PLoS One: Occurrence of influenza antivirals and resistance development in influenza A viruses in aquatic environments: A risk assessment

Photo Credit USGS – Wastewater: The Primary Treatment Process
1. Screening 2. Pumping 3. Aerating 4. Removing sludge 5. 

Removing Scum 6. killing bacteria

#19,350

Almost 20 years ago (January 2007), in The Law of Unintended Consequences, we looked at a study by researchers at the Centre for Ecology and Hydrology in Oxford titled Potential Risks Associated with the Proposed Widespread Use of Tamiflu, that questioned what might happen if millions of people simultaneously began taking Tamiflu and releasing it into our environment.

A large percentage (60%-80%) of the Tamiflu (aka oseltamivir) a person takes is eventually excreted in their urine as oseltamivir carboxylate (OC), a factoid that 20 years ago briefly led to internet speculation about the practice of ‘recycling’ our own urine, to stretch out the supply of Tamiflu during a crisis. 

While that thankfully never became an internet challenge, it did inspire a doctor to publish a proposal in Nature on the co-administration of a generic gout medicine - probenecid - which slows the excretion of certain drugs - potentially increasing the effectiveness (and lowering the overall dose) of oseltamivir. 

But I digress . . . 

The 2006 Oxford study specifically warned that large quantities of oseltamivir carboxylate (OC) could be excreted into sewers during a pandemic - which wastewater plants are largely unable to remove - and could end up in rivers and streams, and eventually birds, where it might promote antiviral resistance in avian flu viruses. 

Similar concerns re-emerged in the fall of 2009 (see Everything Old Is News Again) when researchers at Kyoto University tested wastewater discharge from three local sewage treatment plants and water from two rivers into which they drained during the 2008-09 flu season looking for signs of the active ingredient in Tamiflu, oseltamivir carboxylate (OC).

For years Japan has been the largest consumer of antivirals for seasonal flu, and they found exactly what they were looking for; substantial levels of the Tamiflu metabolite in the environment.

In 2011, in Pandemics & The Law Of Unintended Consequences, we looked at not only the potential effects of antivirals in our sewage system, but also how the consumption (and excretion) of antibiotics during a pandemic might affect wastewater treatment plants (WWTPs).

But a proof of concept was published in 2015, in AAC: LPAI H7N9 Acquires Antiviral Resistance When Exposed To Environmental Oseltamivir, which reported that mallards experimentally infected with LPAI H7N9, and then exposed to low levels of oseltamivir carboxylate (OC) in their water, developed antiviral resistance markers (NA-I222T) in as few as 2 days. 

From the Abstract:

In an in vivo Mallard (Anas platyrhynchos) model, we tested if low-pathogenic avian influenza A(H7N9) virus could become resistant if the host was exposed to low levels of OC. Ducks were experimentally infected and OC was added to their water, where after infection and transmission was maintained by successive introductions of uninfected birds. Daily fecal samples were tested for IAV excretion, genotype and phenotype.

Following Mallard exposure of 2.5 μg/L OC, the resistance related NA-I222T substitution, was detected within 2 days during the first passage and was found in all viruses sequenced from subsequently introduced ducks.

Two of those same authors (Lindström & Järhult) are back with today's report, which provides a relative risk assessment of introducing four different antivirals (3 Neuraminidase inhibitors (NAIs), plus Amantadine, an M2 ion-channel inhibitor) into aquatic environments.  

The authors report that the use of PE (peramivir) and OC (oseltamivir) pose the highest environment risk, and suggest using ZA (zanamivir) whenever possible, and limiting the use of oseltamivir in uncomplicated influenza in non-risk groups.

Zanamivir, however, isn't always a good substitute for oseltamivir because it is an inhaled powder, which can be problematic for those with COPD, asthma, or who are experiencing respiratory symptoms. 

They also recommend stockpiling Baloxavir (see yesterday's blog EID Journal: Comparison of Baloxavir-Based Combinations and Monotherapies for Treating Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Mice) to provide additional therapeutic options.

This is a lengthy, and times technical report. Follow the link to read it in its entirety. I'll have a postscript after the break. 

Occurrence of influenza antivirals and resistance development in influenza A viruses in aquatic environments: A risk assessment

Hanna Söderström Lindström, Sara H. Norström , Chaojun Tang, Richard H. Lindberg, Josef D. Järhult

Published: September 21, 2026
https://doi.org/10.1371/journal.pone.0358447

Abstract

Influenza antivirals (IAs) have been detected in aquatic environments inhabited by dabbling ducks, the natural reservoir of influenza A virus (IAV), raising concerns about the development of antiviral resistance. Because novel human IAV strains often contain genetic material of avian origin, this may contribute to resistance in viruses with pandemic potential. 

