Tuesday, March 17, 2026

Virol Sin.: Emergence of a Novel H4N6 Avian Influenza Virus with Mammalian Adaptation Isolated from Migratory Birds in Zhejiang Province, China, 2024

 

#19,087

There are two broad categories of avian influenza; LPAI (Low Pathogenic Avian Influenza) and HPAI (Highly Pathogenic Avian Influenza).

  • LPAI viruses are common in wild birds, cause little illness, and only rarely death. They are not considered to be a serious health to public health (LPAI H7N9  & LPAI H9N2 being notable exceptions)s. The concern is (particularly with H5 & H7 strains) that some LPAI viruses have the potential to mutate into HPAI strains.
  • HPAI viruses are more dangerous, can produce high morbidity and mortality in wild birds and poultry, and can sometimes infect humans with serious result. Again, H5 and H7 viruses are of greatest concern, but other subtypes have also caused human illness and large poultry losses. 
Until about 20 years ago there was no uniform requirement to report or track LPAI infections. That changed in 2006 when the OIE made reporting of LPAI H5 & H7 viruses mandatory.
While other LPAI subtypes are not currently reportable to WOAH (see Terrestrial Animal Code Article 10.4.1.), that doesn't make them entirely benign.

This non-reportable status has hampered responses to outbreaks (see Belgium: Non-Reportable LPAI H3N1 Outbreaks Continue (n=59)) in the past, and likely contributes to the silent proliferation of these viruses.

The biggest concern right now is LPAI H9N2, which has spread globally, continues to evolve, is largely resistant to existing vaccines, and spills over with relative ease to humans (see China's list (n=17) over last 6 months).

But over the past few years we've seen a growing number of scientific papers out of China describing the shift of many other LPAI viruses towards increased mammalian adaptation. A few (of many) include:

NPJ Vaccines: Impact of Inactivated Vaccine on Transmission and Evolution of H9N2 Avian Influenza Virus in Chickens

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

Vet. Research: Emergence of a Novel Reassortant H3N3 Avian Influenza Virus with Enhanced Pathogenicity and Transmissibility in Chickens in China

Transboundary & Emerg. Dis.: H3 Avian Influenza Virus Isolated from China in 2021–2022 Showed the Emerging H3N8 Posed a Threat to Human Health

Viruses: Genetic and Biological Characteristics of Duck-Origin H4N6 Avian Influenza Virus Isolated in China in 2022

Viruses: Wild Bird-Origin H6N2 Influenza Virus Acquires Enhanced Pathogenicity after Single Passage in Mice

While H9N2 and H3 viruses have captured the bulk of their attention, H4Nx viruses - which are ubiquitous in wild birds around the globe - have raised zoonotic concerns for years.

In 2012's in Seroprevalence Study: Avian Flu In Chinese Pigs, we looked at research that found low levels of H3, H4, and H6 subtypes of avian influenza in Chinese pigs while in 2015 we looked at reports of Avian H4N6 In Midwestern Swine.

Although human infection with H4 viruses are believed to be both mild and rare, a 2011 PLoS One study (Evidence of infection with H4 and H11 avian influenza viruses among Lebanese chicken growers) presented serological evidence suggesting that `. . .  H4 and H11 influenza viruses may possess the ability to cross the species barrier to infect humans.'

This was reinforced last May in Virology Journal: Emerging Zoonotic Potential of H4N1 Avian Influenza Virus: Enhanced Human Receptor Binding and Replication via Novel Mutations, which found - at least in the laboratory - the LPAI H4N1 virus was already surprisingly well adapted to infecting, and replicating within, mammalian hosts.

All of which brings us to a letter, published in Virologica Sinica this week, which describes the detection of a novel H4N6 virus which already appears unusually well adapted to mammals. 

I've only reproduced the highlights below. Follow the link to read it in its entirety.  I'll have a postscript after the break. 

Emergence of a novel H4N6 avian influenza virus with mammalian adaptation isolated from migratory birds in Zhejiang Province, China, 2024

Yongchun Yang a 1, Han Liu a 1, Yaling Li a 1, Lin Liu a, Tiantian Chen a, Jiahao Zhang ba
Received 30 April 2025, Accepted 11 March 2026, Available online 14 March 2026.
https://doi.org/10.1016/j.virs.2026.03.005 
Under a Creative Commons license 

HIGHLIGHTS: 
  • The H4N6/G030 strain, a novel H4N6 avian influenza virus (AIV), was isolated from a red-necked stint. 
  •  The H4N6/G030 is a novel cross-species reassortant derived from wild bird and poultry AIV lineages. 
  •  The H4N6/G030 can bind to both avian and mammalian-type sialic acid receptors, and replicate in both avian and mammalian cells and cause disease in animals.
  • High seroprevalence of H4N6 was observed on surveyed poultry farms nearby.
Dear Editor,

Avian influenza viruses (AIVs) continue to evolve at the interface of wild and domestic birds, posing ongoing threats to animal and public health (Bi et al., 2020; Uyeki et al., 2022). Wild migratory birds serve as natural reservoirs and facilitate viral gene exchange through long-distance migration, whereas dense poultry farming in East Asia creates opportunities for reassortment and spillover (Li et al., 2022; Verhagen et al., 2015).
Historically, H4-subtype AIVs have been considered low-pathogenic, yet recent detections in poultry and swine suggest an expanding host range and genetic plasticity (Li et al., 2024; Song et al., 2024; Parsons et al., 2023). In this study, we identified and characterized a novel reassortant H4N6 virus isolated from a red-necked stint (Calidris ruficollis) during surveillance in Zhejiang Province, China, in May 2024 and evaluated its molecular signatures associated with mammalian adaptation.

(SNIP)

The emergence of H4N6/G030 provides further evidence for active genetic reassortment at the wild-bird-poultry interface in China. Notably, although this virus is classified as a low pathogenic avian influenza virus (LPAIV), its dual receptor-binding affinity and efficient replication in mammalian cells represent a key step toward cross-species adaptation. This adaptive potential is well-established: previous studies show that single amino-acid changes in PB2 or HA can greatly enhance viral replication and transmissibility in mammals (Lin et al., 2024; Gao et al., 2019).
Given the recent reports of H5N1 infection in cats and dairy cattle in North America (Peacock et al., 2025), enhanced surveillance of LPAIVs such as H4 has become increasingly important. The replication of H4N6 in bovine cells observed in vitro indicates that cross-species exposure cannot be ignored. Therefore, this enhanced surveillance that integrates genomic analysis, serology and biosecurity is crucial to identify emerging strains with potential public-health implications.

In conclusion, we identified a novel H4N6 avian influenza virus from migratory birds, which exhibits mammalian adaptation markers, including dual receptor-binding affinity and a reassortant genome from wild-bird and poultry lineages. This, combined with the high seroprevalence in local chickens, compounds the risk and further highlights the urgent need for ongoing molecular and epidemiological surveillance along high-risk migratory flyways.

Lest we forget, two of the three influenza pandemics of the last century (H2N2 and H3N2) were caused by LPAI avian H2 and H3 viruses which appear to have emerged from Chinese poultry or wild birds and then reassorted with seasonal influenza.
While these non-reportable LPAI subtypes aren't officially regarded as being in the same league as H5 and H7 viruses - we continue to see studies suggesting we take these LPAI subtypes more seriously. 

Although I've no particular insight in what virus will spark the next pandemic, history has shown that LPAI viruses can be instigators or at least co-conspirators.  

And that alone ought to be enough to warrant heightened surveillance and research.

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