#18,470
China has often been called the `cradle of influenza', primarily because human, avian, and swine influenza viruses circulate there more-or-less year round, population densities are very high, and because live poultry markets and backyard livestock afford ample opportunities for spillovers.During the 20th century, 2 of the 3 major influenza pandemics (1957 Asian Flu, 1968 Hong Kong Flu) are thought to have originated from this region. The emergence and global spread of H5 A/Goose/Guangdong/1/1996 (gs/GD) lineage in Southeastern China in the mid-1990's only helped to cement that reputation.
In March of 2013, in EID Journal: Predicting Hotspots for Influenza Virus Reassortment, we looked at a paper that identified areas of the globe most likely to spawn the next novel flu virus.
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| EID Influenza Hotspots For Reassortment - 2013 |
The study cited:
Potential geographic foci of reassortment include the northern plains of India, coastal and central provinces of China, the western Korean Peninsula and southwestern Japan in Asia, and the Nile Delta in Egypt.Timing, as they say, is everything. Less than 3 weeks later, China announced the emergence of the biggest avian flu threat seen to date - H7N9 - which first appeared (as predicted) in the central coastal provinces of China (Anhui, Shanghai). Over the next 5 years it would spark 5 distinct waves with an apparent fatality rate (among those hospitalized) of roughly 30%.
A few months later the first of several H10Nx infections were reported in China, and in 2014 they reported the first of (now > 90) H5N6 spillover events, which have been fatal in roughly 50% of reported cases.
China also leads the world in reported human H9N2 infections, and has detected a handful of other zoonotic influenza spillovers (H7N4, H3N8, etc.).
While official reports of novel flu outbreaks and infections from China (and elsewhere) are often belated, `sanitized', or are only released `strategically' (see From Here To Impunity), we've seen a steady stream of refreshingly blunt scientific papers coming out of China warning on the increasing incidence, and complexity, of their novel flu viruses.
A few recent examples include:
Virology Journal: Emerging Zoonotic Potential of H4N1 Avian Influenza Virus: Enhanced Human Receptor Binding and Replication via Novel MutationsTo this list we have a report - published yesterday in Emerging Microbes & Infections - which details the increasingly complex, unique, and intertwined constellation of HPAI H5 viruses circulating in China.
Transboundary & Emerging Dis.: The H5N6 Virus Containing Internal Genes From H9N2 Exhibits Enhanced Pathogenicity and Transmissibility
BMC Genomics: Evidence of an Emerging Triple-reassortant H3N3 Avian Influenza Virus in China
China CDC Weekly: Infection Tracing and Virus Genomic Analysis of Two Cases of Human Infection with Avian Influenza A(H5N6) — Fujian Province, China
Vet. Microbiology: The novel H10N3 Avian Influenza Virus Acquired Airborne Transmission Among Chickens: An Increasing Threat to Public Health
While China's H5N6 virus has been on our radar for more than a decade, it - unlike H5N1 - has only rarely been detected in wild or migratory birds. It has remained geographically limited to Mainland China, with a few excursions into Vietnam, Laos, and Cambodia.
That, however, may be changing as H5N6 continues to co-circulate with, and reassort with, the vagabond clade 2.3.4.4b H5N1 virus. The authors report:
". . . a novel H5N6 genotype, N6.4, has been detected, whose HA gene and some internal gene fragments are directly derived from G-II H5N1 viruses. Animal experimental results further confirm that the N6.4 virus shows greater virulence and pathogenicity in chicken and mouse models than G-I H5N6 viruses, suggesting that it has enhanced adaptability and a heightened potential for cross-host transmission."
There is a lot more to unpack from this research article. I've only posted the abstract and discussion, so follow the link to read it in its entirety. I'll have a postscript after you return.
