Referral (NEJM): Autoantibodies against Type I Interferons and Death from H7N7 Avian Influenza

 
AutoAb development in population
credit Human autoantibodies against type I
interferons in severe viral disease

#19,413

We've a fascinating correspondence  - published yesterday (Nov 11th) in the NEJM - which links a relatively rare autoimmune dysfunction (autoantibodies against Type I Interferons) to increased severity of novel flu infection.  

The authors hypothesize that those with this condition could potentially act as “patients zero” in emerging viral pandemics. 

Since this correspondence is not open access, I'm only able to give some background and a brief synopsis. Those already familiar with the events of the 2003 H7N7 outbreak, and the recent discoveries surrounding this autoimmune condition, may prefer to proceed directly to the link below.   

Autoantibodies against Type I Interferons and Death from H7N7 Avian Influenza
Published November 11, 2026
N Engl J Med 2026;395:1963-1965
DOI: 10.1056/NEJMc2608446
VOL. 395 NO. 19 Copyright © 2026

For those preferring a review:

In 2003, the Netherlands saw an outbreak of H7N7 that resulted in the loss of 30 million birds across 1,000 farms, and saw scores of mild human infections and the death of a veterinarian (see Eurosurveillance Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003).

Another analysis, performed by the RIVM (Ministry of Health) found the spread of the virus to be much greater than originally reported, citing as many as 1,000 human infections (see Executive summary Avian Flu Epidemic 2003: Public health consequences).

Both reports cited likely human-to-human transmission, with the RIVM study finding ` . .  58.9% of the family contacts of persons having direct exposure to poultry had a measurable response in the HI test.' 

Most of these cases reported mild symptoms; primarily conjunctivitis.  A minority reported mild-or-moderate flu-like symptoms (often in conjunction with conjunctivitis), and one patient died. 

While nowhere as deadly to humans as H5N1 or H7N9, this H7N7 outbreak serves as a cautionary tale on the susceptibility of humans to novel influenza.  It also raises questions about the wide spectrum of outcomes from novel flu infection.

Relatively recently a rare immune dysfunction - autoantibodies against type I interferons - has been tagged as a likely determinant of severity in viral infections.  

Six months ago, a review article in Current Opinion in Virology (Human autoantibodies against type I interferons in severe viral disease by Groen & Hale) reported:

Highlights

• AutoAb development is influenced by age, genetics, immune tolerance, and infections.

• IFN-I autoAbs heighten risk for severe infections and live-vaccine adverse events.

• Targeted diagnostic screening for IFN-I autoAbs could benefit certain individuals.

• Understanding autoAb mechanisms will help devise potential therapeutic strategies.

While first discovered in the early 1980s, it wasn't until COVID that AutoAbs impact on viral infections was really appreciated (see Nature Human genetic and immunological determinants of critical COVID-19 pneumonia).

All of which brings us to the NEJM correspondence, where the authors went back and tested stored serum from 35 patients from the 2003 H7N7 outbreak, including the 58 y.o. veterinarian who died. 

They found the fatal case had autoantibodies neutralizing interferon-α, -ω, and -β, while 2 of the remaining 34 mild cases had autoantibodies neutralizing interferon-β only.

Since antibodies against all three subtypes are rare in people under 60, the authors say this is unlikely to be by chance.  Strengthening their case, the fatal H5N1 case in Louisiana in early 2025 carried IFN-I autoAbs. 

Autoantibodies neutralizing type I IFNs in a fatal case of H5N1 avian influenza

Qian Zhang Corresponding Author , Taylor S. Conrad , Marcela Moncada-Velez , Kaijun Jiang ,Anastasija Cupic , Jonathan Eaton , Kimberley Hutchinson ,Adrian Gervais ,Ruyue Chen , Anne Puel , Paul Bastard  , Aurelie Cobat ,Thersa Sokol , RyanA. Langlois  ,Lisa Miorin  , Adolfo García-Sastre  ,John A. Vanchiere , Jean-Laurent Casanova Corresponding Author

Author and Article Information
J Exp Med (2026) 223 (3): e20251962.
https://doi.org/10.1084/jem.20251962

While it is well established that avian flu viruses have a hard time establishing themselves in humans, and that human-to-human transmission is uncommon, this rare autoimmune condition could provide a foothold for novel viruses like H5N1, H7N7, and H9N2 to adapt to humans. 

At least that's the theory. Admittedly, one based on limited evidence.

