A Geospatial Perspective Toward the Role of Wild Bird Migrations and Global Poultry Trade in the Spread of Highly Pathogenic Avian Influenza H5N1

 

Major bird migration flyways - Credit CDC EID Journal

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Twenty years ago, HPAI H5 was viewed as a regional problem; a poultry virus restricted to Southeast Asia which occasionally spilled over into humans. While it could be carried by waterfowl, most of its spread was chalked up to illicit poultry trade. 

In 2005 a new clade of the virus (2.2) appeared at Qinghai Lake in Tibet, and for the first time managed to escape the confines of Asia (see EID Journal: H5N1 Branching Out), turning up six months later in mute swans in Croatia (cite).  

Changes in the virus appeared to have improved its carriage via migratory waterfowl. By the end 2005, 17 (mostly Asian) countries had reported infections, but in 2006 the virus would appear in an additional 39 countries.

By the end of 2007, the virus was endemic in the Middle East, well established in West Africa, and was a frequent return visitor to Europe. Fortunately, carriage by wild birds was still spotty, and strict culling of infected poultry prevented the virus from getting a solid foothold in Europe.

But repeatedly over the years new clades would emerge - and a new subtype (H5N8) - which incrementally improved the virus's ability to spread via migratory birds.  In early 2014, a clade 2.3.4.4 H5N8 virus abruptly appeared in South Korea, ripping through their poultry industry.  

By the end of that year, this new and improved clade had done what no other H5 had done before; it had crossed from Siberia to Alaska, bringing the first HPAI H5 epizootic to North America. 

While devastating, this epizootic was short-lived, and by summer all traces of the virus had disappeared (see PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl).

 The virus was still not able to maintain itself long-term in wild and migratory birds. 

The following year, another reassortment occurred in Russia (see EID Journal: Reassorted HPAI H5N8 Clade 2.3.4.4. - Germany 2016), which led to the unprecedented 2016-2017 epizootic in Europe, one which saw numerous subtypes (H5N8, H5N5, H5N2, H5N9, etc.) emerge, and an increased host range among avian species. 

Additional reassortments, several new subclades (e.g. 2.3.4.4b), and the emergence of competing subtypes (H5N6 then H5N1) would appear over the next 3 years, with the virus gaining new abilities to infect - and persist - in a growing number of bird species. 

In 2017, the virus pushed south through Central Africa, reaching the Southern Hemisphere for the first time. 

In 2020, H5N1 would re-emerge, and in 2021 the virus would make another great leap - crossing the North Atlantic and arriving first in Eastern Canada - then spreading rapidly across North America, arriving in South America the following fall. 

The H5 virus continues to expand its avian host range (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK), as well as branching out into many more mammalian species (e.g. cattle, sheep, goats, rodents, cats, etc.). 

Today, the H5 has made it to every continent except Australia, and many scientists fear that conquest is only a matter of time (see Australia : Biodiversity Council Webinar on HPAI H5 Avian Flu Threat).

Like a snowball rolling down a mountainside, H5N1 is gaining both mass and momentum. Where that leads is unknowable, but the H5 virus we face today is not your father's avian influenza. 

All of which brings us to an excellent research article, published in GeoHealth, which looks at this decades-long evolution of the HPAI H5 virus, and how its spread by wild and migratory birds has changed over the years.  

The full open-access report is very much worth reading in its entirety. You'll find the link, some excepts, and a link to a press release below. 

A Geospatial Perspective Toward the Role of Wild Bird Migrations and Global Poultry Trade in the Spread of Highly Pathogenic Avian Influenza H5N1

Mehak Jindal, Haley Stone, Samsung Lim, C. Raina MacIntyre
First published: 25 March 2025
https://doi.org/10.1029/2024GH001296

Abstract

This study presents the interplay between wild bird migrations and global poultry trade in the unprecedented spread of highly pathogenic avian influenza, particularly the H5N1 clade 2.3.4.4b strain, across the world and diverse ecosystems from 2020 to 2023. We theorized the role of migratory birds in spreading pathogens as various wild bird species traverse major flyways between the northern and southern hemispheres.

Simultaneously, we analyzed the global poultry trade data to assess its role in H5N1's anthropogenic spread, highlighting how human economic activities intersect with natural avian behaviors in disease dynamics. Lastly, we conducted spatial hotspot analysis to identify areas of significant clustering of H5N1 outbreak points over different bird families from 2003 to 2023.

This approach provides a strong framework for identifying specific regions at higher risk for H5N1 outbreaks and upon which to further evaluate these patterns with targeted intervention studies and research into what is driving these patterns. Our findings indicate that both the poultry sector and wild bird migrations significantly contribute to global H5N1 transmission, which helps better understanding of H5N1 transmission mechanisms when combined with ecological, epidemiological, and socio-economic perspectives. The results are intended to inform policy-making and strategic planning in wildlife conservation and the poultry trade to improve public health and animal welfare globally.

