JID: HPAI H5N1 Subclade 2.3.4.4b Isolated from a European Grey Seal (Halichoerus grypus) is Highly Virulent in Ferrets

Gray Seals - Credit Wikipedia

#18,775

Up until 4 about years ago, HPAI H5N1 was considered mostly a disease of birds, with rare (but often serious) spillovers into humans, and very limited and/or sporadic detections in other mammals (primarily captive felines). 

The host range of H5N1 began to change in 2021-2022, with increased detections in foxes, skunks, and other carnivorous peridomestic mammals (see Ontario: CWHC Reports HPAI H5 Infection With Severe Neurological Signs In Wild Foxes (Vulpes vulpes)).

With these new mammalian host infections, we began to see signs of increased mammalian adaptions within the virus (amino acid changes, including HA-T143A, PB2-E627K,  PB2 D701N, PB2 Q591K, HA Q226L, etc.). 

A few examples:

Emerging Microbes & Inf.: Neurotropic HPAI H5N1 Viruses with Mammalian Adaptive Mutations in Free-living Mesocarnivores in Canada

Eurosurveillance: HPAI A(H5N1) Virus Infection in Foxes with PB2-M535I Novel Mammalian Adaptation - Northern Ireland, July 2023

Emerg. Microbes & Inf.: Marked Neurotropism and Potential Adaptation of H5N1 Clade 2.3.4.4.b Virus in Naturally Infected Domestic Cats

J. Gen. Virology: H5N1 2.3.4.4b: A Review of Mammalian Adaptations & Risk of Pandemic Emergence

Due to limited surveillance, testing, and reporting around the globe, we don't have a very good handle on how many different mammalian species have now been infected with clade 2.3.4.4b H5Nx. 

As the following FAO map (zoonotic avian flu reports since Oct 1, 2024) illustrates, semi-robust reporting of avian influenza is pretty much limited to the United States, Southern Canada, Europe, and some parts of Southeast Asia.

Vast swaths of Russia, China, South America, Africa and the Middle East rarely (if ever) report outbreaks, yet there is little doubt that (except for Australia/NZ) the virus is present in - at least in wild birds - most of countries of the world.

The USDA's list of Detections of Highly Pathogenic Avian Influenza in Mammals shows 46 different species, but this excludes livestock (cattle, pigs, goats, alpacas, mink, etc.) and is based primarily on passive surveillance of mostly peridomestic animals. 

The most recent ECDC/EFSA Avian influenza overview March - June 2025 lists more than 90 species (pgs. 28-32). But once again reporting and testing are limited.  

Identifying and tracking H5N1 in terrestrial animals is undoubtedly easier than in marine mammals, yet we've seen numerous reports of H5 infected pinnipeds (seals, sea lions, walruses), particularly from South America (see EID Journal: Mass Mortality of Sea Lions Caused by HPAI A(H5N1) Virus (Peru)).

In last January's Nature Reviews: The Threat of Avian Influenza H5N1 Looms Over Global Biodiversity the authors estimated the loss of hundreds of thousands of marine mammals (seals, sea lions, dolphins, etc.).

 

As the H5N1 virus expands its host range, it also gains access to alternative - and unpredictable - evolutionary pathways. While we focus primarily on HPAI in humans, dairy cows, poultry, and cats . . . we may very well be missing important milestones occurring in deer mice, camels, foxes, seals or other mammalian hosts.

All of which brings us to a study, published Saturday, in The Journal of Infectious Diseases by Guilfoyle et al. that finds that a newer HPAI H5N1 subclade 2.3.4.4b virus - isolated from a European grey seal in 2023 - is significantly more virulent in ferrets than is an older (2005) strain from Indonesia.

Researchers found that ferrets infected with the 2023 seal-derived H5N1 virus succumbed more rapidly than with the 2005 virus; exhibiting severe pneumonia, hypothermia, and histopathological changes in their respiratory tract and other organs. 

Aside from the increased pathogenicity (in ferrets) over the 2005 H5N1 strain, they report a couple of other notable findings.