But if it turns out to be correct, it becomes even more imperative that we take steps to prevent spillovers (PPEs, seasonal flu vaccines to prevent coinfection and reassortment, etc.), and to treat even mild cases as potential public health threats. 

Policies which, based on recent anecdotal reports (see Newsweek Farm Workers Sound Alarm on Underreported Bird Flu Numbers), still appear to be lacking.

UK Scotland: H5N5 Reported In Eurasian Otters - AIPZs Declared for England and Scotland

 

#19,412

We've been watching the co-circulation and spread of an H5N5 subtype of avian flu - primarily in the high latitude regions of the Northern Hemisphere - for the past 3 years (see Preprint: H5N5 virus transmission is driven by repeated cross-Atlantic introductions and transmission among high latitude seabirds).

We've seen numerous reports of H5N5 from Norway, Svalbard island, Iceland, and eastern Canada, often infecting mammals, including cats, polar bears, raccoons, foxes, and walruses.

In the spring of 2025, the UK reported 15 grey seals infected with H5N5. The following November, in UK: HPAI H5N5 Rising, we saw a sudden shift in H5N5 activity in wild birds in the UK, with the APHA reporting:

Since our previous outbreak assessment on 7 October 2024, there have been no new reports of high pathogenicity avian influenza (HPAI) H5 clade 2.3.3.4b in domestic poultry in Great Britain (England, Scotland and Wales). There have, however, been 15 more HPAI H5 clade 2.3.3.4b events involving 26 “found-dead” wild birds in Great Britain. Of these, 25 were HPAI H5N5 with 1 case of HPAI H5N1.

Also in November of 2025 the United States reported the first (and fatal) human infection with H5N5.  While still a minor player in the global scheme of things, H5N5 continues to show surprising resilience and spread. 

While most of these reports have involved wild birds and/or small mammals, in early October Scotland reported an outbreak of H5N5 in commercial poultry in Ness, Isle of Lewis.

3 October 2026

Highly pathogenic avian influenza (HPAI) H5N5 was confirmed in commercial backyard poultry in Ness, Isle of Lewis, Scotland (AIV 2026/20). A 3km protection zone and 10km surveillance zone has been declared around the premises. This is the first outbreak of the 2026 to 2027 season and following confirmation of this case, GB has lost its freedom from highly pathogenic avian influenza (bird flu) status.

In an update, posted today by defra, the UK government has announced AIPZs (avian influenza protection zones) have been declared for both England and Scotland.

11 November 2026
AIPZ declared in England and Scotland from 11 November 2026

Following a number of findings of highly pathogenic avian influenza in wild birds and detections in poultry and increased risk levels, an avian influenza prevention zone (AIPZ) has been declared covering England and Scotland to mitigate the risk of further outbreaks of disease occurring.

This means that it is a legal requirement for all bird keepers in England and Scotland to follow strict biosecurity to prevent bird flu and stop it spreading.

You can read more information on the requirements for certain types of bird:

in the declaration for the AIPZ in England
In the declaration for the AIPZ in Scotland

Additionally, today defra has updated their avian flu in on-avian wildlife list for the first time since early March, adding three recent H5N5 detections over 5 weeks. 

The most recent High pathogenicity avian influenza (HPAI) in Great Britain and Europe Update Assessment (#11) - dated Nov. 6th,  but released yesterday- carries the following map showing 81 detections of HPAI H5 since Oct 1st. 

I've circled the H5N5 detections.  For now, all are on the western and northern coastlines, which fits the narrative that it is primarily carried by sea and shore birds. 

Whether it can establish itself further inland remains to be seen. But for now, it seems to be holding its own against H5N1.

EID Journal: Cross-Protection against Influenza A(H5) Clade 2.3.4.4b Viruses after A(H1N1)pdm09 Infection

#19,411

Over the past 32 months we've seen at least six dozen human infections from HPAI H5 (H5N1 & H5N5) in the United States, and while most have been described as mild or moderate, 3 people have died. 

It seems likely, based on limited seroprevalence testing (see JAMA Open: Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic Testing), that the actual number of infections is higher.

Which suggests that H5N1 may not be quite as deadly as originally feared.  Of course, even a 2%-3% fatality rate would put it in the same league as the 1918 pandemic. 

An early assessment by the CDC (July 14th, 2024 H5N1 Update) reported that `. . . that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States'.

Since then, however, we've seen a number of studies which have reported serological evidence of limited immunity - particularly in older cohorts - against some strains of H5N1.

