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

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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

 

Communications Medicine: Pathogen-specific ripple effects of COVID-19 nonpharmaceutical interventions in reshaping endemic disease dynamics

Heatmap of respiratory infections in Tokyo 2016-2026

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We've a new report in Nature today which looks at the reported incidence of 32 different infectious diseases in Tokyo, Japan over a nearly 10-year span (2016-2025), that  shows the changes that occurred during and after the height of the COVID/NPI era.

While some people still have doubts over the effectiveness of NPIs, the incidence of common respiratory infections (influenza, RSV, pertussis, even chickenpox) plummeted during 2020-2021 (see above graphic). 

But after the NPI mandates ended, most of these viral scourges returned; some with seemingly even greater intensity than before the lockdown. We followed many similar increases around the world.

CDC HAN #0484: Increase in Pediatric Invasive Group A Streptococcal Infections

Denmark SSI Declares A Mycoplasma Pneumonia Epidemic

WHO Statement (DON) On Respiratory Illness Surge Reported In Northern China

CDC HAN #00498: Increased Respiratory Syncytial Virus (RSV) Activity in Parts of the Southeastern United States

Others, like influenza, eventually returned to near pre-pandemic levels, although the influenza B/Yamagata lineage is now considered missing-in-action, with its last sighting in March of 2020. 

Notably, the incidence of tuberculosis reported in Tokyo dropped roughly 40% after the lockdown ended. 

The chart on vector-borne and/or sexually transmitted diseases is equally fascinating, as syphilis and HIV/AIDS reporting suggested only a small reduction during lockdown, and the incidence of syphilis sharply increased after the lockdown ended. 

In fairness, during the height of the pandemic, a lot of testing capacity was diverted to COVID, meaning rising or falling trends during that time period may not have been fully captured, which could account for some of the abrupt shifts seen after the lockdown ended. 

Admittedly, some of these post-pandemic shifts may be incidental findings, and not directly related to the lockdown. The authors warn:

Our cross correlation analyses quantify the temporal alignment between changes in reported incidence and NPI-related indicators (Fig. 2b, c), although these associations should not be interpreted as evidence of the independent causal effect of individual NPIs.

I've only reproduced a small excerpt from the study. Follow the link to read it in its entirety.  I'll have a brief postscript after the break.  

Pathogen-specific ripple effects of COVID-19 nonpharmaceutical interventions in reshaping endemic disease dynamics

Daipeng Chen, Seyed M. Moghadas & Gergely Röst
Communications Medicine (2026) Cite this article
 
We’re sharing this article early to provide faster access to peer-reviewed, accepted research. It is citable and carries a permanent DOI. This version is subject to further edits and will be replaced automatically by the final Version of Record. All legal disclaimers apply.

Abstract

Background

Nonpharmaceutical interventions (NPIs) implemented during COVID-19 disrupted the transmission of many endemic infectious diseases, but their broader, system-wide effects across multiple pathogens remain incompletely understood.

Methods

Using nearly a decade of weekly surveillance data for 32 infectious diseases in Tokyo, we combined time-series analyses, mechanistic modelling, and epidemic-trajectory reconstruction to investigate pathogen-specific changes associated with NPIs.

Results

High-incidence respiratory and intestinal infections decline most sharply in 2020, with reductions closely aligned with NPI stringency. Post-NPI rebounds vary substantially: respiratory syncytial virus and group A streptococcus peak several times above historical baselines, whereas influenza, hand, foot, and mouth disease, and herpangina return to pre-NPI levels. Model-based simulations suggest that differences in rebound magnitude and timing may depend on pathogen-specific epidemiological parameters related to immunity duration and susceptible replenishment. Beyond short-term resurgences, we also identify longer-lasting shifts in reported incidence trajectories, including reduced tuberculosis incidence, increased syphilis incidence, and a biennial phase shift in hand, foot, and mouth disease.