This study aimed to assess the environmental risk posed by four IAs—oseltamivir carboxylate (OC), zanamivir (ZA), peramivir (PE), and amantadine (AM)—based on their potential for environmental release, environmental stability, and induction of antiviral resistance. The assessment combined data from new experiments on (1) environmental release and (2) environmental stability of PE, AM, OC, and ZA, with results from previously published in vivo experiments in a mallard model examining (3) resistance development to OC, PE, and ZA in IAV. 

The risk of environmental release was assessed as high for OC, AM, and PE, and very high for ZA. Environmental stability ranged from very high to low, in the order PE > AM > OC > ZA. The potential to induce resistance in IAV was similar for PE and OC, and lower for ZA.

Overall, the environmental risk ranking was PE > OC > ZA, with PE and OC posing the highest risks. 

Prudent use of IAs requires balancing the risk of resistance development against clinical benefit. In cases of complicated influenza or in high-risk patient groups, the clinical benefits are substantial and justify IA use. However, in uncomplicated influenza among otherwise healthy individuals, the clinical benefit is limited, and the risk of resistance development should be carefully considered. Among the evaluated antivirals, ZA showed the lowest environmental risk and should be preferred when feasible.

        (SNIP)

Conclusions

This is the first study to jointly assess the environmental risk of influenza antivirals (IAs), and the public health risk caused by environmental resistance development in influenza A viruses (IAVs). This comprehensive approach provides new knowledge to support sustainable antiviral use, helping to prevent resistance development in future pandemics and preserve the effectiveness of antiviral stockpiles.

Our study shows that the environmental occurrence of IAs, and resistance development in IAVs in aquatic environments, is a concern for all three IAs (OC, PE, and ZA) studied with a high environmental risk of both PE and OC. Our risk assessment was based on virus experiments on individual IAs which could underestimate the risk for environmental resistance development due to cocktail effects in natural environments.

As antiviral drugs constitute a cornerstone in pandemic preparedness, especially in the first phase before vaccines can be mass-produced, it is crucial to work to retain their effectiveness. Given our assessment of the high environmental risk of both PE and OC, and the risk for the resistance developed to be part of a novel IAV with pandemic potential in humans, non-pandemic use should be prudent. This includes balancing benefits of pre-pandemic use with risks of a resistant pandemic IAV. IAs are important in treating complicated diseases and diseases in risk groups and should be used in these cases. However, in uncomplicated influenza in non-risk groups we argue that the clinical benefit is minimal, and if the use is extensive, it will drive environmental occurrence and risk for resistance development. Therefore, we argue that the risk for resistance development should be considered when treating uncomplicated influenza in non-risk groups.

From our risk assessment, it seems beneficial to use ZA rather than oseltamivir phosphate (the pro-drug for OC) when practically possible. PE is the IA with the highest environmental risk in our assessment, hence highest public health risk and other alternatives should be used when possible. As PE is at present only available as an intravenous formulation, it is likely that the use of this drug will not be extensive.

New influenza antivirals such as baloxavir are a very important addition to the treatment arsenal. They should be considered as additions to stockpiles in pandemic preparedness to have access to alternate antivirals with a different mode of action. This will increase the chances of a viable treatment option in case of a resistant pandemic IAV. At the same time, it is crucial to evaluate the risk for environmental resistance development potential of new antivirals to guide prudent pre-pandemic use.

        (Continue . . . )

Antivirals, antibiotics, and most antifungal medicals all share the same Achilles' heel. Over time - and particularly if they are used recklessly or excessively - the pathogens (viruses, bacteria, or fungi) they were designed to suppress can evolve or mutate enough to render them ineffective.

While many people fear that a hyper-virulent novel virus will someday emerge and kill hundreds of millions of people, the reality is - if we don't protect our limited armamentarium of antibiotics and antivirals - something relatively ordinary, and previously treatable, could do the job equally as well.

But balancing today's needs with those of tomorrow is always easier said than done. For more on the potential environmental risks from wastewater treatment plants, you may wish to revisit: 

Preprint: Spillover of Human Antivirals May Promote Resistant Pathogens in Animal Reservoirs

Study: NDM-1 Bacteria Survive & Thrive In Two Chinese Wastewater Treatment Plants

Study: MRSA In Waste Water Treatment Plants

EID Journal: Comparison of Baloxavir-Based Combinations and Monotherapies for Treating Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Mice

 

Screenshot: CDC's  Interim Guidance on the Use of Antiviral Medications 
for Treatment of Human Infections with Novel Influenza A Viruses Associated 
with Severe Human Disease - July 2025

#19,349

While newer antivirals have been developed (see FDA Approval Of Xofluza : A New Class Of Influenza Antiviral), oseltamivir (aka `Tamiflu') has remained the `Go to' antiviral for influenza treatment in the United States - and much of the world - for more than 20 years. 

