ASM Spectrum: Characterization of H5N1 HPAI Virus Belonging to Clade 2.3.4.4b Isolated from Ezo Red Fox in Japan in a Mouse Model

Credit NIAID

#18,967

In May of 2024 we looked at plan by Japan's MOH To Stockpile 10 Million Doses of H5N1 Vaccine, enough to vaccinate about about 8% of their population.  

Over the past 2 decades more than 4 dozen H5Nx candidate vaccine viruses (CVVs) have been selected by WHO for development. 

Admittedly, many of these older CVVs are for viruses that no longer circulate in the wild, having been supplanted by newer versions.

In a follow-up report last April (see Japan: Updated HPAI H5 Risk Assessment & Pre-pandemic Vaccine Selection), we looked at Japan's decision to go with a locally detected H5N1 virus; a strain isolated from an infected fox with viral meningoencephalitis collected on Hokkaido in 2022.

What makes this choice interesting is this isolate did not carry the amino acid markers (PB2-E627K or PB2-D701N) that we typically associate with increased virulence and replication in mammals. 

Today's report, however, finds that even though lacking these `red flag' mutations -  this isolate produced high virulence and robust replication in mice - suggesting other gene factors may drive pathogenicity.

While the murine model has known limitations in influenza research, it can be useful; particularly in virulence studies (see Animal Models for Influenza Research: Strengths and Weaknesses). 

First, a link and some excerpts from the study, after which I'll return with a postscript. 

Characterization of H5N1 high pathogenicity avian influenza virus belonging to clade 2.3.4.4b isolated from Ezo red fox in Japan in a mouse model
Authors: Shintaro Shichinohe  Takahiro Hiono, Yasushi Itoh , Kosuke Takada, Yurie Kida, Pei Wang, Daisuke Motooka, Norikazu Isoda, Ayato Takada, Yoshihiro Sakoda , Tokiko Watanabe tokikow@biken.osaka-u.ac.jpAuthors Info & Affiliations
https://doi.org/10.1128/spectrum.01097-25

PDF/EPUB

ABSTRACT

H5N1 high pathogenicity avian influenza virus (HPAIV) has spread in wild birds and poultry worldwide. H5N1 HPAIV belonging to the currently predominant clade 2.3.4.4b has infected not only birds but also mammals (wild and domestic animals), with several human infections also being reported, raising concerns for public health.

 In 2022, a clade 2.3.4.4b H5N1 HPAIV strain, A/Ezo red fox/Hokkaido/1/2022 (H5N1; Fox/Hok/1/22), was isolated from an Ezo red fox (Vulpes vulpes schrencki) in Hokkaido, Japan; this was the first reported case of clade 2.3.4.4b H5N1 HPAIV isolation from a mammalian species in Japan. Several amino acid substitutions in the PB2 protein play an important role in the adaptation of avian influenza viruses to mammals, but Fox/Hok/1/22 PB2 does not have any of these well-known mammalian-adapting PB2 substitutions. 

Here, we investigated the biological properties of Fox/Hok/1/22 in a mouse model and found that this virus was highly virulent in mice and replicated well in multiple organs, including the lungs and brain. We then examined whether viruses isolated from these organs acquired known mammalian-adapting PB2 amino acid substitutions, such as PB2 E627K. 

Deep sequencing analysis of viral RNA from mouse brain and lungs revealed that virus with PB2-627E was predominant in three of four mice, whereas the PB2-627K substitution was predominant in one mouse. These results indicate that Fox/Hok/1/22 is highly virulent in mice despite lacking known PB2 substitutions involved in mammalian adaptation.

IMPORTANCE

The H5N1 avian influenza virus has caused severe disease in birds worldwide and is now spreading to mammals, including humans. In 2022, this virus was detected for the first time in an Ezo red fox in Japan. To understand its potential impact on mammals, we studied this virus in mice and found that it caused severe illness, spreading to multiple organs, including the lungs and brain. 

Surprisingly, despite lacking genetic mutations typically associated with mammalian adaptation, the virus was highly virulent in mice.

