#18,447
Eight and a half years ago, in a blog titled Sci Reports: Continual Antigenic Diversification Of HPAI H5N1 In China & Around the World, I opened with:
A recurring theme in this blog has been the remarkable spread and growing diversity of (first) HPAI H5N1, followed later by a bevy of related H5Nx viruses (H5N2, H5N3, H5N5, H5N6, H5N8, etc.), all of which have diverged into a dizzying number of lineages, clades, subclades, and genotypes around the globe.This was written only 5 months after the start of Europe's first major HPAI H5N8 epizootic, which ravaged both wild birds and poultry farms across 29 European nations.
As we discussed last weekend in H5Nx: Reassort & Repeat, the H5N8 virus underwent a series of crucial reassortment events which increased its host range, improved its ability to be carried asymptomatically by some avian species, and generated several new subtypes, including H5N5, H5N3, and H5N9.
As impressive as these gains in diversity were, they pale in comparison to what we've seen since. In short order these HPAI viruses acquired the ability to persist through the summer in some avian hosts, and to be more easily carried across oceans or continents by other species.
HPAI H5N8 gave way to an array of new and improved H5N1 viruses, which began their world tour in earnest in 2021, where they encountered many new LPAI avian viruses with which to reassort.
In North America alone we've seen more than 100 new genotypes emerge, while scores of others have spread across Europe, Asia, and South America. Some are far more successful than others, but each represents a unique evolutionary pathway for the virus to follow.
Some of these reassortant viruses have developed a greater affinity for infecting mammals; the B3.13 genotype is particularly well suited to infect lactating cows, although the D1.1 genotype has also shown that ability.
Where all of this leads is anyone's guess, but the sobering reality is we aren't just dealing with a single H5Nx threat, but rather with a large and ever-growing array of H5 viruses, all randomly tossing the genetic dice in ways that could ultimately decide our future.
All of which brings us to a new preprint with an impressive pedigree - one that looks at how these viruses in both Europe and North America have repeatedly reassorted with local LPAI viruses - producing both host-specialized, and generalist hybrids.
One example they provide is the Charadriiformes-specialist lineage (EA-2022-BB) - which came about as a result of an reassortment between H5N1 and an LPAI H13 virus common in shorebirds.
While many of these reassortants will ultimately fade away - or end up posing no additional risks - host specialization provides our increasingly diverse array of HPAI H5 viruses with new and unpredictable ways to spread and evolve.This BB reassortant now circulates almost exclusively in Charadriiformes (shorebirds or waders), with reduced fitness in ducks/chickens.
Due to its length (36-pages) and technical nature, I've just posted the abstract and a few excerpts, so follow the link to read the preprint in its entirety.
I'll have a postscript after the break.
Genetic reassortment and diversification of host specificity have driven evolutionary trajectories of lineages of panzootic H5N1 influenza
William T Harvey, Rute Maria Pinto, Maryn D Brown, Lu Lu, Jessica L Quantrill, Jiayun Yang, Nunticha Pankaew, Miranda Nel, James Baxter, Alex M P Byrne, Darrell R Kapczynski, Munir Iqbal, Joe James, Ashley C Banyard, Ian Brown, Wendy Barclay, Thomas P Peacock, Paul Digard, Samantha J Lycett
doi: https://doi.org/10.1101/2025.08.20.670882
This article is a preprint and has not been certified by peer review
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Abstract
Since 2021, subclade 2.3.4.4b A(H5N1) high pathogenicity avian influenza (HPAI) viruses have undergone changes in ecology and epidemiology, causing a panzootic of unprecedented scale in wild and domestic birds with spill-over infections and perceptible transmission in a range of mammalian species, raising concern over zoonotic potential.
HPAI viruses readily exchange gene segments with low pathogenicity avian influenza viruses via reassortment, a mechanism that facilitates pronounced phenotypic change. Observations suggest changes in the seasonality and host range of panzootic viruses, however, data on the role of reassortment in determining such features are limited.
Using phylodynamic approaches, we describe the emergence of the panzootic lineage and using a novel global genotype classification system we describe the subsequent emergence and global structuring of genotypes generated by reassortment.
Focusing on evolutionary dynamics in Europe, we show reassortment has produced high fitness genotypes with enhanced capacity for transmission and further we show such advantages can be host-dependent, contrasting successful generalist genotypes with a specialist lineage (EA-2022-BB) adapted to birds of the order Charadriiformes.
Experimental investigation of NS1-mediated shutoff indicates this Charadriiformes-specialist does not inhibit host cellular gene expression and hamper the defences of more typical hosts such as water- and land-fowl. We attribute this primarily to variation at position 127 of the NS1 protein.
Our results emphasise that reassortment has driven phenotypic change, affected viral fitness, and caused diversification of host specificity and seasonality. Such factors should be considered in studies that seek to identify drivers of HPAI spread and map spillover risk.
Additionally, relaxation of host specialisation, ecological diversification, and potential endemicity in atypical host populations present new reassortment opportunities that could result in further novel phenotypes.
(SNIP)
During the ongoing H5N1 panzootic, there is further evidence for host diversification with at least one other instance in which H5N1 viruses have begun to transmit in a novel host population with very limited overlap with the typical community of hosts, the ongoing epizootic in dairy cattle within the USA.
Diversification of host specificity has various interesting evolutionary potential consequences. When viral transmission in different host types becomes increasingly separated, competition between lineages is diminished according to the extent to which lineages cease to transmit within common populations.
With lineages no longer in direct competition for hosts, they can evolve independently in parallel, likely with adaptive changes reflecting the different host associations, increasing the overall genomic diversity of subclade 2.3.4.4b viruses.
Through independent evolution in different host types, they are exposed to distinct selective pressures and novel reassortment opportunities. Viruses are expected to gain adaptive mutations and may acquire genomic segments from influenza viruses that are endemic to different host types, both of which have the potential to further accentuate differences in host specificity.
It is vital to understand how the evolution of these virus lineages in different fitness landscapes could affect their potential to transmit to humans or other mammals.
Evidence suggests that the initial spillover of HPAI H5 (genotype B3.13) to Texas cattle occurred several months before we first learned of it; long enough for the virus to have been spread to multiple states before the first alarm was raised.
It would take nearly a year before a second genotype (D1.1) would be confirmed in cattle in at least 2 western states (Nevada & Arizona).
Despite only limited passive surveillance, we've seen hundreds of reports of HPAI H5 in peridomestic mammals (foxes, skunks, mice, cats, and many others) across the United States, Canada, and in Europe.
Some states appear to be looking harder than others, but even in proactive states these (n=646) reports to the USDA undoubtedly represent just the very tip of the iceberg.
While ignorance may be bliss in the short-term, it has a nasty way of catching up with us over the long run.Since we're not actively looking, we've no idea what other specialist genotypes might be out there in the wild, quietly adapting to a new host.