Oseltamivir is our most studied antiviral, nations of the world have stockpiled hundreds of millions of doses, and now that can be acquired as a generic drug, its cost has plummeted. 

While exact numbers have never been disclosed, our National Strategic Stockpile supposedly has somewhere around 50-60 million courses of oseltamivir on hand; sufficient to treat 15-20% of the nation during a severe flu pandemic (assuming a single, standard dose).

Stockpiles of Baloxavir (aka Xofluza) are similarly unknown, but according to a media report in 2024 (see The U.S. strategic drug stockpile is inadequate for a bird flu outbreak) likely numbers only in the hundreds of thousands of doses.

But oseltamivir's track record against novel flu is far from perfect. To be effective, it must be started early in one's infection (1st 48 hrs, ideally), and even then, a good outcome is far from guaranteed. 

The first barrier is getting the drug to the patient in a timely manner, something which we've struggled with, even during normal flu seasons (see Sporadic Tamiflu (Oseltamivir) Shortages Reported In U.S. & Canada).

There is also the problem of resistance, something that can develop spontaneously in 1%-2% of people receiving treatment, or worse - can become `fixed' in circulating strains - such as we saw with H1N1 in 2008. 

Last year, in - in Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms - we saw a report on a large outbreak of Oseltamivir resistant H5N1 which emerged over several weeks in the fall of 2024.

While we haven't seen that happen on a large scale, 18 months ago concerns over the effectiveness of our current antiviral armamentarium were raised by St. Jude Researchers: Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk. 

Last January, in Nature Comms: Oseltamivir and Baloxavir Monotherapy and Combination Therapy Efficacy Against Clade 2.3.4.4b A(H5N1) Influenza Virus Infection in Ferrets, we saw a CDC study which looked at both mono and combination therapy with oseltamivir and baloxavir in ferrets infected with H5N1 (genotype D1.1).

In short, they found:

• Ferrets infected with H5N1 D1.1 and treated with oseltamivir saw little or no clinical or virologic benefit compared to no treatment, with persistent high fevers, weight loss, and systemic viral replication.
• Ferrets treated with Baloxavir saw significantly less fever, weight loss, and viral replication. Some ferrets, however, saw a late rise in fever (after 4 days) and viral shedding, suggesting a viral rebound. 
• Ferrets treated with both drugs saw similar clinical protection to baloxavir alone, but did not show signs of rebound. 

Note: Ferrets are a good, but not perfect, proxy for humans in influenza research, so these results may not be 100% applicable to humans.  

A month later, we looked at a study (Nature Comms: Baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating lethal influenza A(H5N1) HA clade 2.3.4.4b infection in mice) by Webby & Jones et al. which suggests that baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating clade 2.3.4.4b (circa 2022) H5N1 avian viruses (in mice).

And last April, in Emerg Microbes & Inf: Antiviral Activities of Multiple Antivirals Against HPAI H5N1 in Vitro and in Mice, the authors reported the existing 5-day course of oseltamivir appears inadequate to treat severe HPAI H5N1 infection (at least, in mice).

The authors reported Baloxavir as being more potent, but even a 5-day B.I.D course (10 times the current dose) only saved 16.7% of treated mice.  Extending treatment to 7 days (14 doses), raised survival to 50%. 

While a 7-day course of Baloxavir (BXM) was the strongest single-drug therapy, extended courses of MNP+BXM and OSP+BXM provided the most effective treatments.

The caveat here being that - due to their higher metabolic rate - the half-life of baloxavir is much shorter in mice than in humans. While it remains to be determined, an equivalent dose in humans might be more like 2 or 3 doses spread out over a week's time.

And mice, and ferrets, and other lab animals - while useful - are never a perfect analog for humans. They don't have the same physiology, metabolism, or past virus and/or vaccine exposures that can modify our immune response. 

Adding to this long and winding narrative, we have a new report from the EID Journal which provides additional support for the baloxavir-based strategy described above. 

As in the previous report, the authors found that baloxavir outperformed both oseltamivir and molnupiravir against clade 2.3.4.4b H5N1 in a mouse model, although it should be noted they began treatment just 6 hours after inoculation. 

Combining baloxavir with either oseltamivir or molnupiravir was even more effective in suppressing viral replication and spread beyond the lungs.

The bottom line: both studies suggest oseltamivir monotherapy may be inadequate for severe H5N1, that baloxavir appears more potent, and that combination therapy may prove a more effective regimen - at least in mice. 

How all of this might translate to humans, who would be unlikely to receive antiviral treatment in such short order - remains to be seen. 

I've only posted the abstract and some extended excerpts from the EID dispatch. Follow the link to read it in its entirety.  I'll have a postscript after you return.