Probably not enough to prevent infection, but perhaps enough to reduce the severity of infection.

Initially, the focus was on HA immune imprinting (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression), where the HA group (1 or 2) you are first exposed to is thought to provide some degree of protection against other HAs in that group.

How much real-world protection early or past H1/H2 exposure might offer against H5Nx - or how long it might last - are unknown, but it has been suggested it might provide an `edge' against severe disease.

More recently, we've seen attempts to quantify the impact of the first NA (Neuraminidase) one is exposed to (see last December's Nature Comms: Pre-existing Cross-reactive Immunity to HPAI 2.3.4.4b A(H5N1) Virus in the United States).

This study found`very low levels of pre-existing binding antibodies to the HA head of the HPAI A(H5N1) 2.3.4.4b virus', but slightly more encouragingly, `. . . substantial cross-reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1).

Regarding the the value of cross-reactive antibodies to the N1 Neuraminidase, the authors wrote:

Neuraminidase antibodies have been considered as an independent correlate to protect against influenza 20. Although they cannot prevent infection, neuraminidase antibodies can prevent virus egress, reduce viral shedding, and thus could attenuate disease and lessen disease severity 21,22,23.

All of which brings us to a new research letter, published yesterday in the EID Journal, which reports that ferrets pre-exposed to H1N1 saw less severe illness when challenged with H5N1 or H5N5 than influenza-naive ferrets.

A few caveats:

• While an encouraging finding, this was a relatively small study, and ferrets aren't a perfect analog for humans.

• Also, pre-exposed ferrets only had one prior exposure - to H1N1pdm09 - whereas the human population typically has a much messier exposure history to a variety of flu viruses (many first imprinted with H3N2, or pre-2009 H1N1). 

• The challenge experiments appear to have been conducted roughly 3 months after H1N1 infection, and it is unknown if - or how quickly - protection might wane.  

Not unexpectedly, pre-exposed ferrets exposed to H5N5 did not fare quite as well as those challenged with H5N1, and there are no guarantees that any future H5 pandemic would carry a closely matching N1 Neuraminidase. 

Still, this is a fascinating report, and it may partially explain why recent H5N1 infections have been less deadly than originally feared.

Follow the link to read the report in its entirety.

Volume 32, Number 12—December 2026
Research Letter

Cross-Protection against Influenza A(H5) Clade 2.3.4.4b Viruses after A(H1N1)pdm09 Infection

Xiangjie Sun, Jessica A. Belser, Zhu-Nan Li, Nicole Brock, Joanna A. Pulit-Penaloza, Troy J. Kieran, Claudia Pappas, Hui Zeng, Jessie C. Chang, Paul J. Carney, Brandon L. Bradley-Ferrell, James Stevens, Min Z. Levine, and Taronna R. Maines  

Abstract

We challenged ferrets previously infected with influenza A(H1N1)pdm09 virus with H5N1 or H5N5 clade 2.3.4.4b viruses to assess cross-protection. Results show that previous A(H1N1)pdm09 virus immunity conferred partial protection against both viruses, with slightly reduced protection against H5N5 compared with H5N1, potentially reflecting the absence of cross-reactive N5 neuraminidase antibodies.

(SNIP)

Preimmune ferrets challenged with either H5N1 or H5N5 virus shed similar levels of virus in nasal wash samples during days 1–4 postinfection (range of mean peak titers 103.8–105.2 PFU/mL) as naive controls but exhibited reduced titers in throat swab samples on day 4 for H5N5 virus and days 2 and 3 for H5N1 virus (Figure 2, panels A, B).

Viral clearance from nasal washes occurred 2–4 days earlier in preimmune ferrets. We detected H5N1 virus less frequently in rectal swab samples from preimmune animals than from naive controls, whereas we did not observe that reduction for ferrets infected with H5N5 virus (Figure 2, panels A, B).

Influenza A(H1N1)pdm09 virus preimmunity did not substantially reduce viral titers in the upper respiratory tract (nasal turbinates) or soft palate after H5N1 or H5N5 virus challenge (Figure 2, panels C, D). However, A(H1N1)pdm09 preimmunity largely prevented viral dissemination to the lower respiratory tract (trachea and lungs) and extrapulmonary tissues for both viruses, with only sporadic low-level viral detection. However, intestinal viral titers were comparable between preimmune and naive ferrets challenged with H5N5 virus (Figure 2, panels C, D).