Key Points

• We investigated the role of wild bird migration in the inter-continental spread of avian influenza on a global scale

• We analyzed the global poultry trade data to highlight how human economic activities intersect with disease dynamics

• Our findings indicate that both the poultry sector and wild bird migrations significantly contribute to avian influenza transmission

Plain Language Summary

The unprecedented scale and simultaneous infection of avian influenza across multiple species raise concerns about the potential threats to human health, especially in the upcoming years, if not months. The looming increase in bird migrations to the south adds a layer of complexity and urgency to the situation. As we navigate this evolving landscape, it becomes imperative to closely monitor and comprehend the altered dynamics of the virus to implement effective strategies for mitigating the risks associated with human infections.

In this study, we tracked the movement of some wild birds according to their seasonal migration along with the incidence of avian influenza. While the spread patterns revealed that the avian influenza had started in Asian countries, it is not clear how it spread from Asia to Europe because, with the birds we analyzed, it was unable to find a flyway from Asia to Europe. 

However, every spread after the first incidence of avian influenza in Europe can be correlated with the seasonal migration of birds from one country to the other. Europe to Greenland to North America to South America can be established with different wild birds along with the spread from Europe to Africa.

(SNIP)

Analysis from 2005 to 2023 indicated a cyclic occurrence of the H5N1 every 5 years. However, a noteworthy deviation from this established pattern has become apparent in the latest outbreak since 2020. The ecological dynamics of the virus seem to have undergone a significant shift, manifesting in an unprecedented surge in cases compared to previous outbreaks. What distinguishes this event is the simultaneous and extensive infection of poultry, birds, and mammals during the same season—a phenomenon not witnessed in prior instances.

(Continue . . . )

New carrier birds brought avian flu to Europe and the Americas

Unexpected wild bird species, from pelicans to peregrine falcons, are transporting the virus from poultry to new places around the world and changing where the risk of outbreaks is highest

25 March 2025

         (Excerpt)

Far more bird species than ducks, geese and swans are transporting highly pathogenic H5N1 today, the study found. Cormorants, pelicans, buzzards, vultures, hawks, and peregrine falcons play significant roles in spreading avian flu. That makes them both victims and vectors of the disease and upends traditional approaches to monitoring H5N1 spread and predicting and responding to outbreaks. Culling of poultry birds worked in the past to mitigate burgeoning outbreaks, but it has failed to stop the current outbreak.

“We’ve got to think beyond ducks, geese and swans,” MacIntyre said. “They’re still important, but we have to start looking closely at these other species and other routes and think about what new risks that brings.”

Monitoring wild birds at a global scale is very difficult, so managing poultry bird populations is all the more important, she said. “We can do more about factors in our control — agriculture and farming.” Free-range birds, for instance, are more likely to contact wild birds, so managing them requires more vigilance. And pigs are “an ideal genetic mixing vessel” for viruses, so keeping pigs and poultry in close proximity is dangerous, she said.

“It’s a global problem, and it requires global solutions,” MacIntyre said.

          (Continue . . . )

Experimental Infection of Rats with Influenza A Viruses: Implications for Murine Rodents in Influenza A Virus Ecology

Credit CDC

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Over the years the idea that rats and other rodents could be potential hosts for novel flu viruses has come up a number of times (see 2016's The role of rodents in avian influenza outbreaks in poultry farms: a review), but until recently there has been little evidence to back up those concerns. 

A 2019 study out of Boston found RT-PCR evidence of IAV (Influenza A Virus) in 11% of 163 Norway rats (Rattus norvegicus) trapped and swabbed (note: half came from paw swabs, which may indicate contamination rather than infection). 

But 10 months ago, the USDA reported the detection of rodents (the House Mouse) to their Mammalian Wildlife with H5N1 for the first time, and since then deer mice and black rats have been added as well. 

Today rodents make up 129 of the 574 mammals (22%) on that list, although very little has been released about the circumstances of their discovery.  

The USDA's list is far from exhaustive, since many states have reported zero - or only a few - infections. Reporting is often limited by animals dying in remote and difficult to access places, or by animals that survive the infection. 

But it also seems likely that some states are looking harder for cases than others. 

While the susceptibility of cats (both wild and domestic) to HPAI H5N1 has been long known (see 2015's HPAI H5: Catch As Cats Can), the role that rodents may play in its ecology is less well understood. 

Two recent studies of note, however, include:

• Last August, in Pathogens: Susceptibility of Synanthropic Rodents to H5N1 Subtype HPAI Viruses, we looked at a study where researchers challenged several rodent species (house mice, brown rat, black rat) with two (older 2010, 2007) HPAI H5N1 viruses, and found they are both susceptible to the virus and could potentially play a role it its evolution and spread.

• Also in August 2024, in Emer. Microbe & Inf.: HPAI Virus H5N1 clade 2.3.4.4b in Wild Rats in Egypt during 2023, we a surprisingly high percentage of wild rats testing positive for H5 antibodies in Egypt, suggesting that some number may survive the infection. 