Comparison of Baloxavir-Based Combinations and Monotherapies for Treating Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Mice
 
Seong Cheol Min, Ju Ryeong Lee, Beom Kyu Kim, Ji-Hyun Park, Dong Gyu Lee, Gi Chan Lee, Se Hee An, Santosh Chokkakula, Aman Jain, Young Ki Choi, Yun Hee Baek, and Min-Suk Song
 
 Abstract

Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause animal outbreaks and sporadic zoonotic infections. In a mouse model of lethal influenza disease, we compared oseltamivir, baloxavir, and molnupiravir monotherapies with 2-drug combinations.

Baloxavir-based combinations improved survival, reduced lung viral loads, and prevented extrapulmonary dissemination, supporting H5N1 preparedness strategies. 

Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause widespread outbreaks and sporadic zoonotic infections, underscoring the need to optimize antiviral strategies (1–3). Licensed influenza antiviral drugs can reduce disease severity but might be compromised in severe infections by high viral burdens, treatment delays, and treatment-emergent resistance, motivating evaluation of combination regimens (4–7). 

Recent H5N1 treatment studies using mouse models suggest antiviral performance can vary by exposure route and disease progression (8–11). To inform preparedness-oriented selection, we compared direct-acting antiviral drugs from distinct classes in a lethal mouse model. We tested monotherapies and 2-drug combinations of 2 licensed influenza antiviral agents, oseltamivir phosphate (OSP; neuraminidase inhibitor) and baloxavir acid (BXA; cap-dependent endonuclease inhibitor), and molnupiravir (MPV; nucleoside analog) to assess whether combinations provided synergistic benefit.

(SNIP)

Conclusions

In a lethal clade 2.3.4.4b H5N1 mouse model, monotherapies with OSP, MPV, or BXA improved outcomes in a dose-dependent manner but did not consistently prevent death or extrapulmonary spread. In contrast, 2-drug combinations, particularly those containing BXA, achieved complete survival at both dosing regimens and suppressed pulmonary replication to near LOD while preventing neuroinvasion and cardiac dissemination. 

Those findings are consistent with recent clade 2.3.4.4b A(H5N1) studies showing strong in vivo activity of BXA and BXA-containing regimens and extend those observations by directly comparing BXA/OSP and BXA/MPV with OSP/MPV in a lethal mouse model (8,10,11,14). Our findings extend recent antiviral-combination studies in less virulent influenza models by showing that BXA-containing combinations provided the strongest protection in a lethal clade 2.3.4.4b H5N1 model (14,15). 

Together, our findings provide an experimentally grounded rationale to prioritize BXA-based 2-drug regimens as a preparedness-oriented option for emergent H5N1 infections when antiviral treatment is initiated early after infection, particularly where severe disease or resistance risk can compromise single-agent performance.

        (Continue . . . )

Currently, the CDC's guidance is for prompt oseltamivir treatment of suspected or confirmed novel influenza A infections, while allowing clinicians to consider adding baloxavir in selected severe or high-risk cases.

• Combination antiviral treatment (e.g., oseltamivir and baloxavir) can be considered for hospitalized patients with novel influenza A virus infection because it is possible that some novel influenza A viruses might become resistant to oseltamivir and peramivir during antiviral treatment with one of these agents 36789
• Oseltamivir resistance has been reported in hospitalized patients with HPAI A(H5N1) virus infection, resulting in fatal outcome 3. If a hospitalized patient treated with oseltamivir or peramivir manifests progressive lower respiratory disease, the presence of a resistant virus should be considered. After consultation with CDC's Influenza Division, investigation for antiviral resistance should be performed.
• Combination treatment with a neuraminidase inhibitor and baloxavir did not have clinical benefit compared with neuraminidase inhibitor and placebo in a randomized clinical trial in hospitalized patients with seasonal influenza, but the addition of baloxavir reduced duration of infectious viral shedding 10

Added to this are the logistical considerations: The global supply of oseltamivir is far greater than baloxavir, while the cost is far lower.

The reality is, even oseltamivir may be hard to get - at least during the first critical 24-48 hrs of infection - during any global influenza pandemic. It seems likely that `extended' baloxavir or combination therapy will be limited to hospitalized patients with severe disease.

Combine that with an expected wait of at least 6 months before having any large quantities of vaccine, and we will once again have to rely heavily on preventing infection; wearing face masks, hand washing, improved indoor ventilation, staying home while sick, and avoiding crowds.

While I would certainly avail myself of whatever antivirals are available in an influenza pandemic, my primary strategy is always one of prevention. I've already got my supply of masks, hand sanitizer, and OTC meds in the hall closet, and have stayed current with all of my vaccines.

