Antiviral Research: N70S/Y155H Combined Mutation of Neuraminidase of Avian Influenza H9N2 Virus confers oseltamivir and zanamivir resistance . . .

[Michael Coston]

Antiviral Research: N70S/Y155H Combined Mutation of Neuraminidase of Avian Influenza H9N2 Virus confers oseltamivir and zanamivir resistance and pathogenicity to Mice​

Range Of Endemic H9N2 Viruses

#19,357

LPAI H9N2 has gained a reputation for spreading uncontrollably in Asian and African poultry, for frequently reassorting with other viruses, and for increasingly spilling over into humans.

Nature: Genetic diversity of H9N2 avian influenza viruses in poultry across China and implications for zoonotic transmission

J. Inf.: Zoonotic Threat of Novel H6N2 Avian Influenza Virus with Internal Genes Exclusively Derived from H9N2, China, 2025

Emerg. Microbes & Inf.: Novel emerging reassortant H6 avian influenza viruses with internal genes from G57 genotype of H9N2 pose potential zoonotic risk

WHO WPRO Reports 2 Recent H9N2 Cases From Chinese Mainland

While H9N2 is rarely thought of as being in the same league as H5N1, the CDC lists two lineages (A(H9N2) G1 and A(H9N2) Y280) as having modest pandemic potential, and several candidate vaccines have been developed.




As a standalone virus, H9N2 appears to pose a moderate threat, but it has frequently aided and abetted more formidable novel flu viruses (e.g. H5N1, H5N6, H7N9, H10Nx) by providing some or all of their internal genes (see PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9).

Last month, we looked at report of 6 H6Nx reassortants - all carrying the internal genes from H9N2 - and 5 with its NA from H5N1, and 1 NA from H9N2. Of note, the H6N2 isolate showed dual receptor binding to both avian and human-like receptor cells.

This promiscuous nature magnifies any changes that might increase LPAI H9N2's zoonotic threat, since they could potentially be `shared' with other novel influenza A viruses.

Which brings us to a paper published this week reporting reduced in vitro susceptibility to oseltamivir and zanamivir among H9N2 viruses carrying dual N70S/Y155H neuraminidase mutations—a combination the authors suggest has become common among recently circulating viruses in China.

The authors report as much as a 42-fold reduction in viral inhibition in one isolate tested, and a 23-fold reduction in another.

Neither is enough to render oseltamivir or zanamivir useless, but it could reduce their effectiveness, particularly in cases of delayed treatment or severe infections.

This is a fairly technical paper, so I've only posted a few excerpts. Those wishing a deeper dive will want to follow the link and read the paper in its entirety. I'll have a brief postscript after the break.

N70S/Y155H Combined Mutation of Neuraminidase of Avian Influenza H9N2 Virus confers oseltamivir and zanamivir resistance and pathogenicity to Mice
Shenyu Ma a 1, Yuting Chen a 1, Jianwen Zhu a 1, Yuhan Zong b c, Keyu Cai b c, Zhonglong Yang b c, Wenlei Wang a, Yunfei Guo b c, Yan Guo a, Xinyue Duan a, Ziyan Fang a, Nan Zhu a, Sujuan Chen b c, Pinghu Zhang a c

10.1016/j.antiviral.2026.106540

Highlights

• H9N2 viruses recently circulating in China harbors novel N70S/Y155H dual mutations in N2;

• H9N2 viruses with N70S/Y155H mutations exhibit high pathogenicity to BALB/c mice.

• N70S/Y155H linked mutations in N2 confer resistance to oseltamivir and zanamivir, rather than peramivir.

• Neuraminidase inhibitors exhibited limited efficacy on H9N2 virus with novel N70S /Y155H dual mutations.

Abstract

Recently, H9N2 avian influenza virus (AIV) poses a significant threat to both the poultry industry and public health. Therefore, investigating the impact of its neuraminidase mutations on susceptibility to neuraminidase inhibitors (NAIs) is of great importance for clinically preventing potential cross-species transmission of H9N2.

In this study, our results revealed that NAI resistance-related mutations of most H9N2 viruses isolated from China during 1998 to 2024 mainly occurred at positions N70S, E119A/D/G/V, Q133K, Q136A, D151E, Y155H, I222V, R224K, E276D, R292K, N294S, and R371K.

Among them, the combined N70S and Y155H mutations are common characteristics of H9N2 viruses circulating in recent years. In vivo experiments demonstrated that these H9N2 viruses harboring the combined N70S and Y155H mutations exhibit high pathogenicity to BALB/c mice without prior adaption.

In vitro neuraminidase inhibition assays confirmed that these H9N2 viruses bearing the N70S/Y155H mutations exhibited greater reduced inhibition than their counterparts bearing the N70S or Y155H single mutation to oseltamivir and zanamivir, but remained highly sensitive to peramivir.

Notably, the in vivo protective effect of NAIs against H9N2 virus with combined N70S and Y155H mutations is limited, possibly due to the restricted ability of these drugs to ameliorate the excessive inflammatory responses. Therefore, there is an urgency to strengthen research on epidemiological surveillance and prevention strategies for avian influenza H9N2 harboring these mutations.

(SNIP)

Discussion

In this study, we performed phylogenetic and comparative sequence analyses of the neuraminidase (NA) genes from 125 H9N2 avian influenza viruses isolated from poultry between 1998 and 2024. Our results showed that early H9N2 viruses circulating in China mainly belonged to the G1-like lineage, whereas more recent strains were predominantly classified within the Y280-like lineage.

Sequence analysis further revealed that most of H9N2 viruses harbored multiple mutations associated with reduced susceptibility to neuraminidase inhibitors (NAIs), including substitutions at catalytic or framework residues (E119A/D/G/V, R292K, N294S, and R371K), as well as N70S, D151E, Y155H, R224K, and E276D mutations, which may affect enzyme conformation or the substrate-binding microenvironment[25].

These findings suggest that H9N2 viruses may have gradually accumulated a genetic background associated with altered antiviral susceptibility during long-term evolution.

(SNIP)
Collectively, our findings provide new experimental evidence for understanding the relationship between the combined N70S and Y155H mutations in N2 and altered susceptibility to NAIs in avian influenza H9N2 viruses. This study expands current understanding of the susceptibility of H9N2 to NAIs and highlights the need for continued surveillance of emerging neuraminidase mutations of H9N2 viruses circulating in poultry.

(Continue . . . )

While none of this necessarily elevates the public health threat of LPAI H9N2, this general trend of LPAI H9N2 to accrue resistance mutations bears watching, particularly when you consider the numerous other warnings we've seen of its zoonotic potential.

EM&I: Genetic evolution, phylodynamics, geographic spread of H9N2 avian influenza viruses in China from 2014 to 2025: an increasing potential zoonotic risk

Viruses: Epidemiological and Virological Characteristics of H9N2 Avian Influenza Virus in Jiangsu Province, China, 2024

EM&I: Enhanced Replication of a Contemporary Avian Influenza A H9N2 Virus in Human Respiratory Organoids

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