In addition to rodents, we've recently seen a number of studies showing that shrews, voles, and other small (often peridomestic) mammals are susceptible to novel flu (see Virology: Susceptibilities & Viral Shedding of Peridomestic Wildlife Infected with Clade 2.3.4.4b HPAI Virus (H5N1)) 

Last summer, in  Nature: Decoding the RNA Viromes in Shrew Lungs Along the Eastern Coast of China, we looked at a study that found a wide range of zoonotic viruses - including HPAI H5N6 - in shrews. Previously, in 2015's Taking HPAI To The Bank (Vole), we looked at that species' susceptibility to both H5N1 and H7N1.

Today we have a study which looks at the experimental infection of Sprague-Dawley rats with a variety of IAV subtypes, including H5Nx, H7N9, H9N2, H10N8 and the 2009 pandemic H1N1 (see chart below).  Not included: The North American Clade 2.3.4.4b H5N1 Virus.

Somewhat surprisingly, despite all of the viruses causing significant lung injury, none of the rats succumbed to the virus.  A trait that may enable rats to stealthily carry, and transmit, some strains of IAV (including H5N1).  

I've only included the link, Abstract, and a few excerpts from this study. Follow the link to read it in its entirety.  I'll have a postscript when you return.

Experimental Infection of Rats with Influenza A Viruses: Implications for Murine Rodents in Influenza A Virus Ecology

by 

Long Li

 1,

Rirong Chen

 1,

Zhigang Yan

 1,

Qinglong Cai

 1,

Yi Guan

 1,2,* and

Huachen Zhu

 1,2,*

Viruses 2025, 17(4), 495; https://doi.org/10.3390/v17040495 (registering DOI)

Submission received: 28 February 2025 / Revised: 25 March 2025 / Accepted: 27 March 2025 / Published: 29 March 2025

Abstract

Rattus norvegicus (brown rat), a widely distributed rodent and common biomedical model, is a known reservoir for many zoonotic pathogens but has not been traditionally recognized as a host for influenza A virus (IAV).

To evaluate their susceptibility, we intranasally inoculated Sprague-Dawley rats with various IAV subtypes, including H5Nx, H7N9, H9N2, H10N8 and the 2009 pandemic H1N1.

All strains productively infected the rats, inducing seroconversion without overt clinical signs. While replication efficiency varied, all viruses caused significant lung injury with a preferential tropism for the upper respiratory tract.

Investigation of receptor distribution revealed a predominance of α2,3-linked sialic acid (SA) in the nasal turbinates and trachea, whereas α2,6-linked SA was more abundant in the lungs. Notably, both receptor types coexisted throughout the respiratory tract, aligning with the observed tissue-specific replication patterns and broad viral infectivity.

These findings demonstrate that rats are permissive hosts for multiple IAV subtypes, challenging their exclusion from IAV ecology. The asymptomatic yet pathogenic nature of infection, combined with the global synanthropy of rats, underscores their potential role as cryptic reservoirs in viral maintenance and transmission. This study highlights the need for expanded surveillance of rodents in influenza ecology to mitigate zoonotic risks.

(SNIP)

Discussion

The role of rats and other rodents in influenza ecology remains understudied and controversial. This study provides compelling experimental evidence that SD rats, a representative model of the Rattus species, are susceptible to productive infection by diverse subtypes of contemporary IAVs that pose significant threats to both public health and agriculture. These include avian HPAI H5Nx (clades 1.0 and 2.3.4.4a, b, e, g, both human and avian isolates), H7N9 (HPAI and LPAI), H9N2, H10N8, and the mammalian-adapted pandemic 2009 H1N1 viruses (Table 1). 

Notably, these infections occurred without prior viral adaptation, challenging the conventional assumptions that rats are generally insusceptible and not natural hosts of IAV. Our findings, together with previous reports [11,12,13,14,15,16,17,37,38,39,40], underscore the need to reevaluate rodents as potential reservoirs, mechanical vectors, or bridging hosts in the zoonotic transmission of IAVs. 

The absence of overt clinical signs, despite robust viral replication, seroconversion, and histopathological evidence of lung injury (Figure 1, Figure 2, Figure 3, Figure 4 and Figure 5), positions rats as cryptic carriers capable of sustaining IAV infections undetected in natural settings.

A striking feature of IAV-infected SD rats is the dissociation between their subclinical manifestations and significant virological and immunological findings. Unlike mice and ferrets, which develop observable disease or mortality following experimental IAV challenge [32,33], rats exhibited only a statistically insignificant lower rate of weight gain compared to the control group (Figure 1) and no influenza-like symptoms, even when infected with HPAI H5 or H7N9 strains.

This asymptomatic phenotype resembles that of wild waterfowl, the natural reservoirs of IAV [4,5]. The absence of disease presentation and the induction of seroconversion in most rats suggests that rats may use effective immune mechanisms to limit systemic viral spread while allowing local replication in the upper respiratory tract (this study and [19,20,37]). This balance may facilitate viral infection without compromising host survival, positioning rats as potential stealth vectors in ecosystems where they interact with domestic animals, wildlife, and humans.

          (SNIP)

Conclusions

This study redefines Rattus norvegicus as a permissive host for multiple IAV subtypes prevalent in birds or humans and highlights its ability to sustain subclinical infections with potential ecological consequences. The convergence of broad viral susceptibility, synanthropic behavior, and dual SA receptor expression in the respiratory tracts positions rats as underrecognized players in influenza ecology.