If you aren't similarly prepared, you may want to revisit:

#Natlprep 2026: Pandemic Planning At Both Ends of the Spectrum

H5N1’s Summer Lull: Getting Shorter?

 
Chart generated by Gemini using USDA Data

#19,348

As the above chart illustrates, for the past few years we've witnessed a similar avian flu pattern; a summer lull followed by a sharp increase in outbreaks starting in either September or October, and running through late spring. 

While the amplitude of poultry outbreaks during the winter has fallen (possibly due to better biosecurity measures) a bit, the number of months with elevated activity has increased. 

Avian flu outbreaks in September 2025 and 2026 have far exceeded outbreaks for the same month in 2023 and 2024, while last spring's avian flu activity extended well into May. 

Our summer lull remains, but appears to be shrinking.  

• In 2023-2024, the U.S. saw 3 months of strong activity (> 25 outbreaks/mo). 
• In 2024-2025 that number jumped to 5 months
• And in 2025-2026 we saw 6 months with > 25 outbreak/mo. 

And while September isn't completely in the books - and there are often delays in reporting - over the past 30 days the United States has already reported 20 poultry outbreaks (18 in September). 

After reporting zero outbreaks during June, July, and August - Canada has reported 6 outbreaks in Manitoba over the past 2 weeks (Sept 10th-24th).  

In 2024, Canada's summer break in avian flu reports ran from April 10th to October 21st (194 days). In 2025, the lull lasted from May 15th to September 9th (117 days).  This year, from May 16th to September 10th (also 117 days).

As we saw yesterday in ECDC/EFSA Quarterly Avian Influenza Overview June-August 2026, Europe saw unprecedented levels of HPAI in wild birds over the 2025-2026 season.

And South Korea reported both increased diversity and infectivity among avian flu viruses which sparked a difficult and lengthy 2025-2026 avian flu season, which began 47 days earlier than the 2024-2025 season. 

These shifts aren't necessarily permanent, nor are they reliable indicators of what this fall and winter avian flu season will look like. But we shouldn't ignore them, either. 

By now most commercial poultry producers are presumably well practiced in implementing biosecurity measures to protect their flocks (despite which, outbreaks still happen). But the APPA estimates `Eleven (11) million U.S. households own backyard chickens (a 28% increase from 2023)'.

A recent survey (see MMWR: Knowledge, Attitudes, and Practices Regarding Avian Influenza Among Owners of Backyard Flocks), found significant gaps in their knowledge of dealing with avian flu.

Although the risks of infection are believed low, we've already seen at least two fatalities (here, and here) in the United States from H5Nx following `. . . exposure to a combination of a non-commercial backyard flock and wild birds.'

In an attempt to avoid future incidents, last year the University of Florida's Extension office (UF/IFAS) released two H5N1 related publications; one for backyard poultry owners, and another for consumers of poultry products and milk.

Given what may be on the horizon, both are recommended reading. 

Virus Research: Genetic Diversity of Clade 2.3.4.4b H5Nx High Pathogenicity Avian Influenza Viruses Detected in Korea During the 2025–2026 Winter Season and Pathogenicity of H5N1 and H5N9 Viruses

 

#19,347

Last December - in addition to reporting numerous biosecurity breaches on farms - South Korea's MAFRA Reported Increased Infectivity & Pathogenicity of This Year's Avian Flu Strains, which - for the first time - included 3 HPAI strains (H5N1, H5N6, and H5N9). 

Of particular concern, their Animal and Plant Quarantine Agency conducted an evaluation of the infectivity and pathogenicity of one highly pathogenic avian influenza virus (serotype H5N1) and found that the infectivity was more than 10 times higher than in previous years.

Details at the time were understandably scant, but today we've a research article which sheds new light on the panoply of viruses behind last year's difficult avian flu season in South Korea. 

While this is a fairly technical report, and the use of regional nomenclature for H5N1 genotypes further complicates matters, the gist is pretty simple. 

Last year South Korea was visited by a diverse panoply of H5Nx genotypes (n=16), with at least two -  H5N9 N9-G2 and H5N1 25G2 - displaying unusually high infectivity in chickens.

H5N1 25G2 was also deadly to ducks, whereas H5N9 N9-G2 spread efficiently in ducks, albeit without producing serious illness. 

H5N1 25G2 was the source of nearly half (n=30) of last year's 62 South Korean poultry outbreaks, but it was only detected in environmental samples once, making its prevalence in wild birds unknown. 

Whether 25G2 (or H5N9 N9-G2) will return to South Korea this fall - or turn up in other regions - remains to be seen.   

Due to its technical nature, I've only provided the link, abstract, and a few excerpts.  Follow the link to read the report in its entirety. 

