#18,746
While H5 and H7 viruses get the bulk of our attention - primarily because they often produce severe (sometimes fatal) disease in humans - there are a number of other `lesser' zoonotic influenza threats we keep close watch on as well.
Amongst them, LPAI H9N2 is probably the most evolutionarily agile.
It is has not only become ubiquitous in Asian and Middle Eastern poultry, it readily reassorts with other subtypes (see The Lancet: H9N2’s Role In Evolution Of Novel Avian Influenzas), and has been increasingly reported as spilling over into humans (see last month's HKCHP Reports 8 H9N2 cases).
Although most H9N2 infections have been mild, several deaths have been reported.
A 2021 study (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China)) by researchers from Shanghai and the Netherlands found the current inactivated virus vaccines used in China against H9N2 to be no match for this rapidly evolving pathogen.
The failure of vaccination might be because of inefficient application, low dose, and low vaccination coverage (especially in the household sector).11,12 Moreover, the continuing transmission in combination with the intensive long-term usage of the inactivated virus vaccine may have led to antigenic changes leading to immune escape.
The CDC has identified 2 different lineages (A(H9N2) G1 and A(H9N2) Y280) as having some pandemic potential (see CDC IRAT SCORE) - and several candidate vaccines have been developed - but much of H9's evolution remains hidden.
H9N2 is such a versatile virus, a variant of 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).
Last March, in Cell: Early-warning Signals and the Role of H9N2 in the Spillover of Avian Influenza Viruses, we took a deep dive into the evolving threat from H9N2. Yesterday Nature published a study (see below) on the continued evolution of H9N2 in China that, alas, is behind a paywall.
Published: 03 June 2025(2025)
Jing Yang, Juan Li, Ju Sun, Jiaming Li, Guanghua Fu, Tian Tian, Yongchun Yang, Xuancheng Lu, Shan Li, Lixia Wang, Jia Dong, Mingjia Wu, Yun Liu, Delong Li, Dongfang Hu, Hui Dong, Ruoyu Shang, Yanqing Wang, Kunpeng Yuan, Lin Ran, Honglei Sun, Wenxia Tian, Yu Huang, Jinhua Liu, … Yuhai Bi
Those that have access will certainly want to read the full report, but for the rest of us we have a press release that provides the gist. First some excerpts (emphasis mine), after which I'll have a postscript.
Researchers uncover genetic keys to the increasing threat of H9N2 avian influenza
Peer-Reviewed Publication
Chinese Academy of Sciences Headquarters
Credit: BI Yuhai
A new study published in Nature Microbiology has uncovered significant genetic and antigenic diversity among H9N2 avian influenza viruses (AIVs) circulating in poultry across China, highlighting the growing public health risk posed by H9N2 AIVs.
Although H9N2—first identified in China in 1994—has been targeted by ongoing vaccination strategies, it has remained the dominant subtype in poultry. Its persistence, along with increasing reports of human infections in recent years, has become a growing public health concern.
Previously, the molecular basis for the virus' cross-species transmission and zoonotic potential remained largely unclear. Now, however, a collaborative team led by Prof. BI Yuhai and Prof. George F. Gao (GAO Fu) from the Institute of Microbiology of the Chinese Academy of Sciences, together with Prof. SHI Weifeng of Ruijin Hospital at the Shanghai Jiao Tong University School of Medicine, has conducted a comprehensive investigation into the virus' genetic evolution, antigenic variability, and adaptive mutations. Their findings offer crucial insights concerning the virus' molecular mechanism for mammalian adaptation and evasion of human MxA gene-mediated innate immune responses.
Since 2014, Prof. BI Yuhai has organized teams from the Center for Influenza Research and Early-warning (CASCIRE) to conduct continuous surveillance and early warning of AIVs in China and study cross-species transmission mechanisms of AIVs. Surveillance in live poultry markets from 2019 to 2023 revealed that the A/chicken/Beijing/1/94 (BJ94) lineage of H9N2 AIVs has consistently dominated in poultry.
To better understand its evolutionary trajectory, the team developed a novel clade classification system for BJ94 viruses based on genetic distances and phylogenetic relationships. They also launched an online classification platform to enable global researchers to track and study H9 AIV evolution.
Using this framework, they identified ten hemagglutinin (HA) sub-subclades currently co-circulating among poultry, each exhibiting distinct antigenic variations. These differences may explain why the existing vaccines have been unable to curb the epidemic of H9N2 AIVs.
Additionally, the researchers found a rising prevalence of key mutations associated with increased infectivity and pathogenicity in mammals.
- Between 2021 and 2023, 99.46% of H9N2 isolates carried the HA-L226 mutation linked to human receptor binding;
- 96.17% contained the NP-N52 mutation associated with resistance to the human MxA antiviral protein;
- and 32.61% had the PB2-V627 mutation known to enhance polymerase activity in human cells.
Experiments demonstrated that strains harboring these mutations preferentially bound to human-type receptors, replicated efficiently in human cells, and were capable of direct contact and aerosol transmission in guinea pigs and ferrets—key indicators of zoonotic potential.
These results highlight the heightened zoonotic risks of H9N2 AIVs. This study underscores the urgent need for enhanced surveillance, updated vaccine strategies, and a deeper understanding of avian influenza virus evolution to mitigate the growing threat of H9N2 to public health.
This work was supported by the National Key R&D Program of China and the National Natural Science Foundation of China for Distinguished Young Scholar.
Whether as a standalone zoonotic virus - or a co-conspirator with another subtype - LPAI H9N2 poses a significant public health threat. It is often underestimated because it is not considered a `reportable' disease in poultry, and mild or moderate human cases are unlikely to be picked up by passive surveillance.
While poultry and (potentially) livestock vaccination are being heavily touted to control H5N1, the experience with H9N2 reminds us that poultry vaccination alone hasn't always solved the problem.
A safe and effective vaccination program (see UK Joint Taskforce Policy Paper: Vaccination of Birds Against HPAIV (bird flu)) requires the use of proven, and continually updated vaccines, along with regular testing (and if necessary, quarantining or culling) of vaccinated flocks.
Last April, in NPJ Vaccines: Impact of Inactivated Vaccine on Transmission and Evolution of H9N2 Avian Influenza Virus in Chickens. we looked at a Chinese study that warned that improper or inadequate use of inactivated vaccines have failed to prevent - or even reduce - H9N2 in China's poultry, and may well have driven viral evolution (including mammalian adaptations).
While on paper, an H9N2 pandemic doesn't look to be as fearsome as an H5 or H7 pan-flu, we've only limited experience with human infections with this subtype (< 160 cases), and past performance isn't always indicative of future results.
The H9N2 virus is obviously still evolving, and deserves both our attention and our respect.