This finding suggests that the H5N1 virus may pose a greater threat to mammals, including humans, than previously thought. Given their continued spread among wild and domestic animals, our findings underscore the urgent need to monitor how recent H5N1 viruses behave in mammals.

        (SNIP)      

DISCUSSION

Clade 2.3.4.4b H5N1 HPAIV has caused tremendous damage worldwide, especially in poultry and wild birds, as well as many cases of infection in mammals, including carnivores, such as red foxes, in Asia, Europe, and the USA (1). It has been reported that foxes can be infected with H5N1 HPAIV by feeding on HPAIV-infected birds (14).

Previously, Hiono et al. isolated clade 2.3.4.4b H5N1 HPAIV (Fox/Hok/1/22) from a dead Ezo red fox in Hokkaido, Japan (10). This was the first clade 2.3.4.4b H5N1 HPAIV isolation from a mammal in Japan. Phylogenetic similarity between virus isolated from the fox and that from birds suggests that infection can be caused by fox predation on virus-infected birds (15). 

Here, we investigated the biological properties of Fox/Hok/1/22 in a mammalian model. We found that the MLD50 of Fox/Hok/1/22 was 100.5 PFU, and that Fox/Hok/1/22, like other H5N1 HPAIVs, grew in multiple organs, including the brain and respiratory tract of the virus-infected mice (Table 1). These results indicate that Fox/Hok/1/22 efficiently replicates and is highly virulent in the mouse model.

        (SNIP)

Although efficient transmission among humans has not yet occurred, further outbreaks in various wild mammals should be carefully monitored, and proactive measures should be taken to prevent and treat infections with these viruses.

        (Continue . . . )

This isn't the first time we've seen evidence that HPAI H5N1 can be virulent in mammals without these notorious PB2 mutations.  Eleven months ago, the CDC published  Genetic Sequences of Highly Pathogenic Avian Influenza A(H5N1) Viruses Identified in a Person in Louisiana (who later died), which found:

The genetic sequences of the A(H5N1) viruses from the patient in Louisiana did not have the PB2 E627K change or other changes in polymerase genes associated with adaptation to mammals and no evidence of low frequency changes at critical positions.

And, like other D1.1 genotype viruses found in birds, the sequences lack PB2 M631L, which is associated with viral adaptation to mammalian hosts, and which has been detected in >99% of dairy cow sequences but is only sporadically found in birds.  

Interestingly, the CDC also noted that the HA of this Louisiana isolate was closely aligned with the Ezo fox isolate discussed above. 

Overall, the hemagglutinin (HA) sequences from the two clinical specimens were closely related to HA sequences detected in other D1.1 genotype viruses, including viruses sequenced from samples collected in November and December 2024 in wild birds and poultry in Louisiana. The HA genes of these viruses also were closely related to the A/Ezo red fox/Hokkaido/1/2022 candidate vaccine virus (CVV) with 2 or 3 amino acid changes detected.  

These reports complicate matters, because they suggest we can't automatically assume that just because an HPAI virus doesn't carry these PB2 mutations, that it is guaranteed to be less of a public health threat. 

Preprint: Detection and Isolation of H5N1 clade 2.3.4.4b HPAI Virus from Ticks (Ornithodoros maritimus)

 

Slender-Billed Gull - Credit Wikipedia

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On the heels of yesterday's report on Flies as potential vectors for HPAI H5N1, we've a preprint which finds the first evidence of carriage of HPAI H5 in a soft tick (Ornithodoros maritimus); recovered from a naturally infected Slender-billed Gull from the south of France in 2023. 

While this report has the potential to launch a thousand clickbait headlines, it should be stressed that there is currently no evidence that ticks are a meaningful or efficient vector of the HPAI virus.  

That said, we know that some ticks can carry and transmit similar RNA viruses - including Thogotoviruses - like the Bourbon Virus found a decade ago in the American Midwest or the more recently discovered Oz Virus in Japan.  