Conclusions

COVID-19 NPIs produce profound but highly pathogen-specific changes in other infectious disease dynamics. These effects extend beyond temporary suppression and rebound, with several pathogens exhibiting persistent deviations in reported incidence trajectories after the NPI period. These findings highlight how pathogen-specific epidemiological characteristics may contribute to heterogeneous post-NPI trajectories, which could inform tailored control strategies.

Plain language summary

Measures such as mask wearing, school closures, and reduced social contact were widely used during the COVID-19 pandemic to limit the spread of SARS-CoV-2. These nonpharmaceutical interventions also affected many other infectious diseases, but their broader consequences have not been fully understood. In this study, we analysed nearly 10 years of weekly surveillance data for 32 infectious diseases in Tokyo.

We found that many respiratory and intestinal infections fell sharply during 2020, but their resurgence after restrictions were lifted differed greatly between diseases. Some infections, such as respiratory syncytial virus infection and group A streptococcus infection, rebounded to unusually high levels, whereas others returned to patterns closer to those seen before the pandemic. We also found longer-term changes, including fewer tuberculosis cases, more syphilis cases, and a shift in the two-year cycle of hand, foot, and mouth disease. These results show that different infections may respond differently to large-scale public health measures, which may help improve disease surveillance and future control planning.

       (Continue . . . )

For logistical and political reasons, the world stopped reporting and counting COVID deaths quite early in the pandemic, but a 2022 Lancet report estimated 18.2 million excess deaths during the first 2 years. 

How many have died since then is unknown, as is how many deaths were prevented by the COVID vaccines, social distancing, and NPIs. It is probably fair to say all are measured in the millions. 

But every action (or inaction) has unintended consequences . . some good, some bad.  Some we may be able to predict, others not so much.  

Pandemics, like life, can only be understood by looking backwards. 

But with enough honest introspection, we might better understand - and handle - the next one. 

Novel Swine Flu and Remembrance

 

Yes, that’s me 50 years ago today (1976),
giving Swine Flu Shots.

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Fifty years ago today - Oct 1st 1976 - the United States began a bold, and ultimately ill-fated, emergency vaccination drive against the anticipated arrival of a novel H1N1 `swine flu' virus that had been detected nine months earlier on an army base in New Jersey.  

As an impossibly young, freshly-minted paramedic, who dealt primarily with heart attacks, strokes, and car wrecks, I unexpectedly found myself playing a minor part in the preparations for, and implementation of, our county's  vaccination campaign.

As the county's first, and at that time only, paramedic I'd been on the `rubber chicken circuit' for nearly a year, promoting our new telemetry systems and advanced life support capabilities to every trailer park, condominium, and civic organization who would have us (mostly on my days off). 

So, in the early summer, when the Health Department was ready to start promoting the emergency flu vaccination program, I got the call. Once or twice a week I'd present the case for getting the vaccine when it became available in the fall to anywhere from a few dozen to a few hundred people.

Since much of my audience were elderly, many had been teenagers or young adults during the 1918 pandemic, and so I heard a lot about their experiences at these community meetings. It was sobering, to say the least.

While all of this undoubtedly led to my becoming an infectious disease blogger, the rest of the story - thankfully - is not about me. 

To put things in context, 1976 was an election year, and Gerald Ford was an unelected incumbent, having ascended to the office after Richard Nixon resigned in August of 1974.  

He'd gotten off to a rough start, and badly needed a mandate. 

In February of 1976, a young recruit at Ft. Dix fell ill and died within 24 hours. Tests revealed he had a strain of influenza, previously unseen, dubbed `Swine Flu’. It was an H1N1, a strain that had disappeared `from the wild’ after the 1957 Asian Flu pandemic.

The alarm went out, and while no other deaths occurred at Fort Dix, many of the other soldiers tested positive for the virus. Most were without symptoms, but a few fell ill and recovered.

But CDC director David J. Sencer and others feared this virus could return in the fall - much like it did in 1918 - and spark another global pandemic. After considerable debate, President Ford held a televised press conference in March unveiling the National Swine Flu Immunization Program.

After a long, nervous, bicentennial summer - and no signs of the H1N1 virus - the decision was made to begin vaccination on October 1st. 