Detection of group 1 HA stalk antibodies after A(H1N1)pdm09 infection (Appendix Figure), together with previous evidence of HA stalk-mediated cross-protection against disease caused by the influenza A viruses within the same phylogenetic group (3,9), suggests that cross-reactive HA stalk antibodies might contribute to protection against A(H5) viruses. In addition, N1 cross-reactivity might further enhance protection against H5N1 virus. Consistent with our findings, limited N5 cross-reactivity has been reported in humans despite detectable N1 responses (10).


Further studies using H5-specific HA stalk antigens and functional assays are needed to determine the contribution of cross-reactive antibodies and cellular immunity to protection against zoonotic influenza A viruses. Our findings showed that previous A(H1N1)pdm09 viral infection conferred partial cross-protection against H5N1 and H5N5 viruses in ferrets, reducing disease severity, lethality, and viral dissemination.

Dr. Sun is a microbiologist in the Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Her research primarily focuses on using the ferret model to understand influenza virus pathogenicity and transmissibility.

Oregon ODA Reports Its First Outbreak of HPAI H5 In Dairy Cattle

 

#19,410

A little over a month ago Washington State became the 20th U.S. state to report HPAI H5N1 in dairy cattle, and since has racked up 43 outbreaks. Just over a week ago (Nov 2nd), Indiana Reported their 1st Infected Herds (n=2) becoming the 21st affected state, and late yesterday Oregon became the 22nd.

Oregon had previously reported two pigs infected with H5N1 in the fall of 2024 on a mixed species farm which had experienced an outbreak in poultry. Oregon has also reported 62 poultry outbreaks, primarily among backyard producers (including 1 human infection).  

With the recent addition of Washington and Oregon, only Montana and North Dakota remain unscathed in the western half of the nation. 

 The full statement from the Oregon Department of Agriculture (ODA) follows:

First Detection of Highly Pathogenic Avian Influenza in Oregon Dairy Cattle Confirmed

AFFECTED DAIRY UNDER QUARANTINE; MILK AND FOOD SUPPLY REMAIN SAFE FOR CONSUMPTION

Affected dairy under quarantine; milk and food supply remain safe for consumption

Milk from a Morrow County dairy tested positive for highly pathogenic avian influenza (HPAI). This is the first detection of HPAI in Oregon dairy cattle.

Preliminary detection of HPAI was identified through Oregon's routine statewide milk surveillance program, with preliminary results reported by the Oregon Veterinary Diagnostic Laboratory (OVDL) at Oregon State University (OSU) on November 6, 2026. The Oregon Department of Agriculture (ODA) immediately initiated an on-farm investigation and submitted additional samples to the United States Department of Agriculture (USDA) National Veterinary Services Laboratory (NVSL) for confirmation. Positive results were confirmed on November 10, 2026.

Oregon’s routine statewide milk surveillance program identified the detection, demonstrating the effectiveness of the state's ongoing monitoring efforts. No additional affected dairies have been identified at this time.

Pasteurized milk and dairy products remain safe to consume, and there is no concern about the safety of the commercial milk supply. Pasteurization effectively inactivates the HPAI virus, and milk from sick animals is prohibited from entering the commercial milk supply. The U.S. Food and Drug Administration (FDA) continues to advise against consuming raw (unpasteurized) milk because it does not undergo the heating process that kills viruses and bacteria.

"While this detection is significant, it is not unexpected given the continued spread of HPAI among dairy cattle nationally," said Dr. Ryan Scholz, State Veterinarian for ODA. "Oregon's milk surveillance program worked exactly as intended, identifying this infection quickly and allowing us to respond rapidly with our state and federal partners. This detection demonstrates the value of the monitoring and preparedness efforts supported by Oregon's dairy industry and animal health partners since 2024."

ODA has placed the affected dairy under quarantine, and enhanced biosecurity measures are in place. The quarantine restricts animal movement and implements additional disease control measures while response activities are conducted. Response activities are focused on the impacted dairy and associated epidemiologic investigation. In most cases, infected dairy cows are expected to recover within a few weeks.

ODA is coordinating closely with USDA, Oregon Health Authority (OHA) and Morrow County Public Health officials, OVDL, and Oregon's dairy industry partners as the investigation continues. Oregon's statewide dairy surveillance program, launched in December 2024, was established to detect HPAI early and support rapid response efforts. The program allows state and federal officials to implement disease control measures quickly when detections occur.