In recent years, we've seen a growing interest in tickborne diseases, with new threats continuing to emerge (see Japan: Suspected Animal-to-Human Transmission of SFTS in Veterinarian's Death).  

From a tangentially related 2020 study (see Infestation of small seabirds by Ornithodoros maritimus ticks: Effects on chick body condition, reproduction and associated infectious agents) we learn:

Ticks are divided into two groups: hard ticks (Ixodidae) and soft ticks (Argasidae). Both families can potentially transmit numerous pathogens of medical and veterinary interest (Dietrich et al., 2011 and references therein). However, those transmitted by soft ticks have been less studied due to the specialization of Argasidae to hidden habitats (i.e. crevices) and the short time they spend for blood feeding on the host compared to hard ticks (Vial, 2009).

In today's preprint, researchers necropsied 5 laridae (seabirds), including 1 slender-billed gull, from which they extracted a soft tick larvae which they tested for the presence of HPAI H5 RNA.   

First they washed the `outside' of the tick, but no external virus was detected. Next, they `homogenized the larvae', and inoculated embryonic eggs, where subsequently low to moderate titers of the virus was detected.   

Since we've seen previous evidence of copious viral shedding via feathers (also supported by this report), this two-pronged process helped to confirm ingestion (as opposed to external contamination) of the virus.

The relatively low titers, however, were more consistent with the passive carriage, rather than replication, of the virus in the tick's gut.

The authors do suggest some ways that limited mechanical transmission of the virus - including via allopreening - might occur among birds.  But how much of a factor this really is remains unknown. 

It's a fascinating report, and while I've only posted the abstract and a small excerpt, is very much worth reading in its entirety. 

Detection and isolation of H5N1 clade 2.3.4.4b high pathogenicity avian influenza virus from ticks (Ornithodoros maritimus) recovered from a naturally infected slender-billed gull (Chroicocephalus genei)
Dylan Andrieux, Manuela Crispo, Malorie Dirat, Laura Lebouteiller, Mathilda Walch, Emmanuel Liénard, Guillaume Croville, Maxime Fusade-Boyer, Loïc Palumbo, Julien Hirschinger, Guillaume Le Loc’h, Jean-Luc Guérin, Sébastien Soubies, Nicolas Gaide
doi: https://doi.org/10.1101/2025.11.28.689408
This article is a preprint and has not been certified by peer review
Preview PDF

ABSTRACT

Laridae birds, such as gulls, are known reservoirs of H13 and H16 low pathogenic avian influenza subtypes. However, during the recent outbreaks linked to the reemergence of high pathogenicity avian influenza virus (HPAIV) H5N1 clade 2.3.4.4b of the Goose/Guangdong lineage, European populations of those birds suffered significant losses. HPAI cases were registered not only along the coastlines but also inland areas, particularly in France and Central Europe.

During a diagnostic investigation of a group of Laridae birds, part of a HPAIV outbreak registered in the South of France in 2023, larval stages of Ornithodoros maritimus, a nidicolous soft tick parasitizing seabirds, were recovered from a slender-billed gull (Chroicocephalus genei).

Affected birds exhibited gross and histopathological lesions consistent with systemic HPAI infection. Immunohistochemistry revealed marked neurotropism, oculotropism and multicentric epitheliotropism. Viral isolation and sequencing analysis confirmed the presence of HPAI H5N1 clade 2.3.4.4b in both the gull and ectoparasites, showing from 98.505% to 99.989% nucleotide identity across six out of eight RNA segments.

While additional research is needed to properly assess the vector competence of O. maritimus, ticks may represent an interesting non-invasive surveillance tool for HPAIV surveillance. This is the first time a HPAIV is successfully isolated from ticks larvae. These findings represent a first step toward understanding the potential role played by ticks in the diffusion of avian influenza viruses within marine bird colonies and among other ecosystems, considering the occurrence of specific behavioral traits, such as kleptoparasitim and the position of gulls at the interface between wild and domestic species.(SNIP)

(SNIP)

Additional research is needed to properly assess the vector competence of O. maritimus, both mechanically and biologically. On the one hand, mechanical transmission may result from external contamination of the tick’s rostrum or through allopreening, which can facilitate the removal of ectoparasites. On the other hand, biological transmission, which is not supported by current literature on avian influenza or our data, would require efficient viral replication within the tick. 