Things, famously, did not go as planned. Many of the early vaccine recipients were elderly, and several died within days of getting the shot.  While these appeared to be natural deaths, the media had a field day. 

Two weeks into the campaign, in an attempt to reassure the public of its safety, Gerald Ford got the shot live on TV. 

But the seeds of mistrust had been sown. Fewer and fewer people showed up for the shots. 

That was followed by reports of GBS (Guillain-Barré syndrome) among a small number of vaccine recipients. Whether, or how much, the shots contributed to these cases wasn't known then, but it further tarnished the vaccination campaign. 

In the end, the virus didn't reappear that fall. By December, > forty-million people had received the vaccine, and several hundred adverse events had been reported. The decision to pull the plug came on December 16th.  

You'll find a pretty complete narrative by Dr. Sencer et al., published 20 years ago in the EID Journal. I've only posted some extended excerpts, so follow the link to read it in its entirety.

Reflections on the 1976 Swine Flu Vaccination Program

David J. Sencer* and J. Donald Millar†
Author affiliations: *Atlanta, Georgia, USA;

Abstract

In 1976, 2 recruits at Fort Dix, New Jersey, had an influenza like illness. Isolates of virus taken from them included A/New Jersey/76 (Hsw1n1), a strain similar to the virus believed at the time to be the cause of the 1918 pandemic, commonly known as swine flu. Serologic studies at Fort Dix suggested that >200 soldiers had been infected and that person-to-person transmission had occurred. We review the process by which these events led to the public health decision to mass-vaccinate the American public against the virus and the subsequent events that led to the program's cancellation. Observations of policy and implementation success and failures are presented that could help guide decisions regarding avian influenza.       

(SNIP)

The National Influenza Immunization Program

On March 10, 1976, the Advisory Committee on Immunization Practices of the United States Public Health Service (ACIP) reviewed the findings. The committee concluded that with a new strain (the H1N1 New Jersey strain) that could be transmitted from person to person, a pandemic was a possibility.

Specifically, the following facts were of concern:

1. persons <50 years of age had no antibodies to this new strain;
2. a current interpandemic strain (A/Victoria) of influenza was widely circulating;
3.  this early detection of an outbreak caused by A/New Jersey/76/Hsw1N1 (H1N1) provided an opportunity to produce a vaccine since there was sufficient time between the initial isolates and the advent of an expected influenza season to produce vaccine. In the past when a new pandemic strain had been identified, there had not been enough time to manufacture vaccine on any large scale;
4. influenza vaccines had been used for years with demonstrated safety and efficacy when the currently circulating vaccine strain was incorporated;
5.  the military vaccine formulation for years had included H1N1, an indication that production was possible, and no documented adverse effects had been described.

ACIP recommended that an immunization program be launched to prevent the effects of a possible pandemic. One ACIP member summarized the consensus by stating "If we believe in prevention, we have no alternative but to offer and urge the immunization of the population." One ACIP member expressed the view that the vaccine should be stockpiled, not given.

(SNIP)

Shortly after the national campaign began, 3 elderly persons died after receiving the vaccine in the same clinic. Although investigations found no evidence that the vaccine and deaths were causally related, press frenzy was so intense it drew a televised rebuke from Walter Cronkite for sensationalizing coincidental happenings.

Guillain-Barré Syndrome

What NIIP did not and could not survive, however, was the second blow, finding cases of Guillain-Barré syndrome (GBS) among persons receiving swine flu immunizations. As of 1976, >50 "antecedent events" had been identified in temporal relationship to GBS, events that were considered as possible factors in its cause. The list included viral infections, injections, and "being struck by lightning." Whether or not any of the antecedents had a causal relationship to GBS was, and remains, unclear. When cases of GBS were identified among recipients of the swine flu vaccines, they were, of course, well covered by the press. Because GBS cases are always present in the population, the necessary public health questions concerning the cases among vaccine recipients were "Is the number of cases of GBS among vaccine recipients higher than would be expected? And if so, are the increased cases the result of increased surveillance or a true increase?" Leading epidemiologists debated these points, but the consensus, based on the intensified surveillance for GBS (and other conditions) in recipients of the vaccines, was that the number of cases of GBS appeared to be an excess.