• First, while fever is a common symptom in humans and ferrets infected with H5N1, ferrets infected with this seal-derived virus developed irreversible hypothermia prior to death. 
• Note: We saw reports of hypothermia in cats infected with H5N1 in Washington State earlier this year (link).
• In the past, mostly lab-infected mice have demonstrated hypothermia post H5N1 infection (see Animal Models for Influenza Research: Strengths and Weaknesses). 

• Second, this increased virulence occurred despite the absence of many of the amino acid changes (e.g. E627K, D701N, or S714R in the PB2 protein, and Q226L and G228S in the HA) known to promote mammalian adaptation.

I've posted the link, abstract, and some excerpts from this open access report.  Follow the link to read in its entirety.  I'll have a brief postscript after the break.

Highly Pathogenic Avian Influenza Virus A/H5N1 subclade 2.3.4.4 b isolated from a European grey seal (Halichoerus grypus) is highly virulent in ferrets  

Kate Guilfoyle , Monica Mirolo , Leon de Waal , Geert van Amerongen , Guido van der Net , Theresa Störk , Mara Sophie Lombardo , Wolfgang Baumgärtner , Ásgeir Bjarnason , Hekla Bryndís Jóhannsdóttir ... 

https://doi.org/10.1093/infdis/jiaf348

Published: 28 June 2025 

PDF

Abstract

Highly pathogenic avian influenza A viruses subtype H5N1 (HPAIV H5N1), subclade 2.3.4.4b infect multiple avian and mammalian species, posing a potential pandemic risk.

Here we describe the outcomes of infection of ferrets with a HPAIV H5N1 virus, isolated from a European grey seal in 2023, compared with an older HPAIV H5N1 (A/Indonesia/05/2005).

Overall, infection of ferrets with A/grey seal/Netherlands/302603/2023 caused more rapid mortality than infection of ferrets with A/Indonesia/05/2005. Animals developed severe pneumonia and irreversible hypothermia, associated with high levels of virus replication and histopathological changes in the respiratory tract and peripheral organs.

As animal models for severe avian influenza virus infections in humans play a key role in the development of intervention strategies against these infections, these findings highlight the importance of using 

       (SNIP)

It has been well documented in mammalian species that H5N1 viruses primarily infect the respiratory tract when inoculated intratracheally [17], yet lethal pathogenesis is also associated with virus replication in extra-respiratory organs [37].

In our study, ferrets infected with A/grey seal/NL/2023,displayed severe inflammation of liver and spleen that was characterised by a mild to moderate inflammation and diffuse areas of necrosis, with AIV NP antigen present in necrotic hepatocytes and splenocytes. Although virological analyses revealed slightly higher mean levels of replicating virus and RNA copies in the spleen of ferrets infected with A/grey seal/NL/2023 than in the ferrets infected with A/Indo/2005, these differences were not statistically significant.

Hypothermia and tachypnoea were detected prior to the death of three A/grey seal/NL/2023- infected ferrets.. In contrast, high yet stable body temperature and respiration rates were observed in ferrets infected with A/Indo/2005, corroborating previously published results in which all ferrets survived until at least 4 dpi with this virus [17,19, 23, 24].

In conclusion, our data show that intratracheal infection of ferrets with A/grey seal/NL/2023 causes accelerated mortality, as compared to intratracheal infection with A/Indonesia/05/2005. Collectively, our data supports the development and use of updated ferret models, to test preventive and therapeutic intervention strategies for human H5N1 infections. 

       (Continue . . . )
 

While ferrets are admittedly not a perfect analog for humans, they possess a remarkably human-like physiology and respiratory system, and are considered among the best small animal surrogates for influenza research. 

The fact that this 2023 seal-derived H5N1 virus is significantly more virulent in ferrets than the 2005 Indonesian strain is a concern.

It reminds us that just because the North American Bovine (B3.13 genotype) of H5N1 has produced mostly mild illness in humans, there are no guarantees that every strain that is brewing unseen in scores - perhaps hundreds - of new hosts around the world, will prove as benign.