Addressing these questions would require additional studies, which are beyond the scope of this report. 

Our results show that ticks may represent an environmental sample of interest for HPAIV surveillance. Harvesting engorged ticks in seabird nests may be a suitable and practical method to assess the circulation of HPAIV in a bird colony. The presence of HPAIV in other tick species should also be explored to understand if their collection and testing could be used as an additional and non-invasive surveillance tool for influenza in wild birds.

        (Continue . . . )

Nature Sci Rpts: Detection of H5N1 HPAI virus RNA in filth flies collected from California farms in 2024

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Even after more than 2 decades of outbreaks linked to farms, live markets, and wild birds, there remains a good deal we don't know about how HPAI H5 (and other novel flu types) spread; often defeating ramped up biosecurity measures. 

While many were quick to blame contaminated milking equipment for the spread of H5N1 among dairy herds in 2024, four months ago, in Preprint: Surveillance on California Dairy Farms Reveals Multiple Sources of H5N1 Transmission, we saw evidence that Bird flu is ‘everywhere’ on dairy farms.

Following that report, UNMC's Global Center for Health Security - quoting Dr. Richard Webby as saying “It’s a ridiculously contaminated environment” - published Bird Flu on Dairy Farms May Be Airborne After All.

These airborne concerns go far beyond just`exhaled' breath from infected cattle in milking parlors, or `milk spray', as massive quantities of contaminated milk and manure  must be safely handled and disposed of (along with farm wastewater); none of which are trivial tasks. 

We've seen numerous environmental persistence studies showing that - under the right conditions - HPAI H5 can survive for days, weeks, or even months outside of a living host.

• In 2012's EID Journal: Persistence Of H5N1 In Soil, we looked at several studies that found H5N1 could remain viable on various surfaces, and in different types of soil, for up to 13 days (depending upon temperature, relative humidity, and UV exposure).

• In 2017, researchers showed that - when refrigerated - H5N1 infected poultry could remain infectious for months (see Appl Environ Microbiol: Survival of HPAI H5N1 In Infected Poultry Tissues).

• In 2020 we looked at a study from researchers at the USGS (see Proc. Royal Society B: Influenza A Viruses Remain Viable For Months In Northern Wetlands - USGS), which found long-term (up to 7 months) survival of influenza A viruses in wetlands in both Alaska and Minnesota.

How long avian flu viruses may remain viable, and how far they might be carried (by personnel, vehicles, peridomestic mammals, birds, flies, or even the wind), continues to be poorly understood.

Very early on in this blog (2007) - in Cats and Dogs and Flies, Oh My! - we looked at a 2006 study by Kyoko Sawabe et al. that found that at least 2 types of flies could carry the H5N1 virus.

While flies weren't shown to be infected with the virus, they could ingest (and subsequently regurgitate or defecate) infected material, or potentially spread it mechanically by their feet or body, thereby spreading the disease.

We've revisited this idea a number of times since, including 2023's preprint (later published in Sci Repts: Blowflies As Potential Vectors Of Avian Influenza) that tested blowflies for HPAI at the national wildlife reserve in Izumi City, Kagoshima Prefecture, which is the overwintering home for thousands of endangered Hooded Cranes.

The authors wrote:

In December 2022, 648 Calliphora nigribarbis were collected. Influenza virus RT-PCR testing identified 14 virus-positive samples (2.2% prevalence), with the highest occurrence observed near the crane colony (14.9%). Subtyping revealed the presence of H5N1 and HxN1 in some samples. Subsequent collections in December 2023 identified one HPAI virus-positive specimen from 608 collected flies in total, underscoring the potential involvement of blowflies in HPAI transmission.

