Cell: Early-warning Signals and the Role of H9N2 in the Spillover of Avian Influenza Viruses

 

#18,394

While H9N2 may not be at the very top of our pandemic threats list, this LPAI virus is viewed by many as an important and influential player in the avian flu world. 

• H9N2 has become widespread - even ubiquitous - among poultry across Asia, Europe. the Middle East, and more recently Africa (see Viruses: Genetic Evolution of Avian Influenza A (H9N2) Viruses in Uganda & Evidence of Mammalian Adaptation)

• Serological studies suggest human infection may be far more common than standard surveillance (see FluTrackers List) would suggest (see HK CHP: Mainland China Reports 2 More H9N2 Cases)

• H9N2 reassorts easily with other viruses, and its internal genes are often found inside many avian and swine viruses (including H5N1, H5N6, and H7N9) -  (see EID Journal: Natural Reassortment of EA H1N1 and Avian H9N2 Influenza Viruses in Pigs, China)

• H9N2 viruses continue to accrue evolutionary changes, which include mammalian adaptations, and increased binding to human receptor cells (see PLoS Path: Genetics, Receptor Binding, and Transmissibility Of Avian H9N2).
• Control of H9N2 has been difficult, as the virus continues to mutate, and many countries continue to use outdated and ineffectual vaccines (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China), some of which may be driving its evolution.

While  H9N2 is not considered a `reportable' disease by WOAH (formerly the OIE), the CDC has 2 different lineages (A(H9N2) G1 and A(H9N2) Y280) on their short list of influenza viruses with pandemic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed.

But H9N2's biggest threat may come its ability to reassort with other, potentially more virulent, subtypes. 

Its internal genes have often been found inside many HPAI viruses (including H5N1, H5N6, H7N9, and most recently zoonotic H3N8) - (see last January's Transboundary & Emerging Dis.: The H5N6 Virus Containing Internal Genes From H9N2 Exhibits Enhanced Pathogenicity and Transmissibility).

   

H9N2 is such a versatile virus, it has even been detected in Egyptian Fruit bats (see Preprint: The Bat-borne Influenza A Virus H9N2 Exhibits a Set of Unexpected Pre-pandemic Features).

Seven years ago, in EID Journal: Two H9N2 Studies Of Note, we looked at two reports which warned that H9N2 continues to evolve away from current (pre-pandemic and poultry) vaccines and is potentially on a path towards better adaptation to human hosts.

All of which serves as prelude to an article, published this week in Cell, which examines H9N2's role in facilitating the spillover of avian flu viruses to humans.   This is a lengthy, and detailed report, and I've only posted some brief excerpts.  

Follow the link to read it in its entirety. I'll have a bit more after the break. 

Article Online now 100639 March 25, 2025 Open access

Early-warning signals and the role of H9N2 in the spillover of avian influenza viruses

Yan-He Wang1,2,12 ∙ Jin-Jin Chen1,3,12 ∙ Jun Ma1,4,12∙ … ∙ Yan-Song Sun1 sunys6443@126.com ∙ Wei Liu1,7 liuwei@bmi.ac.cn ∙ Li-Qun Fang1,4,7,13 fang_lq@163.com… Show more Context and significance

Highlights

Wang et al. provided valuable insights into the epidemiological patterns of avian influenza virus (AIV) spillover and the role of H9N2 in the process. Their analysis highlighted the significant contribution of the internal genes (INGEs) from 12 key strains of H9N2 in facilitating human adaptability by reducing the species barrier between poultry and humans, essentially acting as internal genetic donors for AIV spillover.

Due to its low pathogenicity, H9N2 has been neglected in poultry vaccination programs, leading to a lack of vaccines specifically targeting the INGEs of these 12 key strains. Their findings suggest that reducing the prevalence of H9N2 is fundamental to mitigating AIV spillover risks.

• H9N2 exerts a promoting effect on the spillover of avian influenza viruses (AIVs)

• Expansion of AIV spatial and host ranges reveals an emerging risk of its spillover

• Prevalence of AIVs in human-contacted hosts reveals a re-emergence risk in humans

Summary

Background

The spillover of avian influenza viruses (AIVs) presents a significant global public health threat, leading to unpredictable and recurring pandemics. Current pandemic assessment tools suffer from deficiencies in terms of timeliness, capability for automation, and ability to generate risk estimates for multiple subtypes in the absence of documented human cases.

Methods

To address these challenges, we created an integrated database encompassing global AIV-related data from 1981 to 2022. This database enabled us to estimate the rapid expansion of spatial range and host diversity for specific AIV subtypes, alongside their increasing prevalence in hosts that have close contact with humans. These factors were used as early-warning signals for potential AIV spillover. We analyzed spillover patterns of AIVs using machine learning models, spatial Durbin models, and phylogenetic analysis.

Findings

Our results indicate a high potential for future spillover by subtypes H3N1, H4N6, H5N2, H5N3, H6N2, and H11N9. Additionally, we identified a significant risk for re-emergence by subtypes H5N1, H5N6, H5N8, and H9N2. Furthermore, our analysis highlighted 12 key strains of H9N2 as internal genetic donors for human adaptation in AIVs, demonstrating the crucial role of H9N2 in facilitating AIV spillover.

Conclusions

These findings provide a foundation for rapidly identifying high-risk subtypes, thus optimizing resource allocation in vaccine manufacture. They also underscore the potential significance of reducing the prevalence of H9N2 as a complementary strategy to mitigate chances of AIV spillovers.

(SNIP)

The H9N2 virus has been prevalent in poultry for an extended period. Despite its low pathogenicity and case fatality rate,10,34 our data show that it plays a crucial role in the spillover of AIVs within local and surrounding areas.

Moreover, H9N2 viruses contributed to recombination events involving eight AIV subtypes that recently spilled over into humans by providing their six INGEs to these viruses. This suggests that H9N2 facilitates the generation of human adaptivity by reducing the species barrier between poultry and humans.57,58

These findings highlight that reducing the prevalence of H9N2 could potentially mitigate the spillover of AIVs, serving as an alternative strategy for preventing individual subtypes such as H5N1, H5N6, and H7N9.

(Continue . . . )

While undoubtedly much older, LPAI H9N2 was first identified in Wisconsin poultry in 1966.  In the 1990s it swept across much of Eurasia, becoming `hyperendemic' in many affected countries (see 2019's Viruses: A Global Perspective on H9N2 Avian Influenza Virus).

Range Of Endemic H9N2 Viruses

While some attempts have been made at controlling the virus (including using largely ineffective vaccines) - since H9N2 produces relatively mild illness in poultry - it is often tolerated or ignored. 

Over the past 3 decades H9N2 has managed to spread across much of Asia, and into Europe, Africa and the Middle East. It has diverged into two distinct lineages, has increased its ability to  infect mammals, and it continues to fuel the emergence and spillover of new subtypes. 

It seems likely that unless and until H9N2 can be better controlled, our avian flu woes may extend far beyond just H5Nx in the years ahead.