#18,888
While the HPAI H5N1 clade 2.3.4.4b virus currently circulating in the United States is a direct decendent of the Eurasian H5N1 strain, it quickly became genetically distinct due to constant reassortment with North American avian viruses (see Rapid Evolution of A(H5N1) Influenza Viruses After Intercontinental Spread to North America).As a result, we've seen far more mammalian spillovers, especially to livestock, than have been reported elsewhere, and infected cats and other peridomestic mammals have often shown systemic infection and profound neurological manifestations.
The chart above (from today's study) shows a pair of mutations (PB2 478I and NP 450N) remains rare in the Eurasian lineage (left/blue) but has become nearly fixed in the American lineage (right/red).
While these aren't the only differences, these mutations appear to significantly increase viral polymerase activity, resulting in enhanced replication efficiency in mammals.
There are obviously other mutations of concern we are watching, including:
- PB2 mutations: E627K, D701N, Q591K, and M631L
- HA mutations: Changes like Q226L and E190D
- Resistance mutations: PA-I38M and NA-S247N
But today's study focuses on the tag-team of PB2 478I and NP 450N which appear to be doing much of the heavy lifting when it comes to mammalian spillovers of the H5N1 virus in North America.
This is a lengthy, detailed, and highly technical research article, most of which is primarily of interest to virologists. Those wanting full details will want to follow the link to read it in its entirety.
- This paper identifies two mutations (PB2 478I and NP 450N) as critical for the virus’s enhanced replication, systemic dissemination, neuroinvasion, and unusually high mortality in ferrets.
- Using reverse genetics they found that reverting either mutation to the Eurasian-type in a North American virus resulted in attenuation: replication efficiency droped, systemic spread was blocked, and infected animals survived without severe disease.
- These researchers cite PB2 478I and NP 450N as urgent targets for surveillance in North American and transboundary H5N1 outbreaks
First, the link, abstract, and a few excerpts from the study, after which I'll have a brief postscript.
PB2 and NP of North American H5N1 virus drive immune cell replication and systemic infections
Young-Il Kim , Seung-Gyu Jang , Woohyun Kwon, Jaemoo Kim , Dongbin Park , Isaac Choi , Jeong Ho Choi , Juryeon Gil , Mina Yu , [...] , and Young Ki Choi +11 authors Authors Info & Affiliations
Science Advances
26 Sep 2025
Vol 11, Issue 39
DOI: 10.1126/sciadv.ady1208
Abstract
The 2022 North American outbreak of 2.3.4.4b H5N1 avian influenza virus revealed substantial mammalian adaptation and pathogenicity, yet mechanisms remain unclear.
To address this knowledge gap, we investigated the North American H5N1 strain (GA/W22-145E/22), which demonstrated unique immune cell–mediated systemic dissemination, neuroinvasion, and 100% mortality in ferrets, unlike the nonlethal Eurasian strain (KR/W811/21).
Genomic and reverse genetics studies identified PB2478I and NP450N mutations as key determinants of enhanced polymerase activity, immune cell tropism, and pathogenicity.
Mutant GA/W22-145E/22 virus carrying PB2478V/NP450S showed complete survival without systemic dissemination. Furthermore, GA/W22-145E/22 demonstrated robust replication in human peripheral blood mononuclear cells and bovine mammary gland organoids, raising concerns about zoonotic spillover.
These findings underscore PB2478I and NP450N as pivotal markers of pathogenicity, emphasizing the urgent need for enhanced surveillance and targeted interventions.
(SNIP)
In summary, we identify PB2478I and NP450N as key molecular determinants of virulence in the GA/W22-145E/22 strain. These mutations drive immune cell–mediated systemic spread, neuroinvasion, and potential vertical transmission.
Our findings highlight the evolving pathogenic landscape of NAm clade 2.3.4.4b H5N1 viruses and underscore the urgent need for active surveillance, preparedness, and targeted interventions to mitigate zoonotic and pandemic threats.
While the reporting of new cases, and outbreaks, has plummeted over the past 6 months - and the situation looks better `on paper' - the HPAI problem has not gone away.
Last March we saw the average time to submit sequences to GISAID was 7 months, with some countries taking more than twice that. Many countries remain slow to share outbreak information, and some appear to be burying `bad news' completely (see From Here To Impunity).
As we've seen a hundred times before, this paper notes `. . . the urgent need for active surveillance, preparedness, and targeted interventions', but substantive action - if any - has been coming at a glacial pace.
HPAI H5 is not a single threat, it is a collection of hundreds of related - but genetically distinct viruses - all of which are on their own evolutionary path.As they spread globally they reassort with new viruses - and spillover into new hosts - which affords them fresh opportunities to evolve and adapt. Yet the world continues to HPAI H5 as more of an economic or political concern, than as a potential public health threat.
And while that may be true today, it could abruptly change with little warning.
