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| Credit NIAID |
#19,172
While LPAI H9N2 remains far from our biggest pandemic concern, the CDC has designated 2 different lineages (A(H9N2) G1 and A(H9N2) Y280) as having at least some pandemic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed.Many will be surprised to find that, in terms of risk of emergence, the H9N2 Y280 lineage is ranked higher than H5N1, while the G1 lineage is ranked only slightly lower.
Although our concerns are primarily with the Asian lineages of H9N2, only a week ago in Preprint: Outbreak of H9N2 Avian Influenza Viruses in Lesser Rhea in Peru, June-July 2025 we looked at the unexpected emergence of a South American lineage.
H9N2 viruses are infamously promiscuous, and are constantly reassorting with other subtypes, which only increases their pandemic potential (see PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9).
All of which makes it important to know how much existing immunity their might be in the community should LPAI H9N2 ever embark on a world tour; particularly from regions of the world where the virus has not been circulating.
To that end we have the following Rapid Communication - published yesterday in the journal Eurosurveillance - which looks at a relatively small cohort (n=298) of serum samples collected in NYC between between Feb 2024 and Apr 2025, which they tested for signs of pre-existing immunity against 1 specific strain (A/Changsha/SR353/2025 - Y280 lineage) of LPAI H9N2.
In brief, they found widespread - but weak - cross-reactive haemagglutinin (HA)-binding antibodies among the 298 samples, likely due to previous seasonal flu vaccinations and/or exposures (see comparison chart below).
At least that's the hope.
Interestingly, there is a small but perceptible dip in both HA and NA inhibition activity in those born in the mid-to-late 1980s and early 1990s, but given the small sample size and weak response, this may not be significant.
Although the news isn't all bad, this study looks at only one small and geographically limited dataset - and one specific strain of LPAI H9N2 - so there is only so much we can infer from their findings.
I've only posted the link and some excerpts below, most will want to follow the link to read the report in its entirety.
Open Access
Cross-reactive human antibody responses to H9N2 influenza virus, New York, United States, 2025Gagandeep Singh1,2 , Disha Bhavsar1,2 , Lucas M Ferreri3 , Jessica R Nardulli1,2 , Charles Gleason1,2 , Neko Lyttle1,2 , Yuexing Chen1,2 , Anice C Lowen3 , Viviana Simon1,2,4,5,6 , Florian Krammer1,2,6,7,8
Avian influenza A(H9N2) viruses have been endemic in poultry for many years across Asia, the Middle East, and Northern and Western Africa and have been detected periodically in the Americas and Europe. Since their first detection in 1966, H9N2 viruses have evolved into multiple lineages and exhibit a high propensity for reassortment, contributing internal genes to zoonotic viruses such as H5N1, H7N9 and H10N8 [1,2].
Human infections with H9N2 viruses have been reported since 1998, with most cases linked to poultry exposure and typically resulting in mild or asymptomatic disease but severe cases and deaths have been observed as well. Despite these observations, population-level immunity to H9N2 remains poorly defined, particularly in regions without endemic exposure to the virus.
(SNIP)Here, we assessed cross-reactive antibody responses to H9N2 viruses using a panel of recently collected human sera from the general population of a large metropolitan city in North America (New York City)
Our work describes pre-existing immunity at population level to avian influenza A(H9N2) viruses in adults from New York City. We observed widespread cross-reactive haemagglutinin (HA)-binding antibodies in the sampled group; however, these responses were of lower magnitude than those against seasonal H3. Consistent with this, HI and neutralising antibody responses to H9N2 were low or undetectable in most individuals, indicating limited functional immunity.
In contrast, a high proportion of individuals exhibited N2-binding and NI antibodies, including cross-reactive responses to H9N2. Although NA-directed antibodies do not prevent infection, they may reduce viral replication and disease severity, potentially providing the population with some degree of resilience against emerging influenza viruses [6,7]. The comparable magnitude of NI responses to H9N2 and H3N2 suggests that prior exposure to seasonal influenza viruses has generated cross-reactive NA immunity. This is consistent with historical observations that pre-existing anti-N2 antibodies, induced during circulation of A(H2N2) viruses, may have contributed to reduced disease severity during the emergence of the A(H3N2) pandemic [17,18].
The difference between HA and NA responses is not surprising. Comparative sequence analysis revealed substantial divergence between the HA proteins of lineage B4.7.2 virus A/Changsha/SR353/2025 (H9N2) and seasonal A/Thailand/8/2022 (H3N2), with only approximately 40% amino acid identity. In contrast, the N2 neuraminidases of the two viruses showed high conservation, sharing approximately 89% amino-acid identity.
Our study also has several limitations. Vaccination data were not captured, and we therefore cannot draw any conclusions about the effect of seasonal vaccination on H9N2 immunity. Furthermore, our analysis was restricted to a small, geographically limited group of individuals. Finally, different lineages of H9N2 circulate and they are antigenically distinct. This study only used one of these viruses as reagent and cross-reactive responses to other lineages of H9N2 may differ.
Conclusion
In summary, we found that pre-existing immunity to H9N2 in humans that is dominated by cross-reactive but largely non-neutralising antibodies, with a greater contribution from NA-directed responses. Given the pandemic potential of H9N2 viruses, these findings have important implications for risk assessment and support the inclusion of NA immunity in vaccine development strategies.
Further studies are needed to confirm whether cross-reactive NI antibodies confer protection against H9N2 infection or modulate disease severity, but our results suggest that the antibodies against H9N2 virus might derive from exposure to conserved epitopes shared between the avian-origin and seasonal strains.(Continue . . . )