Genetic Diversity of Clade 2.3.4.4b H5Nx High Pathogenicity Avian Influenza Viruses Detected in Korea During the 2025–2026 Winter Season and Pathogenicity of H5N1 and H5N9 Viruses

Yunyueng Jang, Ra Mi Cha, Min-Ji Park, Jong-Min Kim, Eui Hyeon Lim, Gyeong-Beom Heo, Se-Hee An, Bina Lee, Hyun-ji Seo, Kwang-Nyeong Lee, Youn-Jeong Lee, Eun-Kyoung Lee

10.1016/j.virusres.2026.199807

PDF

Highlights

• During 2025-2026, clade 2.3.4.4b H5N1, H5N6, and H5N9 HPAIVs were detected in Korea, causing 62 H5Nx HPAI outbreaks in poultry, and 63 cases in wild birds.
• Ten genotypes (24G1, 25G2–25G7, and N9-G1–3) identified in poultry, among which 25G2 was the dominant genotype.
• Most genotypes were reassortants containing gene segments derived from East Asian clade 2.3.4.4b H5N1 HPAIVs since 2022 and LPAIVs from wild birds.
• The 25G2 and N9-G2 genotype showed high infectivity in chickens with 103.3 and 103.2 EID50 of LD50 values, respectively.
• The 25G2 caused rapid duck mortality, whereas H5N9 caused asymptomatic infection with efficient transmission.

ABSTRACT

Clade 2.3.4.4b H5N1, H5N6, and H5N9 high pathogenicity avian influenza viruses (HPAIVs) were detected in poultry and wild birds during the 2025–2026 winter season in Korea. During this period, 62 H5Nx HPAI outbreaks occurred in poultry, and 63 cases were reported in wild birds.

Genome constellation analysis revealed substantial genotype diversity. Most H5N1 and H5N9 genotypes were reassortants containing gene segments derived from East Asian clade 2.3.4.4b H5N1 HPAIVs since 2022 and low-pathogenicity avian influenza viruses from wild birds. 

Notably, the European H5N1 genotype EA-2024-DI.2.1, which spread rapidly across Europe in 2025, and its reassortants were identified in Korea. The novel poultry genotypes were also detected in wild birds, supporting wild bird to poultry spillover, whereas one genotype detected in previous season was identified in small-scale poultry farms.

H5N1 (C588) of major 25G2 genotype in poultry and H5N9 (C722) of N9-G2 genotype showed high infectivity in chickens with 103.3 and 103.2 EID50 of median lethal dose (LD50) values, respectively. The predominance of the 25G2 genotype in poultry may have been influenced by efficient infection and virus introduction into high-density poultry production areas, potentially facilitating horizontal transmission under field conditions.

In young ducks, H5N1 caused rapid mortality, whereas H5N9 induced limited clinical signs without mortality. Both viruses were transmitted to all contact ducks, increasing the risk of transmission to poultry. Despite intensified surveillance and early detection efforts to limit virus spread, H5Nx HPAIV outbreaks occurred during the 2025–2026 winter season. These findings highlight the need for continued surveillance, together with rapid genomic and pathogenic characterization of newly introduced viruses.

(SNIP)

Genotype 25G2 was the predominant genotype detected in poultry during the 2025–2026 season, accounting for 30 outbreaks. However, it was identified in only one environmental sample collected during an epidemiological investigation of migratory bird habitats. This outbreak pattern differed from those observed during previous seasons in Korea, in which the predominant genotypes were generally similar between wild birds and poultry (Cha et al., 2023; Cha et al., 2025; Cha et al., 2026). 

The predominance of genotype 25G2 in poultry may have been influenced by higher infectivity under field conditions, particularly in layer farms located in high-density poultry farming areas where HPAI outbreaks were concentrated. However, introduction through environmental contamination associated with wild birds cannot be excluded, and the potential influence of sampling bias resulting from spatial and temporal variations in bird migration and surveillance should also be considered (Hayes et al., 2025; Llanos-Soto, Yaffy, Pavlak and Ivanek, 2025).

This study revealed multiple introductions of genetically diverse H5 viruses during the 2025–2026 winter season and demonstrated their relatively high infectivity in chickens. Epidemiological investigations of concurrent outbreaks, together with virus detection and genetic analyses, helped identify potential sources of virus introduction in the affected regions and provided evidence of viral contamination in the surrounding environment. Despite enhanced surveillance and early detection efforts to limit virus spread, H5 HPAI outbreaks still occurred in poultry farms. These findings highlight the importance of continued surveillance in wild birds and poultry, coupled with the rapid genomic and pathogenic characterization of newly emerging viruses, to support the implementation of effective avian influenza control disease.