Emerging Microbes & InfectionsLatest ArticlesResearch ArticleUnique Phenomenon of H5 Highly Pathogenic Avian Influenza Virus in China: Co-circulation of Clade 2.3.4.4b H5N1 and H5N6 results in diversity of H5 VirusXinkui Zhang,Yujia Yang,Xinyu Han,Dandan Wei,Beibei Niu,Qiuhong Huang,show allArticle: 2502005 | Accepted author version posted online: 06 May 2025
Abstract
Recently, Clade 2.3.4.4b H5N1 virus has been widely prevalent globally. Although no outbreaks of Avian Influenza have occurred in poultry in China recently, Clade 2.3.4.4b H5 virus can still be isolated from wild birds, live poultry markets and environment, indicating the ongoing co-circulation of H5N1 and H5N6 viruses.
In this study, phylogenetic analysis of global Clade 2.3.4.4b viruses and 20 laboratory-isolated H5 strains revealed that Chinese H5N1 and H5N6 viruses since 2021 cluster into two distinct groups, G-I and G-II. Bayesian phylodynamic analysis reveals that G-I H5N6 virus has become an endemic virus in China. In contrast, G-II H5N1 virus, with South China as its main epicentre, has been disseminated in China and its surrounding countries, with its transmission more reliant on the connections of wild birds and waterfowl.
Reassortment analysis indicates that since 2023, Clade 2.3.4.4b H5 viruses isolated in China have formed seven genotypes. The genome of H5 viruses has undergone changes compared to those previously prevalent in China. Animal experiments have shown that prevalent H5 viruses exhibit significant lethality in chickens. Additionally, certain H5 viruses have shown the capability of systemic replication in mice.
It is noted that H5N6 viruses with HA genes derived from H5N1 viruses demonstrate stronger virulence and pathogenicity in chickens and mice compared to G-I H5N6 viruses. Our study indicates that the co-circulation of H5N1 and H5N6 viruses in China has increased the diversity of H5 viruses, making continuous surveillance of H5 viruses essential.
(SNIP)
Discussion
Since the autumn of 2021, the Clade 2.3.4.4b H5N1 AIV has been widely circulating among wild birds and domestic poultry in various countries. Although the H5N1 subtype has become the predominant strain, other subtypes such as H5N2, H5N6, and H5N8 have also been detected in avian populations[35–37]. The novel H5N6 and H5N1 viruses from the Clade 2.3.4.4b emerged in China in 2021 and have since been co-circulating and spreading.
This study elucidates the differences in transmission patterns and genotypic evolution of Clade 2.3.4.4b H5N1 and H5N6 viruses in China since 2021. The discrepancy in the spread of G-I H5N6 and G-II H5N1 viruses is closely related to the host ranges of the two viruses and the seasonal transmission patterns of AI in Asia[38].
H5N6 viruses in G-I groups mainly spread among poultry in China, and this host specificity may restrict their ability to spread widely geographically via wild bird migration. Studies have shown that once AIV adapt to domestic chickens, their adaptability in wild birds is reduced, making it difficult for them to re-enter the wild bird virus pool[1,39].
In contrast, the H5N1 virus exhibits a broader host range, with wild birds playing a pivotal role in its transmission. Wild birds, being the natural reservoirs of AIV, are diverse and widely distributed, driving the global spread of AIV through long-distance migration[40,41]. Moreover, the South China region, as an epicenter for H5 viruses in China, owes its geographical hub status to multiple ecological factors. The region is densely populated with poultry farms and live poultry markets, has frequent cross-regional poultry movement, and lies along the East Asian-Australasian Flyway, making it a crucial habitat for numerous migratory birds[42–45]. This unique combination of factors facilitates the coexistence and circulation of diverse viral genotypes in the region, thereby increasing the likelihood of genetic reassortment and further enhancing regional viral diversity.
Since 2023, the Clade 2.3.4.4b H5 virus in China has exhibited complex reassortment patterns, evolving into multiple genotypes with significant genomic differences from the earlier prevalent H5N1 and H5N6 viruses. During 2020–2021, the genes of H5N1 viruses prevalent in China mainly originated from H5 viruses in Europe and Russia, as well as from LPAI viruses. In contrast, H5N6 viruses were formed by the reassortment of the globally disseminated H5N8 viruses with local H5N6 and LPAI viruses in China[16,20]. Currently, the genes of H5N1 viruses mainly come from H5N1 viruses in Asia and LPAI viruses, while H5N6 viruses have more complex genetic origins than before.
