ISRV: Nomenclature Updates to the Hemagglutinin Gene Clade Designations Resulting From the Continued Evolution of High Pathogenicity Avian Influenza A(H5) Virus Clades 2.3.2.1c and 2.3.4.4

(Credit CDC)

#19,367

Thirteen years ago in 2013's EID Journal: The Expanding Variants Of H5N1, we looked at the continued evolution and diversification of H5N1 viruses around the globe.  At that time I wrote:

H5N1 virus was first identified in 1996 it has expanded into more than 20 different clades and subclades, and various versions of the virus now circulate in different parts of the world. You can see the evolution of the virus through 2011 in the chart below. 

NOTE: Not all of these clades continue to circulate.

 Clade 2.3.2 (and now 2.3.2.1) are very common in South East Asia, clades 2.2.1 and 2.2 are endemic in Egypt and clades 2.1.1, 2.1.2. and 2.1.3 are found in Indonesia.

This snapshot was taken before the emergence, and eventual world domination, of H5N8  clade 2.3.4.4, which would begin decimating South Korean poultry just two months after this was published, and of an H5N6 clade 2.3.4.4a virus which emerged in Sichuan, China a few months after that. 

In many ways, 2014 was a pivotal year for H5Nx viruses, with H5N1's dominance soon to be supplanted by a less deadly (to humans), but more easily spread by migratory birds, H5N8 clade 2.3.4.4x lineage.  

Older clades, such as Cambodia's 2.3.2.1c H5N1 virus went to ground (but would return roughly a decade later).  H5N8 dominated until 2020-2021, when an H5N1 clade 2.3.4.4b came roaring back, largely supplanting H5N8. 

In the spring of 2025, Cambodia's clade 2.3.2.1c was provisionally redesignated clade 2.3.2.1e  after analysis showed it had drifted away from the older clade. 

Similar evolutionary shifts have been happening in other clades over the past dozen years, which is why the WHO/WOAH/FAO H5 Evolution Working Group has updated the naming system for H5 bird flu viruses for the first time since their 2014 update.

Today's report from Influenza and Other Respiratory Viruses updates the official nomenclature for H5 viruses up to July 4, 2024.  

The working group added 12 new subclade designations:

• Clade 2.3.2.1c was split into 2.3.2.1c–g. 
• 2.3.2.1d: China, 2014–2016.
• 2.3.2.1e: Vietnam and Cambodia, 2020–2024. 
• 2.3.2.1f: India, the Middle East and Africa.
• 2.3.2.1g: Indonesia, 2012–2016.

• Clade 2.3.4.4 was split into 2.3.4.4a–h 
• plus a "2.3.4.4-like" label for 125 outlier viruses that don't fit neatly

Some of these designations have been used provisionally for years, but are now made official. 

Although there was enough divergence among clade 2.3.4.4b viruses to technically warrant additional subclade splits, that decision has been deferred for now:  The Authors explained:

Furthermore, several of the newly designated 2.3.4.4 subclades had intra-clade APDs over the 1.5% threshold required for further splitting of clades due to the rapid expansion of these clades into new regions (e.g., 1.98% intra-clade APD of 2.3.4.4b representing over 13,000 sequences). Due to sampling biases stemming from the overrepresentation of sequences from specific outbreaks and insufficient data from regions with recent introductions, further subdivision of subclades with intra-clade APDs greater than 1.5% was deferred. Additional genetic data are needed to better assess the endemicity of specific clusters and justify further splits beyond the current subclades 2.3.4.4a–h.

Due to the highly technical and niche nature of today's study, I've only posted the link and abstract. Those wanting a deeper dive will want to follow the link to read it in its entirety. 

I'll have a brief postscript after the break.

Nomenclature Updates to the Hemagglutinin Gene Clade Designations Resulting From the Continued Evolution of High Pathogenicity Avian Influenza A(H5) Virus Clades 2.3.2.1c and 2.3.4.4

Tommy T. Lam, C. Todd Davis … See all authors 

First published: 07 October 2026 https://doi.org/10.1111/irv.70317

Group members and collaborators are provided in the Supporting Information (Data S1). 

 

ABSTRACT

Background and Methods

The evolutionary divergence of the A(H5) hemagglutinin (HA) gene of high pathogenicity avian influenza (HPAI) viruses (A/goose/Guangdong/96 lineage) was analyzed by phylogenetic and average pairwise distance methods to identify clades that merit nomenclature updates.

Results and Conclusions

Based on this assessment, 12 new clade designations were recommended based on division of clade 2.3.2.1c and 2.3.4.4 viruses, which were reported in Africa, Antarctica, Asia, Europe, the Middle East, the Americas, and Oceania since the most recent WHO/WOAH/FAO H5 Evolution Working Group update.

        (Continue . . . )

H5's evolution continues, and we will undoubtedly see additional `provisional' clade and subclade designations added in the years ahead.  

The bottom line is that H5 viruses have not only grown more diverse, they are a far cry from what emerged in China in the 1990s, and sparked pandemic fears in the early 2000s. 

Whether any of that gives them the ability to spark a human pandemic remains to be seen.  But it would be reckless to assume that since their ancestors didn't, their descendants never will.