, we are only seeing part of the picture.
As we are so frequently reminded - evolution never stops - and while our current antiviral armamentarium remains effective against seasonal H1N1, the events of 2008 reminds us how quickly that can change.
Stay tuned.