While their role as “mixing vessels” remains speculative, the risk of environmental virus amplification and spillover to domestic animals or humans cannot be dismissed. Strengthening surveillance in rodent populations and integrating rats into One Health frameworks will be essential for mitigating zoonotic threats in an era of escalating avian influenza activity.

          (Continue . . .)

Not so very long ago, HPAI H5 was regarded ass pretty much just an avian virus, with occasional spillovers to humans, or to cats unlucky enough to be fed a diet of raw chicken. But 2021 - following a series of reassortment events - we began to see reports of numerous spillovers into a much wider range of mammals (see graphic below).

Credit ECDC/EFSA

While surveillance, testing, and reporting of infected mammals remains severely (some would say, criminally) limited, the growing global impact of HPAI H5 on our shared environment these past few years is unmistakable (see  Nature Reviews: The Threat of Avian Influenza H5N1 Looms Over Global Biodiversity).

As the HPAI H5 virus continues to find new mammalian hosts it only increases the chances that it will find new evolutionary pathways that were unavailable to it when it was primarily a disease of birds. 

  

Where that leads us in anyone's guess, but the more entrenched the virus becomes in the environment, the fewer our options will become to deal with it. 

NPJ Vaccines: Modeling the Impact of Early Vaccination in an Influenza Pandemic in the United States

 

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Although there are no guarantees that avian H5N1 will spark the next pandemic, it is a pretty good bet that the next pandemic will be caused by a novel `flu-like' virus (with influenza and coronaviruses being at the top of that list).  

While once thought of as a `once-in-a-generation' event, in my lifetime I've already experienced 4 legitimate pandemics (1957, 1968, 2009, 2020), 2 pseudo-pandemics (1977, 2003), and one `near-miss ' (1976).

Given recent trends (see PNAS Research: Intensity and Frequency of Extreme Novel Epidemics) - even at my age - it is entirely possible I'll see another.  While it is unknown what the next pandemic will look like, it is likely we'll go into it without a vaccine and with relatively few therapeutic options. 

Recent studies looking at avian H5 have raised concerns over the effectiveness of current antivirals, and there are a great many barriers to rapidly producing, and distributing, a novel flu vaccine. 

As Maggie Fox explained last year in SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1, our options during the opening months of any pandemic will be limited. Unpopular as they might be, NPIs (non-pharmaceutical interventions like masks, social distancing, etc.) will once again become our first line of defense. 

The rub with any new vaccine is that they tend to arrive late into a pandemic, after most people have already been exposed.  They can certainly be useful for dealing with a `second wave', but they are unlikely to blunt the impact of the opening months.

It might be possible to shave weeks, or even months, off the delivery time of a pandemic vaccine if an older CVV (Candidate Vaccine Virus) were used instead waiting to isolate a new strain, but it might prove far less effective.  

Which brings us the question: is it better to have a less-well-matched vaccine earlier (at 3 months), or wait (6 months or more) for a well-matched vaccine?

It is not an easy question to answer, because there are so many unknown variables.  As the old saying goes, `If you've seen one pandemic . . . . you've seen one pandemic'.  The speed of transmission (R0), its place of origin, its virulence (CFR and Attack Rate), and even its impact on different age groups, all change the outcome. 

We've a study today that attempts to model the impact of early vs. late vaccination in a variety of pandemic scenarios, juggling virulence (moderate or severe), and vaccine effectiveness (high, moderate, or  low), in order to try to quantify the probable benefits. 

In order to keep all of this manageable the authors had to make a number of assumptions that may, or may not, hold true in the next pandemic; an origin in the Southern Hemisphere, a greater impact on older patients, and a single wave, etc.   

While the full report is well worth reading in its entirety, the take-away is that it is better to have a less-well-matched vaccine available early, than a well-matched vaccine late.  Follow the link to read the full report.  

I'll have a postscript when you return.

Modeling the impact of early vaccination in an influenza pandemic in the United States

Van Hung Nguyen, Pascal Crépey, B. Adam Williams, Verna L. Welch, Jean Marie Pivette, Charles H. Jones & Jane M. True

npj Vaccines volume 10, Article number: 62 (2025) Cite this article

Abstract


We modeled the impact of initiating one-dose influenza vaccination at 3 months vs 6 months after declaration of a pandemic over a 1-year timeframe in the US population. Three vaccine effectiveness (VE) and two pandemic severity levels were considered, using an epidemic curve based on typical seasonal influenza epidemics.

Vaccination from 3 months with a high, moderate, or low effectiveness vaccine would prevent ~95%, 84%, or 38% deaths post-vaccination, respectively, compared with 21%, 18%, and 8%, respectively following vaccination at 6 months, irrespective of pandemic severity.

While the pandemic curve would not be flattened from vaccination from 6 months, a moderate/high effectiveness vaccine could flatten the curve if administered from 3 months.

Overall, speed of initiating a vaccination campaign is more important than VE in reducing the health impacts of an influenza pandemic. Preparedness strategies may be able to minimize future pandemic impacts by prioritizing rapid vaccine roll-out.