Public health officials are providing education to farm workers exposed to infected animals and will monitor them for symptoms of avian influenza throughout the outbreak. "With the use of appropriate personal protective equipment, the risk to farm workers remains low. Our public health approach is focused on ensuring rapid testing and treatment for any individuals who develop symptoms to prevent severe disease," said Melissa Sutton, M.D., medical director, respiratory viral pathogens, OHA. No human cases associated with this incident have been identified in Oregon. According to OHA and the Centers for Disease Control and Prevention (CDC), the current public health risk to the general population remains low. No cases of person-to-person transmission associated with this virus have been identified.

HPAI was first detected in U.S. dairy cattle in March 2024 and has since been identified in multiple states. USDA provides current information on HPAI detections in livestock. Oregon began statewide dairy milk surveillance in December 2024 and continues to test milk from all licensed dairy operations routinely. ODA appreciates the cooperation of Oregon dairy producers and industry partners who participate in ongoing surveillance, disease reporting, and biosecurity efforts that help protect animal health and Oregon's dairy industry.

Symptoms of HPAI in Dairy Cattle

Symptoms can include:

• Decrease in feed consumption with a simultaneous decrease in rumination and rumen motility.
• Respiratory signs, including clear nasal discharge.
• Acute drop in milk production.
• Abnormal tacky or loose feces.
• Lethargy.
• Dehydration.
• Fever.
• Thicker, more concentrated, colostrum-like milk, or no milk production in severely affected animals.

Some infected cattle may show no clinical signs. Most infected cattle recover within two to three weeks.

Suspected cases of HPAI in any animal species should be reported immediately to ODA at 503-986-4711.

For more information regarding HPAI in livestock, please visit the ODA HPAI webpage (http://oda.direct/AvianInfluenza).

After a slow start in the spring of 2024, HPAI detections in cattle peaked that fall (see chart below), and then began a sharp decline during the spring of 2025.

Between June 2025 and April 2026 monthly detections were reduced to single digits. 

(Chart generated with Gemini AI using USDA data)

After nearly a year of greatly diminished activity, we began to see an increase in reports - first from Idaho, and then from other states - starting in June of 2026.   

While we are still well below the levels reported in Oct-Dec 2024, this recent uptick is noteworthy, as is the recent spread to 3 previously unaffected states. 

Stay tuned.  

HK CHP Reports 6 H9N2 Cases over the past 4 Reporting Periods

 

#19,409

As of today's report, Hong Kong's CHP has reported a total of 23 H9N2 cases over the past 6 months, with 6 of those reported by the CHP since October 19th.   As you can see by the dates in the above graphic, there continue to be substantial delays in reporting, with 5 of the 6 cases reported occuring in September. 

Four of the six cases are in children (who are more likely to be screened for the virus), while two are in elderly adults. 

While H9N2 infection is typically mild or moderate, some patients are hospitalized, and a few deaths have been reported.  The two most recent cases - announced today - were previously reported on in the WHO WPRO weekly avian flu report released on October 28th.

Human infection with avian influenza A(H9N2) virus

From 23 to 29 October 2026, two new cases of human infection with avian influenza A(H9N2) virus were reported to WHO in the Western Pacific Region, both from China. Both cases were paediatric patients, one from Liaoning Province, with symptom onset on 20 September 2026, and one from Guangxi Zhuang Autonomous Region, with symptom onset on 13 October 2026. Both cases had exposure to poultry. All close contacts of both cases tested negative for influenza A. Both cases had fully recovered at the time of reporting.

Since 2015, a total of 189 cases of human infection with avian influenza A(H9N2), including two deaths (both with underlying conditions), have been reported to WHO in the Western Pacific Region. Of these,186 were reported from China, two were from Cambodia, and one was from Viet Nam.

Most human infections with avian influenza A(H9N2) have been associated with exposure to infected poultry or contaminated poultry environments, and the majority of cases have been mild. Sporadic human infections continue to be expected in areas where H9N2 viruses circulate in poultry populations. Current evidence indicates that H9N2 viruses have not acquired the ability for sustained human-to-human transmission, and the risk of further community-level spread remains low.

Last August, in WHO Influenza at the human-animal interface (Aug 7th) - Uptick in H9N2 Cases in China, we looked at this recent increase in reported cases. Whether this is due to more frequent spillovers, or better surveillance, isn't known.

