#18,773
While current seasonal (and novel) influenza viruses remain largely susceptible to our limited antiviral armamentarium (primarily oseltamivir and other NAIs, and the newer Baloxavir), we are constantly looking for signs of increased resistance.Although these detections have been limited, growing antiviral resistance is not an idle concern. Twice over the past 2 decades we've seen two frontline antivirals quickly loose effectiveness against seasonal influenza viruses.
First in 2005, our preferred influenza anti-viral drug - Amantadine - suddenly lost effectiveness after decades of use (see MMWR Levels of Adamantane Resistance Among Influenza A (H3N2) Viruses and Interim Guidelines for Use of Antiviral Agents --- United States, 2005--06 Influenza Season).Luckily, there was already an alternative available - Oseltamivir (aka `Tamiflu') - although it was far more expensive.
While occasional instances of Oseltamivir resistance had been observed, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’).
Studies suggested that these resistant strains were `less biologically fit’, and were therefore unlikely to spread from human-to-human.
And that happy status quo held until `biologically fit' highly resistant H1N1 viruses emerged in early 2008. By the end of that year - nearly all H1N1 viruses were resistant, forcing the CDC to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).
It seemed as if antiviral crisis was inevitable, but a new swine-origin H1N1 virus - that happened to retain its sensitivity to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus.This resistance was primarily due to an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)).
Since then oseltamivir has remained effective against 99% of seasonal flu viruses, but over the past couple of years we've seen some new cracks in its veneer.
Fifteen months ago we saw a worrisome report in The Lancet - Global Emergence of Neuraminidase Inhibitor-Resistant Influenza A(H1N1)pdm09 Viruses with I223V and S247N Mutations - which reported a much higher incidence of oseltamivir resistance among samples tested in Hong Kong in 2023 (along with a concurrent rise in GISAID sequences deposited since last summer).
Instead of the H275Y mutation which caused so much trouble in 2008, these viruses carried dual I223V/S247N mutations.
While neither of these mutations are anywhere near as impactful as H275Y, they are believed able to work synergistically with other mutations (including H275Y) to dramatically impair antiviral effectiveness (see Viruses: Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases).
It seems likely that the viruses have reached the next stage in the evolution of prerequisite viruses that enable the emergence and spread of stable lineages of resistant viruses, in which the substitutions NA-I223V and NA-S247N may have been added in 2023–2024 after the appearance of the two permissive substitutions NA-V241I and NA-N369K in 2011.
If synergistic amino acid changes such as NA-I223V and NA-S247N spread globally, there is the risk that other NA mutations which may have previously caused only slight or moderate reductions in susceptibility could instead cumulatively decrease NAI susceptibility to levels that may be clinically significant and affect treatment efficacy [37]
A year ago, in EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024, we saw a report which found this resistance signature has spread from Asia to Europe, and suggested it may be just as `biologically fit' as antiviral susceptible viruses.
All of which brings us to a new study, published this week in Virus Research, which reports a sharp increase in the NA-S247N mutation in seasonal flu viruses collected in Spain over the 2023-2024 flu season.
Iván Sanz-Muñoz, Alejandro Martín-Toribio, Adrián García-Concejo, Irene Arroyo-Hernantes, Marina Toquero-Asensio, Javier Sánchez-Martínez , Carla Rodríguez-Crespo , Silvia Rojo-Rello , Marta Domínguez-Gil, Eduardo Tamayo-Gómez, Marta Hernández-Pérez , José M Eiroshttps://doi.org/10.1016/j.virusres.2025.199599Highlights• 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.AbstractThe therapeutic arsenal against influenza is extremely limited and resistance often arises due to the emergence of mutations, especially in the neuraminidase (NA) gene. This study aimed to evaluate the evolution of NA mutations over 15 years in Spain. To do so, we used the GISAID database from which we downloaded a total of 11,125 influenza A(H1N1)pdm09, A(H3N2), B/Victoria and B/Yamagata NA virus sequences, and analyzed the resistance mutations using FluSurver software.
Our results showed that the occurrence of NA resistance mutations remained constant in the four viruses during the 15 seasons evaluated, being around 0.5-5%. Most of the resistance was found in the A(H1N1)pdm09 subtype (around 70%), especially from the 2023-2024 season onwards, when a significant increase in the occurrence of S247N mutation was observed.
The occurrence of this type of mutation before 2022 was rare, but in the 2023-2024 season a total of 44 influenza viruses harboring S247N mutations were detected, while in the other years, only two cases were observed. Some studies have described a significant increase in this mutation over the past two seasons and although it appears to confer only slightly reduced inhibition to oseltamivir, its increase is noteworthy and should be a reason for increased their vigilance.
(SNIP)
To summarize, the prevalence of antiviral drug resistance mutations against NA has remained stable in the influenza viruses analyzed in Spain over the last 15 years, 70% of them being detected in viruses of A(H1N1)pdm09 subtype.
Significantly, a remarkable increase of the S247N mutation has been observed in this subtype during the 2023-2024 influenza seasons. Although this mutation does not significantly reduce susceptibility to antiviral drugs, it may pose, in combination with other mutations such as H275Y, a real risk to the limited therapeutic arsenal currently available against this virus.
The available information shows that this mutation is stable in cell culture and does not negatively affect viral fitness. Therefore, these data should reinforce surveillance efforts through the genotyping of a relevant number of influenza samples each year by every country.
While this study only reviews data from Spain, it seems to align with other studies we've seen suggesting that the S247N mutation continues to spread globally.
It will be of particular interest if we should see this trend has continued throughout the 2024-2025 flu season (and beyond).
While this study deals with seasonal flu, these resistance mutations also increase the threat from novel flu viruses.
Three months ago, St. Jude Researchers warned Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk, and last February we learned from Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms.Although we've not seen any reports of H275Y in D1.1 samples collected in the United States, last November the CDC did report finding the above mentioned NA-S247N mutation in 3 poultry workers from Washington State, which they stated may slightly reduce the virus's susceptibility to antivirals.
All of which serve as sobering reminders that evolution never stops - and while our pharmacological victories over bacteria, fungi, and viruses can be lifesaving - they are often fleeting.