          (SNIP)

Discussion

Our analysis shows that the speed of vaccination is key to reducing the impact of an influenza pandemic. Even with a low effectiveness vaccine, initiating vaccination 3 months after the declaration of a pandemic would lower the disease burden compared with initiating a higher effectiveness vaccine at 6 months, with 23–94% incremental benefits across health outcomes and VEs.

While moderately and highly effective vaccines could flatten the pandemic curve if administered from 3 months, none of the scenarios evaluated could flatten the curve if administered from 6 months. Acute and ICU bed availability would also be less constrained under the early vaccination scenario, particularly with higher effectiveness vaccines, but administration of a vaccine at 6 months would not be able to prevent a surge in demand above bed availability thresholds in a severe pandemic, irrespective of VE.

          (SNIP)

In summary, our analysis has demonstrated the importance of rapid initiation of mass vaccination during a future influenza pandemic, with speed of vaccination playing a more important role than VE on population-level health outcomes.

Preparedness exercises such as stockpiling potential pre-pandemic vaccines, as well as pre-emptive collection of data from newer vaccine manufacturing platforms, such as mRNA vaccines, will be paramount for ensuring a rapid and effective response in a future influenza pandemic.

          (Continue . . . )

This study uses a lot of epidemiological assumptions, which may (or may not) be a good fit for the next pandemic.  Much will also depend upon how society reacts to the next pandemic.  

• Will lockdowns be tolerated, or will people refuse masks and social distancing?   

• Assuming a vaccine could be produced in quantity in 3 months, would large segments of the public actually embrace it?  How much extra resistance against an mRNA vaccine? 

• How much tolerance would the public have for (real or imagined) vaccine side effects, particularly in a low VE jab?  

While I'm not particularly hopeful that an emergency vaccine of any VE can be produced and deployed within the first 3 months of a novel pandemic - in the event of a severe disease - this study strongly suggests that the earlier that can happen, the better. 

Avian Flu: What Goes Around, Comes Around (Twice Each Year)

 

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A decade ago, some experts were still bitterly divided over the impact of  migratory birds on the spread of avian flu (see 2014's Bird Flu Spread: The Flyway Or The Highway?).  Many conservationists had long insisted  that `sick birds don't fly', and that it was illicit poultry trade that was driving the spread of the virus. 

A 2015 statement by UN CMS/FAO Co-Convened Scientific Task Force on Avian Influenza and Wild Birds maintained that `. . .  typically the spread of HPAI virus is via contaminated poultry, poultry products and inanimate objects although wild birds may also play a role.'

While the poultry industry undoubtedly contributed to the local spread of the virus, after the H5N8 virus crossed the Pacific in late 2014 and sparked a major North American Epizootic (see map below), the role of migratory birds became much harder to ignore.

But curiously, this epizootic caused relatively few wild bird deaths, and completely disappeared over the summer of 2015.  A year later, in PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl, Robert Webster et al. reported that migratory birds were not a good `long-term' reservoir host for HPAI viruses. 

While could be infected, and spread HPAI H5 across long distances, their pre-existing immunity prevented long-term carriage of the virus. 

But since 2015 HPAI H5Nx viruses (both in Asia and Europe) have undergone numerous evolutionary changes, morphing from H5N8, to H5N6, and more recently to H5N1 and H5N5 subtypes.  A 2016 reassortment event  in Russia led to Europe's record setting H5 epizootic of 2016-2017, which also featured unusual mortality in wild birds.  

And unlike in North America in 2015, while avian flu reports decreased sharply over the summer of 2017 in Europe, the virus never completely disappeared.  A trend which has only increased in the years since (see Ain't No Cure For the Summer Bird Flu).

Over time H5 viruses have become better suited for carriage by migratory birds, have greatly increased their avian host range (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK), and have shown a greater affinity for infecting mammals.

Over the past decade these changes have enabled the virus to spread globally, crossing both the Atlantic and Pacific Oceans repeatedly (see Multiple Introductions of H5 HPAI Viruses into Canada Via both East Asia-Australasia/Pacific & Atlantic Flyways).

With their newfound persistence, these viruses are carried north each spring to the high latitude roosting areas of migratory birds (mostly above the Arctic Circle) where they are shared by hundreds of species - and can potentially reassort - before heading south once again in the fall. 

We looked at this twice yearly migratory cycle in 2016's Sci Repts.: Southward Autumn Migration Of Waterfowl Facilitates Transmission Of HPAI H5N1.  In North America more than 200 bird species spend their summers in the Alaskan Arctic Refuge, and then funnel south each fall via 4 distinct North American Flyways (see map below).

Complicating matters, the roosting areas in Alaska are also overlapped by the East Asian flyway, which may allow birds from Siberia and Mongolia to intermix with native migratory bird population (see USGS: Alaska - A Hotspot For Eurasian Avian Flu Introductions).

Albeit on a smaller scale, a mirror-image of this occurs in the Southern Hemisphere as well.  A process that may eventually bring HPAI H5 to Australia/NZ by way of Antarctica (see Australia : Biodiversity Council Webinar on HPAI H5 Avian Flu Threat).