Despite being clearly zoonotic - LPAI H9N2 is considered a `non-reportable' disease in poultry or wild birds by WOAH (see Terrestrial Animal Code). Complicating matters, China's attempts to control LPAI H9N2 through vaccines have been less than successful.

Several recent Chinese studies have found signs that LPAI H9N2 is becoming better adapted to mammals, warning of its pandemic potential; including:

• In early August, in EM&I: Genetic evolution, phylodynamics, geographic spread of H9N2 avian influenza viruses in China from 2014 to 2025: an increasing potential zoonotic risk, we saw yet another Chinese study warning that H9N2 was accruing mammalian adaptations which increases its zoonotic risk.

• Five months ago, in Viruses: Epidemiological and Virological Characteristics of H9N2 Avian Influenza Virus in Jiangsu Province, China, 2024, researchers warned that that Jiangsu’s circulating H9N2 viruses have acquired human receptor preference and mammalian adaptation, posing silent infection and pandemic risks

• In October 2025, in China CDC Weekly: Epidemiological and Genetic Characterization of Three H9N2 Viruses Causing Human Infections, investigators reported a number of indicators of increased mammalian adaptation within the virus, including an enhanced ability to infect upper respiratory (α2,6-sialic acid) tract receptors, and a number of HA protein mutations, including; H191N, A198V, Q226L, and Q234L.

• The Asian Y280/G57 lineages have shown increasing signs of mammalian adaptation (see EM&I: Enhanced Replication of a Contemporary Avian Influenza A H9N2 Virus in Human Respiratory Organoids)), while the African and Middle Eastern Lineages (mostly European G1-like) are older and less evolved.

• In the summer of 2025, in Nature: Genetic diversity of H9N2 avian influenza viruses in poultry across China and implications for zoonotic transmission, researchers reported rising prevalence of key mutations associated with increased infectivity and pathogenicity in mammals.

While H9N2 doesn't garner the kind of headlines that H5N1 gets, our own CDC lists two lineages (A(H9N2) G1 and A(H9N2) Y280) as having at least some pandemic potential, and several candidate vaccines have been developed.

So we watch these developments with more than just academic interest. 

PNAS: Rare recovery of reassortants between contemporary clade 2.3.4.4b H5N1 viruses and human influenza A viruses in vitro

 

Coinfection leading to Antigenic `Shift' 

or Reassortment 

#19,408

Last week, in When Flu Viruses Collide, we looked at the concerns over rare - but documented - instances of seasonal flu reassorting with a novel flu virus, and producing a biologically `fit' hybrid.  

At least 2 pandemics in the last century (1957 and 1968) are believed the product of such an interaction. This is the reason why yearly flu vaccination has long been recommended for people who raise pigs or work with poultry and the CDC now urges vaccination in dairy workers.

In 2024, Chinese scientists looked at the reassortment potential of H5N1 and H3N2 (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses) and predicted the risks to be relatively high.

Another, older (2010) study (see PNAS: H3N2 And H5N1 Reassortment) found that Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence.

While viewed as possible, it isn't clear how compatible contemporary seasonal viruses are for reassorting with currently circulating HPAI H5Nx viruses.

Complicating matters, since there is great diversity among all of these viruses - and they continually evolve - only partial answers are obtainable.

To that end, we have a brief report published yesterday in PNAS, which describes (partially successful) attempts to create reassortants using `weakened' (live attenuated NS1-truncated) clade 2.3.4.4b H5N1 HPAIVs of the B3.13 and D1.1 genotypes, and older (circa 2009 and 1968) human-adapted pdmH1N1 and H3N2 IAVs in MDCK II cells. 

Today's panoply of seasonal flu viruses have evolved considerably since those lineages emerged. But these are well characterized lab strains, with reverse genetic clones widely available, and their use likely makes comparisons with earlier studies easier. 

The authors acknowledge these (and other) limitations, but despite those constraints, they were able to generate 20 reassortants (0.74%). They report: 

Polymerase assays identified human IAV subunits, particularly H1N1 PA or H3N2 PB2, that increased H5N1 polymerase activity. Thus, contemporary clade 2.3.4.4b H5N1 viruses can reassort with human IAVs, but factors beyond polymerase compatibility may limit their recovery.

This study did not test these reassortants' fitness, transmissibility or disease severity, so it cannot predict real-world risk.  It does, however, suggest that contemporary clade 2.3.4.4b H5N1 viruses can reassort with human IAVs. 

