Abrupt rise in resistance in Catalonia, Spain - fall 2025
#18,973
For the past couple of years we've been seeing 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 resistance - and its incidence was modest; typically in the low single digits.
Five months ago, 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.
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
Two months ago, Taiwan's CDC reported that 6.5% of the H1N1 viruses they have characterized in 2025 have shown signs of oseltamivir resistance, and just yesterday we looked at a similar report out of China: National Influenza Center Reporting Increased Oseltamivir Resistance in Seasonal H1N1.
The good news, at least short-term, is that this does not affect the H3N2 virus, only H1N1.
Yesterday the ECDC Journal Eurosurveillance published a Rapid Communications which reports - over the past 3 months - a dramatic surge in H1N1 viruses carrying the NA:S247N mutation in Catalonia Spain, and parts of Europe.
So far, the CDC hasn't reported similar surges in the United States (see FluView Week 47 Report), but fewer than 100 H1N1 viruses have been characterized this fall.
Another encouraging note is that the I223V substitution - which further decreases oseltamivir susceptibility when combined with S274N - was not detected in these recent Catalonia isolates.The reported 4-to-6 fold reduction in inhibition with this S247N mutation isn't usually enough to render oseltamivir clinically useless, but it may modestly reduce its effectiveness.
The concern is that I223V - or other permissive amino acid changes - could emerge over time (see Viruses: Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases).
Prior to the 2008 collapse of the effectiveness of oseltamivir against the old (pre-2009) H1N1 virus, the assumption was that the changes that created resistance exacted a `fitness penalty' on the virus, limiting its ability to transmit from human-to-human.
That `fitness penalty' evaporated unexpectedly in 2008, and seasonal H1N1 - carrying the H275Y mutation - spread globally in a matter of months.
Since then, we've only seen limited transmission of H1N1 viruses with resistance markers. That is, until recently. The authors state:
Importantly, it has been demonstrated that the S247N strains do not show reduced transmissibility in comparison with strains not carrying this mutation
Narcís Saubi1,2 , Cristina Andrés1,2 , Ignasi Prats-Méndez1,2 , Alejandra González-Sánchez1,2, Alysa Davtyan1 , Rodrigo Vásquez-Mercado1 , Ariadna Rando3 , Patricia Nadal3 , Juliana Esperalba3,4, Maria Arnedo3 , Marina Vicente3 , Eva Balada3 , Jacobo Mendioroz5 , María Carmen Martín3 , Karen García-Camuñas3 , Raquel Vaz3 , Adrià Najarro3 , Susana Bernalte3 , Nieves Larrosa3,4 , Andrés Antón1,2,4 , on behalf of the SIVIC Infectious diseases sentinel network6
During the sentinel surveillance of respiratory viruses in Catalonia, Spain, an increase in the percentage of influenza A(H1N1)pdm09 sequences harbouring the NA:S247N substitution was detected from summer 2025 when compared with previous years [1-5]. This substitution is related to lower oseltamivir susceptibility, and not resistance [6,7]. Here, we present the results obtained from surveillance in Catalonia, together with phenotypic test results of susceptibility to oseltamivir. We compare our results with the presence of the NA:S47N substitution in other European countries, using sequences downloaded from GISAID.
Presence of NA:S247N in Catalonia
Through the respiratory virus sentinel surveillance network in Catalonia (SIVIC; https://sivic.salut.gencat.cat), influenza viruses — submitted from 37 sentinel primary care centres and 7 hospitals (Hospital Universitari de Bellvitge; Hospital Universitari Germans Trias i Pujol; Hospital Universitari Doctor Trueta; Hospital Universitari Joan XXIII,; Hospital Universitari Verge de la Cinta; Hospital Arnau de Vilanova; Hospital Universitari Vall d’Hebron) distributed across Catalonia — are genetically characterised by whole genome sequencing using the Illumina platform. An in-house bioinformatic application, mitMutFinder [8], detects the amino acid substitutions responsible for resistance to antivirals (according to the list provided by the World Health Organization) [9].
An analysis from week 36/2024 to week 41/2025 showed that the prevalence of influenza A(H1N1)pdm09 strains (genetic clades 6B.1A.5a.2a.1 and 6B.1A.5a.2a) carrying the NA:S247N amino acid substitution had increased notably in the last 12 weeks of this period. During the whole period of study, the S247N mutation was detected in 11.8% (63/532) of A(H1N1)pdm09 strains in Catalonia.However, most of the S247N sequences were detected between weeks 30/2025 and 41/2025 (56 S247N/117 A(H1N1)pdm09), with proportions ranging from 20 to 100% (Figure 1A). No I223V substitution, a synergistic substitution that decreases oseltamivir susceptibility when combined to S274N [3], was detected in the sequences from Catalonia.
Notably, the World Health Organization, only reported sporadic strains harbouring the S247N mutation in the most recent documents recommending the vaccine composition for the northern and southern hemispheres, respectively [1,19]. Importantly, it has been demonstrated that the S247N strains do not show reduced transmissibility in comparison with strains not carrying this mutation [20].
In our series, the proportion of strains carrying the S247N mutation was much higher, i.e. 20–100% on a weekly basis, with an annual average of 11.8%. Similar results were observed in other Spanish regions and several European countries based on GISAID sequence data. It is important to note that no I223V substitution was detected in the sequences from Catalonia, which, combined with S247N, would further decrease drug susceptibility [21].
Conclusion
In Europe, the 2025/26 influenza season has started 3–4 weeks early, dominated by A(H3N2) viruses. However, the fact that the proportion of A(H1N1) NA:S247N sequences observed from July to October 2025 was very high in some countries even approaching 100% in some weeks, together with evidence that this mutation does not reduce virus infectivity, warrants strengthening surveillance on the evolution of these A(H1N1) strains.(Continue . . . .)
And as we've seen (see EID Journal: Influenza A(H1N1)pdm09 Virus with Reduced Susceptibility to Baloxavir, Japan, 2024), Baloxavir is susceptible to its own set of resistance mutations (e.g. PA I38T ).
Which suggests that public health authorities may need to start thinking about stockpiling alternatives (e.g., zanamivir, baloxavir) should these trends continue.