Over the next two months the spring northbound migration of wild birds will peak across the United States (see map at top of blog), during which time, we may see another increase in spillovers.  This week the Washington State Department of Agriculture has published a lengthy and informative blog on the topic (see below).

I've only posted the link, and a few excerpts.  Follow the link to read it in its entirety.  I'll have more after you return. 

Clearing the air — What to know about avian influenza and spring bird migration

As spring bird migration brings thousands of birds to Washington state, it also increases the risk of avian influenza (bird flu) spreading through the region. Migratory waterfowl like ducks, geese, and swans, can carry the virus without showing symptoms and can introduce it to local wildlife. This migration typically peaks from March to May, when birds traveling along the Pacific Flyway stop to rest and feed in Washington’s wetlands and coastal areas.

In this blog, we’ll explore how migrating waterfowl spreads avian influenza, what exactly it is, where it came from, symptoms to watch for, preventive measures you can take, and what to do if you suspect your animals have the virus.

          (Continue . . . )

While the focus is on the next couple of months - after which we will hopefully have a few months respite - the reality is the virus continues to expand both its geographic and host ranges, and with that comes increased genetic diversity.

In North America alone, more than 100 genotypes have been identified over the past 3 years, with new ones fully expected to emerge over time.  Over the past year, four new reassortments of note have emerged:

• B3.13 aka the `bovine' strain affecting dairy cattle in at least 16 states and infecting dozens of humans
• D1.1   a wild bird/poultry strain which has spilled over into > a dozen people in Washington State and a teenager in British Columbia
• D1.2  a wild bird/poultry strain which recently detected in poultry and 2 pigs in Oregon

• D1.3  a recently detected wild bird/poultry strain which has been infection poultry and at least 1 human

While we can't predict what kind of changes may occur in the HPAI H5 virus over the summer - or during the Southern Hemisphere's winter - history suggests that we can expect some surprises when the virus returns next fall.   

A perilous pattern that we can expect to be repeated twice yearly, ad nauseum, for the foreseeable future. 

Cell: Early-warning Signals and the Role of H9N2 in the Spillover of Avian Influenza Viruses

 

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While H9N2 may not be at the very top of our pandemic threats list, this LPAI virus is viewed by many as an important and influential player in the avian flu world. 

• H9N2 has become widespread - even ubiquitous - among poultry across Asia, Europe. the Middle East, and more recently Africa (see Viruses: Genetic Evolution of Avian Influenza A (H9N2) Viruses in Uganda & Evidence of Mammalian Adaptation)

• Serological studies suggest human infection may be far more common than standard surveillance (see FluTrackers List) would suggest (see HK CHP: Mainland China Reports 2 More H9N2 Cases)

• H9N2 reassorts easily with other viruses, and its internal genes are often found inside many avian and swine viruses (including H5N1, H5N6, and H7N9) -  (see EID Journal: Natural Reassortment of EA H1N1 and Avian H9N2 Influenza Viruses in Pigs, China)

• H9N2 viruses continue to accrue evolutionary changes, which include mammalian adaptations, and increased binding to human receptor cells (see PLoS Path: Genetics, Receptor Binding, and Transmissibility Of Avian H9N2).
• Control of H9N2 has been difficult, as the virus continues to mutate, and many countries continue to use outdated and ineffectual vaccines (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China), some of which may be driving its evolution.

While  H9N2 is not considered a `reportable' disease by WOAH (formerly the OIE), the CDC has 2 different lineages (A(H9N2) G1 and A(H9N2) Y280) on their short list of influenza viruses with pandemic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed.

But H9N2's biggest threat may come its ability to reassort with other, potentially more virulent, subtypes. 

Its internal genes have often been found inside many HPAI viruses (including H5N1, H5N6, H7N9, and most recently zoonotic H3N8) - (see last January's Transboundary & Emerging Dis.: The H5N6 Virus Containing Internal Genes From H9N2 Exhibits Enhanced Pathogenicity and Transmissibility).

   

H9N2 is such a versatile virus, it has even been detected in Egyptian Fruit bats (see Preprint: The Bat-borne Influenza A Virus H9N2 Exhibits a Set of Unexpected Pre-pandemic Features).

Seven years ago, in EID Journal: Two H9N2 Studies Of Note, we looked at two reports which warned that H9N2 continues to evolve away from current (pre-pandemic and poultry) vaccines and is potentially on a path towards better adaptation to human hosts.

All of which serves as prelude to an article, published this week in Cell, which examines H9N2's role in facilitating the spillover of avian flu viruses to humans.   This is a lengthy, and detailed report, and I've only posted some brief excerpts.  

Follow the link to read it in its entirety. I'll have a bit more after the break. 