Our observations suggest C. nigribarbis may acquire the HPAI virus from deceased wild birds directly or from fecal materials from infected birds, highlighting the need to add blowflies as a target of HPAI vector control.

And last July, in H5N1 in California: The Return of the Fly, after Raj Rajnarayanan @RajlabN - Associate Dean of Research and Associate Professor, NYITCOM at Arkansas State University - uploaded to X/Twitter a quick analysis of H5N1 sequences sampled from a HouseFly uploaded to @GISAID from California (2.3.4.4b B3.13 Collected Oct 2024).

Today we've a report, published this week in Scientific Reports, which documents the detection of HPAI H5N1 RNA in flies collected from several California dairy farms in 2024. 

While they state that `. . . infectious virus was not detected in this study', based on the following, it appears they did not attempt to isolate or culture the virus. 

The successful amplification and sequencing of full-length HPAI H5N1 genomic DNA from fly samples collected from positive dairy operations, along with the incidence of relatively low Ct values in some pools, together suggest the presence of intact viral genomes at the time of fly collection. 

However, the detection of intact genomes does not necessarily equate to the presence of infectious virus, which is a limitation of our approach that could be improved if virus culture precedes molecular characterization.

As this report points out:

Prior bioassays determined that infectious HPAI H5N1 survives in the digestive tract (including crop) of house flies for up to 72 h [18] and blow flies for up to 24 h [24], although viral RNA can be detected for much longer (for example, up to 4 days in house flies and 14 days in blow flies).

Due to its length, I've only posted the abstract and a brief excerpt.  Follow the link to read it in its entirety.  I'll have a brief postscript after you return.

Detection of H5N1 highly pathogenic avian influenza virus RNA in filth flies collected from California farms in 2024
Dana Nayduch, Stacey L.P. Scroggs, Phillip Shults, Luke A. Brendel, Lindsey M. Reister-Hendricks, Caitlin Taylor, Edward Bird, Brina Lopez & Edith S. Marshall

Scientific Reports , Article number: (2025) Cite this article

Abstract


The emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in U.S. dairy cattle highlights the urgent need to understand transmission dynamics within and among farms. House flies (Musca domestica) and blow flies (Calliphoridae), ubiquitous in agricultural settings, are suspected mechanical vectors of numerous pathogens, including viruses. 

We investigated the presence of H5N1 viral RNA in filth flies collected opportunistically from four H5N1-positive farms (three dairy and one poultry) in California during the 2024 outbreak. H5N1 RNA was detected via qRT-PCR in fly pools from all four locations, with the lowest Ct values (highest viral RNA) in house flies collected near milking parlors and dead animals. Whole-genome sequencing confirmed H5N1 viral genomes in flies from dairy farms, demonstrating high similarity (99.92–99.95%) to the B3.13 lineage circulating in the region and grouping closely with farm-associated viral sequences from milk.

Although infectious virus was not detected in this study, our findings suggest that filth flies acquire HPAI H5N1 RNA from their environment, supporting their potential role as sentinels and/or mechanical vectors. These results underscore the critical importance of fly control, targeted surveillance, and integrated pest management strategies in agricultural settings to enhance biosecurity and potentially mitigate HPAI H5N1 transmission.

       (SNIP)

Our data suggest that both the milking parlor and dead animals may be potentially potent sources of virus for flies on the two dairy operations for which we had these metadata, as indicated by low Ct values (i.e., high viral RNA template), a high prevalence of positive fly pools collected from these locations, and the close relatedness of genomes of fly-associated and milk-associated virus from the same farm and nearby farms in the same  county (e.g., Fig. 1).

Together, these findings support local acquisition of HPAI H5N1 by house flies from both milk and dead animals (carcasses, aborted fetus), which concurs with the trophic behaviors of filth flies.