Although it is not a particularly long report, I've only posted some excerpts. Follow the link to read it in its entirety. 

Rare recovery of reassortants between contemporary clade 2.3.4.4b H5N1 viruses and human influenza A viruses in vitro

Jakob Ankerhold, Susanne Kessler https://orcid.org/0000-0002-9720-8291, Philipp P. Petric, +4 , and Kevin Ciminski https://orcid.org/0000-0001-5397-7497 kevin.ciminski@uniklinik-freiburg.deAuthors Info & Affiliations

Edited by Peter M. Palese, Icahn School of Medicine at Mount Sinai, New York, NY; received September 8, 2026; accepted October 12, 2026 

November 9, 2026

123 (46) e2631654123

https://doi.org/10.1073/pnas.2631654123 

Abstract

Influenza A virus (IAV) pandemics can arise when animal-derived and human-adapted IAVs exchange genome segments; however, whether contemporary clade 2.3.4.4b H5N1 viruses can generate viable reassortants with human IAVs is unclear. Here, we tested the reassortment potential of two clade 2.3.4.4b H5N1 viruses with human-adapted H1N1 and H3N2 IAVs using a biosafe reassortment system. Across multiple coinfection conditions, we genotyped 2,698 plaque-purified viral clones and recovered 20 reassortants (0.74%). Polymerase assays identified human IAV subunits, particularly H1N1 PA or H3N2 PB2, that increased H5N1 polymerase activity. Thus, contemporary clade 2.3.4.4b H5N1 viruses can reassort with human IAVs, but factors beyond polymerase compatibility may limit their recovery.

 

Zoonotic influenza A viruses (IAVs) pose a constant pandemic threat, with previous pandemics often associated with reassortment between animal-derived and human-adapted IAVs (1). Reassortment requires coinfection of a cell and compatibility between viral genome segments from different host-adapted lineages (2). Highly pathogenic avian influenza viruses (HPAIVs) of the H5 clade 2.3.4.4b have created an unusually broad ecological interface for such events. Since 2020, these viruses have spread globally among wild birds and mammals and entered U.S. dairy cattle, resulting in human exposure and zoonotic infections (3–6). Although sustained human transmission has not been documented, cocirculation with seasonal human IAVs creates opportunities for coinfection and reassortment.

Previous studies showed that prepanzootic H5N1 HPAIVs can reassort with human IAVs (7–10). However, the reassortment potential of contemporary clade 2.3.4.4b H5N1 HPAIVs remains unknown. Here, we tested two clade 2.3.4.4b H5N1 HPAIVs, representing different viral genotypes associated with U.S. dairy cattle outbreaks (3, 5) in combination with human-adapted H1N1 and H3N2 IAVs. We show that contemporary clade 2.3.4.4b H5N1 viruses can form viable reassortants with human IAVs in vitro and identify distinct vRNP compatibility patterns.

(SNIP)

Discussion

In this study, we show that contemporary clade 2.3.4.4b H5N1 HPAIVs can reassort with human-adapted H1N1 and H3N2 IAVs, but reassortants represented only 0 to 2.3% of plaque-purified clones under the in vitro conditions tested. This finding is consistent with the absence of documented reassortment events involving human IAV segments in clade 2.3.4.4b H5N1 HPAIVs to date.

However, the low observed recovery frequency of reassortants does not indicate complete genetic incompatibility, as recovered reassortants carried human IAV polymerase segments and selected human IAV subunits increased H5N1 polymerase activity in human cells. Thus, our data separate reassortant recovery under the tested conditions from the functional properties of the resulting polymerase constellations.

As clade 2.3.4.4b H5 HPAIVs undergo frequent and complex reassortment with avian IAVs (4, 6), the factors potentially limiting reassortment with human-adapted IAVs remain unclear (2). Several limitations should be considered: MDCK II cells do not recapitulate natural infection dynamics or selective pressures, and the observed H5N1 replication advantage and viral progeny composition may differ in relevant hosts. Additionally, using NS1-truncated viruses and early pandemic representatives rather than contemporary seasonal isolates limits generalizability, while the absence of reassortant characterization limits conclusions about replication fitness, transmissibility, and pathogenicity.

Because no standardized benchmark for IAV reassortment exists, observed recovery frequencies cannot be directly compared across IAV combinations. Despite these limitations, our study provides a functional framework for interpreting reassortment risk during the ongoing clade 2.3.4.4b H5 panzootic.

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