Article Online now 100639 March 25, 2025 Open access

Early-warning signals and the role of H9N2 in the spillover of avian influenza viruses

Yan-He Wang1,2,12 ∙ Jin-Jin Chen1,3,12 ∙ Jun Ma1,4,12∙ … ∙ Yan-Song Sun1 sunys6443@126.com ∙ Wei Liu1,7 liuwei@bmi.ac.cn ∙ Li-Qun Fang1,4,7,13 fang_lq@163.com… Show more Context and significance

Highlights

Wang et al. provided valuable insights into the epidemiological patterns of avian influenza virus (AIV) spillover and the role of H9N2 in the process. Their analysis highlighted the significant contribution of the internal genes (INGEs) from 12 key strains of H9N2 in facilitating human adaptability by reducing the species barrier between poultry and humans, essentially acting as internal genetic donors for AIV spillover.

Due to its low pathogenicity, H9N2 has been neglected in poultry vaccination programs, leading to a lack of vaccines specifically targeting the INGEs of these 12 key strains. Their findings suggest that reducing the prevalence of H9N2 is fundamental to mitigating AIV spillover risks.

• H9N2 exerts a promoting effect on the spillover of avian influenza viruses (AIVs)

• Expansion of AIV spatial and host ranges reveals an emerging risk of its spillover

• Prevalence of AIVs in human-contacted hosts reveals a re-emergence risk in humans

Summary

Background

The spillover of avian influenza viruses (AIVs) presents a significant global public health threat, leading to unpredictable and recurring pandemics. Current pandemic assessment tools suffer from deficiencies in terms of timeliness, capability for automation, and ability to generate risk estimates for multiple subtypes in the absence of documented human cases.

Methods

To address these challenges, we created an integrated database encompassing global AIV-related data from 1981 to 2022. This database enabled us to estimate the rapid expansion of spatial range and host diversity for specific AIV subtypes, alongside their increasing prevalence in hosts that have close contact with humans. These factors were used as early-warning signals for potential AIV spillover. We analyzed spillover patterns of AIVs using machine learning models, spatial Durbin models, and phylogenetic analysis.

Findings

Our results indicate a high potential for future spillover by subtypes H3N1, H4N6, H5N2, H5N3, H6N2, and H11N9. Additionally, we identified a significant risk for re-emergence by subtypes H5N1, H5N6, H5N8, and H9N2. Furthermore, our analysis highlighted 12 key strains of H9N2 as internal genetic donors for human adaptation in AIVs, demonstrating the crucial role of H9N2 in facilitating AIV spillover.

Conclusions

These findings provide a foundation for rapidly identifying high-risk subtypes, thus optimizing resource allocation in vaccine manufacture. They also underscore the potential significance of reducing the prevalence of H9N2 as a complementary strategy to mitigate chances of AIV spillovers.

(SNIP)

The H9N2 virus has been prevalent in poultry for an extended period. Despite its low pathogenicity and case fatality rate,10,34 our data show that it plays a crucial role in the spillover of AIVs within local and surrounding areas.

Moreover, H9N2 viruses contributed to recombination events involving eight AIV subtypes that recently spilled over into humans by providing their six INGEs to these viruses. This suggests that H9N2 facilitates the generation of human adaptivity by reducing the species barrier between poultry and humans.57,58

These findings highlight that reducing the prevalence of H9N2 could potentially mitigate the spillover of AIVs, serving as an alternative strategy for preventing individual subtypes such as H5N1, H5N6, and H7N9.

(Continue . . . )

While undoubtedly much older, LPAI H9N2 was first identified in Wisconsin poultry in 1966.  In the 1990s it swept across much of Eurasia, becoming `hyperendemic' in many affected countries (see 2019's Viruses: A Global Perspective on H9N2 Avian Influenza Virus).

Range Of Endemic H9N2 Viruses

While some attempts have been made at controlling the virus (including using largely ineffective vaccines) - since H9N2 produces relatively mild illness in poultry - it is often tolerated or ignored. 

Over the past 3 decades H9N2 has managed to spread across much of Asia, and into Europe, Africa and the Middle East. It has diverged into two distinct lineages, has increased its ability to  infect mammals, and it continues to fuel the emergence and spillover of new subtypes. 

It seems likely that unless and until H9N2 can be better controlled, our avian flu woes may extend far beyond just H5Nx in the years ahead.   

Virology: Detection of Antibodies Against Influenza A Viruses in Cattle

 

#18,393

A year ago today, in the wake of the surprise announcement of the first detection of H5N1 in dairy cows in Texas and Kansas, I wrote A Brief History Of Influenza A In Cattle/Ruminants, where we looked at a number of past papers on both influenza and influenza-like illnesses in cattle and goats.

In some cases, viruses were identified, while in other cases they were not. So, while the detection of H5 in cattle may have been unexpected, it wasn't entirely without precedents. 

Since then, HPAI H5 has turned up in hundreds of cattle herds, along with sporadic spillovers into goats, alpacas, pigs, and most recently a sheep in the UK.  Quite frankly, the more we look, the more we find that H5 in livestock is more common than we knew. 

All of which brings us to a new study, published this week in Virology, which looks for IAV antibodies in United States cattle in the year prior to the discovery of H5N1 in dairy cows.  And once again, we find that evidence of (non-H5) IAV infection was common across a wide sampling of serum samples taken in 2023 and early 2024. 

Of particular note, this study found that IAV infection isn't limited to lactating dairy cows.  Male cattle (bulls and steers) were just as likely to carry antibodies to IAV as cows and heifers.

