#19,362
While worrisome, HPAI H5Nx remains primarily an avian-adapted virus, despite increasingly spilling over into mammalian species (including humans). These spillovers, however, provide opportunities for the virus to adapt - through amino acid substitutions (mutations) - to mammals.
Without changes the virus remains optimized for avian physiology. Mammalian infection remains possible, but is less likely to spread efficiently through a population.
While there are a number of these adaptive mutations, one we watch for carefully is PB2-E627K, which increases the ability of avian flu viruses to replicate in a mammalian host.
This mutation is rarely seen in birds, but can appear in mammals after they are infected by birds (see Mammalian Adaptation in the PB2 Gene of Avian H5N1 Influenza Virus).
It has always been a bit of a mystery why this 627K mutation hasn't become `fixed' in avian hosts during this current panzootic, with some researchers suggesting it may impose some kind of `fitness penalty' in birds.
While found in about 1% of avian H5N1 sequences, it is reportedly more common (based on limited surveillance) in avian hosts infected with H5N5.
In 2024, however, we looked at a slightly different mutation at the same location in the PB2 gene (E627V), which has emerged in poultry viruses (see Preprint: An Emerging PB2-627 Polymorphism Increases the Pandemic Potential of Avian Influenza).
The authors report that the PB2-627V mutation not only maintains viral fitness in poultry, it facilitates the respiratory transmission of AIVs between ferrets. The concern was this mutation could go a long way in overcoming the `species barrier' between avian and mammalian-adapted influenza viruses.
This 627V mutation has also appeared in other avian viruses (H9N2, H7N9, H5N6, etc.) with zoonotic potential (see Vet. Research: E627V Mutation in PB2 Protein Promotes the Mammalian Adaptation of Novel H10N3 Avian Influenza Virus).
All of which brings us to a preprint, authored by a number of well known UK researchers, which investigates whether the PB2 E627K mutation exacts a fitness penalty in birds.
They report finding no `measurable fitness cost in chickens and ducks', which suggests there may be other `ecological and epidemiological constraints' at work.
This, they suggest, means that mammalian-adaptive mutations acquired during spillover could spread and persist in avian populations, potentially raising zoonotic risk.
They go on to stress the value of surveillance for such mutations in birds.
Due to copyright issues, I can't do my regular deep dissection of the paper, but I can refer you to the preprint, which is very much worth reading.
The mammalian-adaptive PB2-E627K substitution preserves viral fitness of clade 2.3.4.4b H5N1 HPAIV in birds.
Elizabeth Billington, Sofia Riccio, Maryn D. Brown, Benjamin Mollett, Jessica L. Quantrill, Simon Johnson, Cecilia Di Genova, Jiayun Yang, Jean-Remy Sadeyen, Audra-Lynne Schlachter, Kelly J. Roper, Jafar Hassan, Benjamin Clifton, Kajal Ralh, Caroline Janet Warren, Georgina Ward, Dilhani De Silva, Alejandro Nunez, Holly A. Coombes, Marek J Slomka, Munir Iqbal, Wendy S. Barclay, Thomas Peacock, Ashley C Banyard, Joe James
doi: https://doi.org/10.64898/2026.10.06.757006
It isn't known what mutation - or series of mutations - would be needed to turn H5Nx into a genuine pandemic threat. What we know is 1) these viruses continue to evolve, 2) they have spread globally, and 3) in recent years they have expanded both their avian and mammalian host ranges.
H5Nx continues to surprise, but whether that will lead to a global health crisis is anyone's guess. But just because it hasn't yet, doesn't mean it can't.
Which is reason enough to remain vigilant.