        (Continue . . . )

ECDC/EFSA Quarterly Avian Influenza Overview June-August 2026

 
2025-2026: HPAI's Biggest Surge in Wild Birds to Date (Europe)

#19,346

As the above EDC/EFSA chart illustrates, after a couple of lackluster years (2023-2025) avian flu returned to Europe with a vengeance last year. We saw similar upticks in places like South Korea, and North America, but reporting from large swaths of the world - particularly in Asia and Africa - is often lacking (see FAO graphic below).

Every 3 months the ECDC/EFSA publishes a highly detailed avian influenza surveillance report, and while they tend to be EU centric, in its 67 pages you'll find ample coverage of outbreaks and infections from around the world on a wide variety of avian subtypes.

While today's report covers the slowest part (June-August)  of the year, these highly detailed quarterly reports make excellent reference material, and are well worth perusing.

This edition does contain one milestone, however; the long-dreaded arrival of HPAI to Australia/New Zealand, which was first reported in June.  I've posted the Abstract, and a few excerpts below. 

I'll have a brief postscript after the break.

Abstract 

Between 5 June and 28 August 2026, 110 highly pathogenic avian influenza (HPAI) A(H5N1) virus detections were reported in domestic (7) and wild (103) birds in 12 countries in Europe.The number of detections remained at a seasonal low throughout the summer, continuing the decline observed since spring. In contrast to previous years, fewer colony-breeding seabirds were affected, and the geographical range of detections was more limited. Further sporadic detections of HPAI A(H5) virus were reported in wild terrestrial carnivores and pinnipeds.

Outside Europe, the epidemic continued in the Americas, where also the HPAI A(H7N3) subtype was detected in Mexico. Following its first introduction to mainland Australia, HPAI A(H5N1) virus spread within local wild bird populations and spilled over to terrestrial carnivores and marine mammals. In the US, the number of dairy cattle farms reportedly affected by HPAI A(H5N1) increased, while detections in captive American minks were reported for the first time.

Between 5 June and 31 August 2026, 15 cases of avian influenza virus infection were publicly reported in humans (no fatal cases) in three countries and territories: Bangladesh (one A(H5N1) case), Cambodia (one A(H5N1) case) and China (13 A(H9N2) cases). All human cases reported exposure to poultry or a poultry environment prior to detection or onset of illness. Human infections with avian influenza viruses remain rare and no sustained human-to-human transmission has been documented.

The risk posed by avian influenza A(H5N1) clade 2.3.4.4b viruses currently circulating in Europe remains low for the general public in the European  Union/European Economic Area (EU/EEA) and low-to-moderate for those occupationally or otherwise exposed to infected animals or contaminated environments.

©2026 European Food Safety Authority, European Centre for Disease Prevention and Control,European Union Reference Laboratory for Avian Influenza. EFSA Journal published by Wiley-VCH GmbH on behalf of European Food Safety Authority

        (Continued . . . )

As the chart at the top of this blog indicates, each avian flu season (which runs Oct 1st -Sept 30th) is different, sometimes punctuated by the arrival of new subtypes or genotypes, and often varying in intensity. 

As we go into a new fall season, migratory birds in the Northern Hemisphere are expected to bring with them a new wave of HPAI from their high-latitude breeding grounds (see H5Nx: Reassort & Repeat).

While we can't know what kind of avian flu season lies ahead, now would be a good time to review the things you can do to lower your (currently, low) risk of exposure. 

WHO Interim Guidance to Reduce the Risk of Infection in People Exposed to Avian Influenza Viruses

Backyard Flock Owners: Protect Yourself from Bird Flu (CDC Guidance)

UF/IFAS Extension: What Backyard Flock Owners Need to Know about Bird Flu (Influenza H5N1)

EM&I: Limited added benefit of seasonal influenza vaccination before A(H5) vaccination in mice and ferrets challenged with A(H5N1)

 

Credit ACIP/CDC

#19,345

One of the biggest challenges during any future H5Nx pandemic would be the rapid production and timely deployment of a two-dose (given 30 days apart) H5 vaccine to billions of people (see Referral: SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).  

While it's not a new idea (see 2008's Seasonal Flu Vaccine May Offer Some Protection To H5N1), the notion of using the existing seasonal flu vaccine as either a `stop-gap measure' - or as a `prime-boost' for the first pandemic jab, during the opening months of an H5 pandemic - has persisted. 

An early, encouraging 2010 study in the journal Vaccines (Seasonal influenza vaccine elicits heterosubtypic immunity against H5N1 that can be further boosted by H5N1 vaccination) reported:

Recent findings indicate that seasonal influenza vaccination or infection of healthy humans may contribute to heterosubtypic immunity against new influenza A subtypes, such as H5N1. Here, we investigated whether seasonal influenza vaccination in a mouse model could induce any immunity against the H5N1 subtype.