In the current context of co-prevalence of H5N1 and H5N6 viruses, a novel H5N6 genotype, N6.4, has been detected, whose HA gene and some internal gene fragments are directly derived from G-II H5N1 viruses. Animal experimental results further confirm that the N6.4 virus shows greater virulence and pathogenicity in chicken and mouse models than G-I H5N6 viruses, suggesting that it has enhanced adaptability and a heightened potential for cross-host transmission. This finding underscores the potential changes in biological properties that may arise from genetic reassortment among H5 viruses. Such reassortment allows for rapid viral evolution, facilitating interspecies transmission and posing an ongoing threat to public health[46].
The viruses isolated in this study have Q226 and G228 at the HA receptor-binding site, indicating a preference for avian-type α-2,3 sialic acid receptors. However, the presence of amino acids 137A, 158N, 160A, 186N, and 192I in the HA protein also suggests a potential for binding to human-type α-2,6 sialic acid receptors(Table S9a)[47–49]. Notably, significant amino acid differences at positions 83, 154, 188, and 487 (H5 numbering) were observed in the HA between G-I and G-II group isolates(Table S10). These variations may be related to the differences in virulence and pathogenicity of the two types of viruses in animal models in this study, but the specific biological mechanisms still need further research. In addition, we identified the PB2-E627 K substitution in one isolate—a well-documented mutation associated with enhanced viral polymerase activity and mammalian adaptation[50].
Furthermore, a series of amino acid substitutions previously reported to be associated with increased mouse virulence were identified in different proteins of the isolated strains, further supporting the potential risk of zoonotic transmission of these strains(Table S9)[48]. The mouse experiments in this study provide an early warning of the zoonotic potential of these viruses. Although the risk of human-to-human transmission of H5 viruses is still low now, their expanding host range and the outbreak of H5N1 in the US dairy cattle emphasize that Clade 2.3.4.4b viruses are constantly adapting to mammals[51,52].
Since 2023, seven H5 virus genotypes have emerged in China. However, overall genetic diversity remains lower than in Europe and the Americas[53]. This is partly attributable to inactivated vaccines are widely used in China, effectively curbing the spread of H5 viruses[54,55]. Also, H5N6 mainly spreads in poultry, restricting its gene pool expansion. Nevertheless, the emergence of new N6.3 and N6.4 genotypes in 2024 indicates that the co-circulation of H5N1 and H5N6 viruses is driving viral diversity evolution in China.
Antigenic analysis shows that vaccine-induced antisera have good cross-reactivity with Clade 2.3.4.4b H5 isolates. Yet, given the ongoing genetic reassortment and evolution of H5 viruses, it is crucial to continue updating vaccine strains dynamically. In the future, monitoring of H5 viruses and vaccine development should be strengthened to provide solid scientific support for AI prevention and control in China, and contribute Chinese expertise to global AI prevention.
We rarely see reports of H5N6 in Chinese poultry, likely because the H5+H7 vaccines used in China can sometimes mask the symptoms while still allowing them to spread (see Preprint: Association of Poultry Vaccination with the Interspecies Transmission and Molecular Evolution of H5 Subtype Avian Influenza Virus).
Often, when human cases do emerge, testing of asymptomatic flocks turns up the virus (see China CDC Weekly: Infection Tracing and Virus Genomic Analysis of Two Cases of Human Infection with Avian Influenza A(H5N6) — Fujian Province, China).
The prospect of seeing a more host-adaptable or more widespread H5N6 virus is not a welcome one. And since reassortment can be a two-way street, anything that might increase the virulence of our current H5N1 virus would be equally unwelcome.
While the recent lull in human case reports in the United States is encouraging - given the limits of surveillance and reporting - most of H5's evolution and global spread occurs outside of our view.
The brief glimpses we do get, however, suggest any respite we enjoy today may be fleeting.