Female filth flies readily seek out and feed on proteinaceous substances like milk (e.g., house flies; [15]) and both species visit dead or decaying materials for oviposition [28,29], often ingesting the substrate during this process. Interestingly, milk seems to extend the stability of HPAI H5N1 in wastewater and on structural surfaces [30,31]. Milk also has been shown to increase persistence, perhaps by decreasing degradation rates, of SARS CoV-2 ingested by house flies [32].

       (Continue . . . )

While there are probably multiple pathways that HPAI utilizes to spread within and between farms, it seems increasingly likely that flies are at least part of the equation. 

In addition to flies, over the years we've looked at a number of other `less obvious' ways the virus may be spreading.

• There is growing evidence that HPAI may be spread via `contaminated dust particles' - carried by the wind - from one farm to the next (see Preprint: Genetic & Meteorological Data Supporting Windborne Transmission of HPAI H5N1).

• The role of peridomestic mammals - particularly in and around farms - in the spread of HPAI is only partially understood, and remains under-researched (see Emer. Microbe & Inf.: HPAI Virus H5N1 clade 2.3.4.4b in Wild Rats in Egypt during 2023).

• While contaminated milking machines have been blamed for the cow-to-cow spread of HPAI, a recent preprint (Dairy Cows Infected with Influenza A(H5N1) Reveals Low Infectious Dose and Transmission Barriers) was unable to duplicate transmission in a controlled lab setting, leading researchers to warn `. . . Other agent, host, and environmental cofactors that might contribute to transmission cannot be ruled out and must be explored . . . ).

Unless and until we get a better handle on how HPAI is spreading in the wild - and among and between farms - our ability to slow or contain these outbreaks will remain limited. 

Referral : Science - Avian-origin influenza A viruses tolerate elevated pyrexic temperatures in mammals

 

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While I try to focus primarily on open-access studies that allow me to read them in their entirety, and hopefully lift an excerpt or two, every once in awhile I'll find a paywalled or copyright restricted paper that seems worthy of referral.

Today we've a study, published behind a paywall in Science, which shows that that avian-origin PB1 segments make human-adapted influenza A viruses more tolerant of febrile temperatures (~40–41 °C) in vitro and in a mouse model with artificially elevated body temperature. 

We've often talked about the fact that birds run `hotter’ than mammals, with a normal body temperature that hovers at or above 40°C, which would be considered a `fever level' in humans. 

These viruses replicate primarily in the avian gut - which is several degrees warmer than the human airway - and it means that an avian virus must adapt to replicate at a lower temperature in order to become a bigger human threat.

One of the mutations we look for is (PB2-E627K); the swapping out of the amino acid Glutamic acid (E) at position 627 for Lysine (K) - which allows an influenza virus to replicate at the lower temperatures (roughly 33°C) normally found in the upper human respiratory tract (see Eurosurveillance: Genetic Analysis Of Novel H7N9 Virus).

Today's study looks at the impact of a different Avian-origin gene segment (PB1) and focuses on `two amino acid substitutions' (which, disappointingly are not specified in the abstract) that allow avian viruses to tolerate (and even thrive) at higher temperatures. 

The human immune system's most obvious response to any infection is to mount a fever, which often slows or inhibits the replication of the invading pathogen. This is why many doctors suggest allowing a mild or moderate fever to run its course. 

But an influenza virus that is both tolerant of higher temperatures and replicates at the lower temperatures in the human airway would complicate matters considerably. 

As the authors point out, the pandemic viruses of 1918, 1957, and 1968 all acquired an avian-origin PB1, which may help explain why they were more virulent than seasonal flu.

While I'm more than a little hobbled by my lack of access to the full paper, the Editor’s summary and graphical and text abstracts are interesting enough for me to recommend that you might want to take a deeper look. 

