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

 

#18,749

The sobering reality of the HPAI H5 avian flu threat is we are not just dealing with a single entity - one specific subtype/genotype circulating in one host species - but rather a growing array of similar viruses, spreading in numerous avian and mammalian hosts, and each on its own evolutionary path. 

The map above illustrates some of the better known spillover/adaptations, but vast regions of the world are blank, suggesting are either not looking for - or simply not reporting - local activity. 

Complicating matters, while HPAI H5 may be the most obvious pandemic threat today, it is simply one of many influenza A viruses we are watching.  In China, we've seen concerns raised over Swine H1Nx, Avian H3Nx and H9N2 viruses, while in Europe Swine H1Nx viruses are being closely watched. 

The CDC's IRAT list of zoonotic influenza A viruses with pandemic potential now lists 27 different viruses, of which just 12 belong to the H5 subtype. This list, however, is far from complete. 

As a segmented virus with 8 largely interchangeable parts, the flu virus is like a viral LEGO (TM) set which allows for the creation of a vast number of unique variants via reassortment.  And each subtype/genotype is also subject to amino acid changes (mutations) due to replication errors and host adaptation.

The emergence of new clades, subtypes, genotypes or variants can be associated with abrupt changes to the behavior (transmissibility, pathogenicity, host range, etc.) of the H5 virus. 

 Sometimes we get lucky, and it attenuates the virus's threat. Sometimes it enhances it. 

While we are far from knowing what every amino acid change does (particularly in concert with other changes), we do have a short list of known mutations of concern (e.g. PB2 E627K, PB2 D701N, PB2 Q591K, HA Q226L, etc.). 

While evolution is often depicted as a straight line, it isn't linear. It branches, meanders, and sometimes even regresses. 

Which is why we've seen HPAI H5 appear to be on the cusp of exploding before, only to see it lose its momentum, and virulence (Indonesia & Egypt were once both hotbeds of human infections).

Sometimes, nature has to go back to the drawing board. 

Despite attempts to generate risk analyses, limited surveillance and the complexity of viral evolution mean we aren't to the point of being able to predict what this virus will do next. But, today we have an excellent review of the recent changes in the H5 virus, and in its ability to infect mammalian hosts. 

 

One that focuses not only on the changes that have already been observed, but also on what the virus would likely need to do next to pose a greater pandemic threat. 

Due to its length, and technical nature, I'll just provide the link and a few excerpts.  Those who wish a deep dive into H5's recent evolution will want to read it in its entirety. 

Review Article
Open Access
H5N1 2.3.4.4b: a review of mammalian adaptations and risk of pandemic emergence 

Fernando Capelastegui1​ and Daniel H. Goldhill1​
 
Published: 04 June 2025 https://doi.org/10.1099/jgv.0.002109

PDF

 

 
ABSTRACT

Avian influenza viruses can cause severe disease when they spill over into mammalian and human hosts. H5N1 clade 2.3.4.4b has spread globally since 2021, decimating avian species, and has spilled over into mammalian species, causing sporadic infections and fatal outbreaks in sea lions, cats, mink and dairy cattle. Increased human cases of H5N1 are fuelling concern that H5N1 could soon adapt to become a new pandemic virus.

Adaptive mutations have emerged following spillover, which support H5N1 outbreaks in mammalian populations and include changes to the PB2 such as E627K, D701N, M631L and T271A. Further changes to haemagglutinin, altering binding preference to human-like α2,6 sialic acid receptors have yet to be seen. Here, we review the adaptations that have emerged in mammals throughout the 2.3.4.4b outbreak and the molecular mechanisms behind these mutations to assess the pandemic risk of this virus.

         (SNIP)

Our understanding of the mechanism behind adaptation allows us to predict whether a virus is adapting to human hosts and assess the risk it poses to public health. Deep mutational scanning coupled to the potential of AI models promises a future where we may have greater predictive power over which mutations and viruses pose the greatest threat. Further research should focus on key unknowns such as the determinants of severity across species and the importance of modes of transmission.

The prevalence of infection across so many species creates a perfect storm for exposure to new hosts and the potential for further adaptive mutations to emerge. There is also a significant risk of reassortment with other circulating influenza viruses, which may fast-track the acquisition of human adaptive mutations from seasonal lineages or other AIVs. Ultimately, time will tell if this virus evolves into a pandemic virus. However, we can be certain that limiting transmission and the opportunities avian viruses have to adapt is important to prevent existing and new mammalian epidemics.

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