For the past year, we've seen a continued reluctance to test beef cattle for H5N1, using the rationale that cattle are generally not susceptible to IAV infection, and H5 has a special affinity for lactating cows. 

Since beef cattle are only rarely tested, they maintain their `clean record', and are therefore not considered `high risk. Essentially the same reasoning that delayed the testing of dairy cattle for H5N1 for several months in early 2024, which probably gave the virus more time to spread. 

Today's report is well worth reading in its entirety, as it raises serious questions about how widespread IAV infection truly is in bovine species, and should inspire even greater scrutiny of other livestock species (both here in the United States, and around the globe). 

Detection of antibodies against influenza A viruses in cattle

Authors: Yuekun Lang, Lei Shi, Sawrab Roy, Dipali Gupta, Chao Dai, Muhammad Afnan Khalid, Michael Z. Zhang, Shuping Zhang, Xiu-Feng Wan, Richard Webby, Wenjun Ma wma@missouri.eduAuthors Info & Affiliations

https://doi.org/10.1128/jvi.02138-24

ABSTRACT

Unexpected outbreaks caused by the H5N1 highly pathogenic avian influenza virus (HPAIV) in dairy cows in the United States (US) have raised significant veterinary and public health concerns. When and how the H5N1 HPAIV was introduced into dairy cows and the broader epidemiology of influenza A virus (IAV) infections in cattle in the US remain unclear.

Herein, we performed a retrospective study to screen more than 1,700 cattle serum samples collected from different bovine breeds in the US from January 2023 to May 2024 using an enzyme-linked immunosorbent assay (ELISA) targeting the nucleoprotein (NP) to detect IAV infections, and the positive samples were further tested by hemagglutination inhibition (HI) assay. 

Results showed that 586 of 1,724 samples (33.99%) from 15 US states were seropositive by the NP ELISA assay, including 78 samples collected in 2024 and 508 samples collected in 2023. Moreover, the HI assay revealed that 45 of these ELISA-positive samples were positive to human seasonal H1N1 and H3N2 and swine H3N2 and H1N2 viruses, and some were positive to two or three tested IAVs. 

Surprisingly, none of these ELISA-positive samples were HI positive for the circulating bovine H5N1 strain. Our results demonstrate that IAVs other than H5N1 can infect cattle, infections are not limited to dairy cows, and that bovine infections with swine and human IAVs have occurred prior to the H5N1 outbreaks. All results highlight the value in monitoring IAV epidemiology in cattle, as the viruses might adapt to cattle and/or reassort with the currently circulating H5N1 HPAIV, increasing risk to humans.

IMPORTANCE

Influenza A virus (IAV) is an important zoonotic pathogen that can infect different species. Although cattle were not historically considered vulnerable to IAV infections, an unexpected outbreak caused by H5N1 highly pathogenic avian influenza virus in dairy cows in the United States (US) in early 2024 has raised significant concerns. When and how the virus was introduced into dairy cows and the wider impact of IAV infections in cattle in the US remain unclear. Our retrospective serological screen provided evidence of human and swine H1 and H3 IAV infections in different cattle breeds in addition to dairy cows, although no H5N1 infection was detected. Our results underline the necessity to monitor IAV epidemiology in cattle, as reassortment of IAVs from different species may occur in cattle, generating novel viruses that pose threats to public and animal health.

         (SNIP) 

We identified several serum samples that were HI-positive to both swine and human IAVs. Considering the potential cross-reaction between seasonal huH1N1 and swH1N2v and seasonal huH3N2 and cluster I swH3N2 viruses, we retested seasonal huH1N1 HI-positive samples against the swH1N2v and cluster I swH3N2 HI-positive samples against the seasonal huH3N2 virus and vice versa. The results confirmed that no cross HI titer was detected in these samples (Table S1), indicating that IAV dual or triple infections in cattle appear to be genuine. Notably, one sample was HI-positive to both cluster I swH3N2 and seasonal huH1N1 viruses, while another sample was positive for cluster I swH3N2, seasonal huH3N2 and huH1N1 viruses.

These findings indicate that co-infection with IAVs might occur in some individual cattle. Considering that the H5N1 HPAIV is circulating in dairy cattle herds (8) and cattle can be infected with human and swine IAVs, reassortment of IAVs from different species might happen in cattle (10), generating novel genotypes of H5Nx virus with pandemic potential or at least with increased ability for zoonotic transmission.

In summary, our retrospective serological study demonstrated that IAVs other than H5N1 HPAIV are able to infect different breeds of cattle regardless of their gender and age. Therefore, IAV infection in cattle is likely more complicated than recognized. It is necessary to monitor bovine IAV epidemiology through systematic influenza surveillance to prevent IAV adaptation and potential reassortment that would increase the threat to public health.

(Continue . . . )

While this new information should inspire a paradigm shift in the way we deal with IAV in livestock, we have a long history of denying potential health threats and of maintaining the status quo when facts are either inconvenient, expensive, or difficult to deal with. 

But at least with the help of this kind of research, we'll know why we failed.