Avian-origin influenza A viruses tolerate elevated pyrexic temperatures in mammals
Matthew L. Turnbull , Yingxue Wang, Simon Clare, Gauthier Lieber , Stephanie L. Williams , Marko Noerenberg , Akira J. T. Alexander , Sara Clohisey Hendry , Douglas G. Stewart, [...] , and Sam J. Wilson +22 authors Authors Info & Affiliations
Science 27 Nov 2025
Vol 390, Issue 6776
DOI: 10.1126/science.adq4691

J.I.D.: Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13

 
Flu Virus binding to Receptor Cells – Credit CDC

#18,963

While there has been no shortage of (understandable) relief over the relatively mild presentation of the `Bovine' B3.13 genotype of HPAI H5N1 in humans (0 Severe/Fatal cases), the same cannot be said for the D1.1 genotype, which emerged in North America in October of 2024.

• In November of 2024, we learned of a severe case involving a teenage girl in British Columbia (see NEJM: Critical Illness in an Adolescent with Influenza A(H5N1) Virus Infection)
• The following January the Louisiana Department of Health Announced the 1st U.S. H5N1-related Fatality
• And a Fatal case was reported in Mexico (see WHO DON Update On Mexico's Fatal H5N1 Infection) in April.

The exact number of human infections with the D1.1 genotype is unknown, since not all of the (now, roughly 6 dozen) North American human cases have been fully characterized. Today's study describes this ambiguity as:

A total of 53 strains were identified, of which 6 strains had 2 sequences deposited. These 53 strains were collected from patients between March 28, 2024 and February 12, 2025 (Supplementary Table S3). Of these 53 strains, 22 (41.5%) were assigned to genotype B3.13, 8 (15.1%) were assigned to D1.1, 1 (1.9%) was assigned to D1.3, and 22 (41.5%) could not be assigned to any genotypes according to GenoFLU version 1.06 (https://github.com/USDA-VS/GenoFLU). 

It appears, however, that Bovine B3.13 human infections have likely outnumbered D1.1 infections by a factor of 2:1, making the difference in virulence even more pronounced. 

Today's report, from researchers at the University of Hong Kong, provides some insight on why D1.1 human infections appear to be more severe than B3.13.  

They demonstrate that the D1.1 genotype replicates better in lab-grown nasal and lung tissues than the bovine B3.13 strain, and it binds more tightly to human‑type (α2,6-linked SA) receptors.  

I've reproduced the abstract, and a brief excerpt, below. Follow the link to read the full report.  I'll have a bit more after the break. 

Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13

 Xiaojuan Zhang, Stephanie Joy-Ann Lam, Lin-Lei Chen, Carol Ho-Yan Fong, Wan-Mui Chan, Jonathan Daniel Ip, Shaofeng Deng, Siwen Liu, Rachel Chun-Yee Tam, Pui Wang

The Journal of Infectious Diseases, jiaf598, https://doi.org/10.1093/infdis/jiaf598
Published:24 November 2025 Article history

PDF

Abstract

Three critically ill or fatal avian influenza A(H5N1) human infections have been reported in North America since November 2024. Notably, all were infected with genotype D1.1 instead of B3.13, the dominant genotype before November 2024. Here, we demonstrated that D1.1 could replicate to higher titers in human nasal and airway organoid-derived transwell monolayers from 6 donors.

D1.1 exhibited a better binding to α2,3- and α2,6-linked SA than B3.13. No significant differences in most inflammatory or antiviral cytokines/chemokines was observed. These observations suggest that D1.1 is better adapted to both the upper and lower human respiratory tract epithelium than B3.13.

(SNIP)

Our observations suggest that D1.1 genotype may be better adapted to humans than B3.13. Further studies are required to determine if there are differences in the replication of different strains within the same clade. As D1.1 is now widespread among dairy cows in the United States, there is an increasing risk of further adaptation of D1.1 with higher transmissibility or virulence among mammals. Continuous phenotypic monitoring using human organoids and other in vivo models will provide critical information for assessing the risk of D1.1 or other novel genotypes in humans.

       (Continue. . . )

Almost 13 years ago, in  Differences In Virulence Between Closely Related H5N1 Strains, we looked at the varying impact of HPAI H5N1 viruses around the globe.  Some countries saw CFRs (Case Fatality Rates) of 50%-80%, while others reported relatively few deaths (see chart below). 