It could be demonstrated that, largely due to the H1N1 component strain A/NewCaledonia/20/99, parenteral immunization of mice with a trivalent seasonal influenza vaccine elicited heterosubtype H5-reactive antibodies able to confer partial protection against H5N1 influenza virus infection.

Furthermore, the trivalent seasonal influenza vaccine was found to be compatible with a whole virus H5N1 vaccine in a heterologous prime-boost immunization regimen, achieving superior efficacy compared to a single immunization with an equivalent low-dose of the H5N1 vaccine.

More recent evidence remains both mixed and modest - and has often relied on ferret or mouse models (which may not fully apply to humans) -  including:

Nature Comms: Adjuvanted Influenza Vaccination Increases Pre-existing H5N1 Cross-reactive Antibodies

mBio: Low levels of influenza H5N1 HA and NA antibodies in the human population are boosted by seasonal H1N1 infection but not by H3N2 infection or influenza vaccination

EID Journal: Effect of Seasonal Influenza Vaccines on Avian Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Ferrets

EID Journal: Investigation of Influenza A(H5N1) Virus Neutralization by Quadrivalent Seasonal Vaccines, United Kingdom, 2021–2024

Note: Regardless of whether the seasonal flu vaccine directly protects against H5N1 infection, there are still good reasons to get the jab, prior to - and even during - an H5Nx pandemic.

1. It still may provide some small boost to your immune response.  Neutralizing antibodies aren't the only immune defense against infection. 
2. It could help prevent a co-infection with H5N1 and seasonal flu, which has the potential for being more severe.
3. Co-infections could also help generate a reassorted `hybrid' virus (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses).

While it may not be the last word on the topic, today we've a study in EM&I from researchers at the CDC's NCIRD Influenza Division, which frankly, offers little encouragement on the effectiveness of using seasonal flu vaccines as a `prime-boost' for H5N1 vaccines. 

I've only reproduced the abstract and a few excerpts, so follow the link to read the report in its entirety.  I'll have a brief postscript after the break.

Limited added benefit of seasonal influenza vaccination before A(H5) vaccination in mice and ferrets challenged with A(H5N1)

Masato Hatta , Ying Huang , Jeremy A. Duke , Joseph R. Rouse , Chenchen Feng ,
Xudong Lin , show all
Article: 2731495 | Received 29 Jun 2026, Accepted 05 Sep 2026, Published online: 21 Sep 2026
 https://doi.org/10.1080/22221751.2026.2731495

Limited A(H5)-specific vaccine supply is expected early in a potential A(H5N1) pandemic, raising the question of whether licensed seasonal influenza vaccines could enhance protection when administered before A(H5) vaccination. We evaluated this strategy in mouse and ferret models using clade 2.3.4.4b A(H5N1) viruses.

Seasonal influenza vaccination induced antibodies to seasonal haemagglutinins but did not induce detectable antibodies against A(H5) and did not consistently enhance A(H5)-directed antibody responses after A(H5) vaccination.

In lethal challenge studies, seasonal vaccine priming before A(H5) vaccination was associated with improved outcomes compared with A(H5) vaccination alone in one of three mouse experiments, but this effect was not observed in the other two mouse experiments or in ferrets. These findings suggest that seasonal influenza vaccine priming provides limited added benefit to A(H5) vaccine-mediated protection against A(H5N1) under the conditions tested.

(SNIP)

Accordingly, clinical studies are needed to further evaluate the strategy of administering seasonal influenza vaccine prior to A(H5) vaccination. However, such studies would likely rely on immunological endpoints rather than direct assessment of protection. Evidence of cross-reactivity alone should therefore be interpreted cautiously when informing decision-making, as it may not reliably predict protection against severe or lethal A(H5N1) infection.

In the absence of a clear added benefit, prioritizing seasonal influenza vaccination as a priming strategy to enhance protection against A(H5N1) during the early phase of a pandemic may offer limited value, particularly when resources may need to be directed toward A(H5)-specific vaccination and other countermeasures. Continued efforts to improve the development, availability, and deployment of antigenically similar A(H5) vaccines should remain a priority for pandemic preparedness [13,14].

       (Continue . . . )

Although the prospect of using seasonal vaccine as a bridge - or as a primer for a first H5 dose - remains biologically plausible, the evidence of its effectiveness has been both inconsistent and weak. 

Today's CDC study reports that prior seasonal vaccination offered little reproducible improvement over H5 vaccination alone (at least, in mice and ferrets). While disappointing, it is hardly unexpected. 

Which suggests that during the opening months of any novel flu pandemic we will (once again) have to rely on NPIs (Non-pharmaceutical Interventions) like social distancing and face masks - and our limited supply of antivirals -  while a strain-specific vaccine is produced and deployed.

For some specific preparedness advice, you may wish to revisit #Natlprep 2026: Pandemic Planning At Both Ends of the Spectrum.