While we're thankfully not seeing the kind of high CFR H5N1 in North America and Europe that once was far too common in Indonesia, Vietnam, and Egypt, the events over the past 3 years in Cambodia remind us that severe H5N1 still exists. 

And recent offshoots of H5N1 - like the H5N5 case in Washington State and the Novel Reassortant H5N2 case in Mexico - demonstrate that these HPAI viruses continue to reinvent themselves at a rapid pace. 

Whether this ultimately leads to another pandemic is anyone's guess, but right now HPAI H5 appears to be on a roll, and should give all of us pause. 

Reminder: Thanksgiving Is National Family History Day

 

Free Online Tool From HHS to Collect Family HX

#18,962


One of the perils of blogging for two decades is that over time embedded links to outside sources no longer function. The past couple of years have been particularly bad following major upgrades/revamping of both the CDC and WHO websites, where even some of their internal links go nowhere.

Normally, the day before Thanksgiving I repost my annual `Thanksgiving Is National Family History Day' blog, with links and quotes from the CDC, the HHS, and the Office of the Surgeon General. 

Since 2023, some of those links (here & here) have gone missing, although the CDC retains an abbreviated version at https://www.cdc.gov/family-health-history/

So, starting over . . . 

Every year since 2004 the Surgeon General of the United States has declared Thanksgiving – a day when families traditionally gather together - as National Family History Day, since it provides an excellent opportunity to ask about and document the medical history of relatives.

As a former paramedic, I am keenly aware of how important it is for everyone to know and have access to their personal and family medical history.

During routine visits with your doctor, knowing your family history can provide important information regarding your care. Under more urgent conditions, emergency room doctors are often faced with patients unable to remember or relay their health history, current medications, or even drug allergies during a medical crisis.

Which is why I always keep an EMERGENCY MEDICAL HISTORY CARD – filled out and frequently updated – in my wallet, and have urged (and have helped) others in my family to do the same.

I addressed this issue at some length in a 2009 blog called Those Who Forget Their History . . . . A few excerpts (but follow the link to read the whole thing):

Since you can’t always know, in advance when you might need medical care it is important to carry with you some kind of medical history at all times. It can tell doctors important information about your history, medications, and allergies when you can’t.

Many hospitals and pharmacies provide – either free, or for a very nominal sum – folding wallet medical history forms with a plastic sleeve to protect them. Alternatively, there are templates available online.

I’ve scanned the one offered by one of our local hospitals below. It is rudimentary, but covers the basics.

Since family gatherings are common over the holidays, Thanksgiving can be an ideal time to ask family members about their medical history. The HHS even provides a free, online tool, for organizing and storing this information.

The CDC's website contains additional information, including:

Family Health History and Adults

Key points

• If you have a family health history of a chronic disease such as cancer, heart disease, or diabetes, you are more likely to get that disease yourself.
• Knowing your family health history risk can help you—if you act on it.
• Share your family health history with your healthcare provider, who can help you take steps to prevent disease and catch it early if it develops.
• Finding disease early can often mean better health in the long run.

And lastly, a couple of other items that - while not exactly a medical history - may merit discussion in your family as it has in mine (see 2012's His Bags Are Packed, He’s Ready To Go).

• First, all adults should consider having a Living Will that specifies what types of medical treatment you would desire should you become incapacitated, and unable to communicate your wishes.  
• While not a `legal document' the CDC also provides a `Complete Care Plan' PDF tool  for managing day-to-day care. 

• You may also wish to consider assigning someone as your Health Care Proxy, who can make decisions regarding your treatment should you be unable to do so for yourself. 

• Elderly family members with chronic health problems, or those with terminal illnesses, may even desire a home DNR (Do Not Resuscitate) Order. 
• Without legal documentation, verbal instructions by family members – even if the patient is in the last stages of an incurable illness – are likely to be ignored by emergency personnel.

While admittedly, not the cheeriest topic of conversation in the world, a few minutes spent during this Thanksgiving holiday putting together concise written medical histories could spare you and your family a great deal of anguish down the road.