Had H1N1 influenza been transmitted at that time, the small apparent risk of GBS from immunization would have been eclipsed by the obvious immediate benefit of vaccine-induced protection against swine flu. However, in December 1976, with >40 million persons immunized and no evidence of H1N1 transmission, federal health officials decided that the possibility of an association of GBS with the vaccine, however small, necessitated stopping immunization, at least until the issue could be explored. 

A moratorium on the use of the influenza vaccines was announced on December 16; it effectively ended NIIP of 1976. Four days later the New York Times published an op-ed article that began by asserting, "Misunderstandings and misconceptions... have marked Government ... during the last eight years," attributing NIIP and its consequences to "political expediency" and "the self interest of government health bureaucracy" (7). These simple and sinister innuendos had traction, as did 2 epithets used in the article to describe the program, "debacle" in the text and "Swine Flu Fiasco" in the title.

On February 7, the new secretary of DHEW, Joseph A. Califano, announced the resumption of immunization of high-risk populations with monovalent A/Victoria vaccine that had been prepared as part of the federal contracts, and he dismissed the director of CDC.

        (Continue . . . )

To this day, some political observers believe the decision to vaccinate the nation was politically motivated, and blame the Swine Flu fiasco for Gerald Ford’s loss that November. 

Hindsight being 20/20, it’s easy to second-guess the decision to go ahead with the vaccinations now.

But the choice back then was to take a chance on rolling out a new and untried vaccine, or risk hundreds of thousands of deaths from a flu pandemic.

Of course, had the Swine Flu pandemic hit in the winter 1976, the incidence of side effects would likely have been considered acceptable.

 
Looking back, I have a hard time faulting the government for going ahead with the vaccination program. I know, it is very popular now to paint them as incompetent, or worse, but I believe that they believed the threat was genuine.

Unfortunately, good intentions don’t always guarantee good outcomes.

Ironically, H1N1 would reappear a year later as the `Russian Flu', which mainly affected those under the age of 20.  Many believe it escaped from a Russian or Chinese lab, as it was nearly identical to a strain that had last been seen in the 1950s (see Microorganisms: The Growing Phenomenon of ‘Frozen’ Virus Genome Sequences and Their Likely Origin in Research Facility Escapes).

Thankfully, the flu vaccines of today are far different from the crude whole-virus or early split-virus preparations common in 1976.  It should also be noted we used the old pneumo-jet system, instead of syringes with needles. 

Today, that delivery system has fallen out of favor. Too much chance, in this age of AIDS and Hepatitis, of spreading other diseases. And mishandled, the high pressure injection could rip the skin.

Modern vaccines now use highly purified split-virus, subunit, recombinant, or cell-culture technologies that isolate key surface antigens - are generally administered using sterile, single-use disposable syringes - and have an enviable safety profile.

While the debacle of 1976 undoubtedly damaged the public's faith in flu vaccines, the successful rollout of an H1N1 pandemic vaccine in 2009 - and the COVID vaccine six years ago - hopefully gives the public more confidence going forward that a safe and effective vaccine can be developed and deployed in an emergency. 

Because like it or not, another pandemic is all but inevitable.   

Nature Comms: Diminished sialoside binding in novel H5N1 influenza hemagglutinin variants identified in a human patient

 

Flu Virus binding to Receptor Cells – Credit CDC

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In November of 2024, we learned (see Canada: PHAC Confirms HPAI H5N1 Genotype D1.1 In B.C. Human Infection) of a severe H5N1 influenza infection involving a teenage girl in British Columbia which was caused by the recently emerged D1.1 genotype.

Despite an intense investigation, the source of her infection was never determined.

In late December, it was disclosed (see NEJM: Critical Illness in an Adolescent with Influenza A(H5N1) Virus Infection) that the patient was a 13-year-old girl, and that after several weeks of intensive care she was able to come off ECMO (November 22nd), and was extubated on November 28th.  

In Referral: MedCram On Avian Flu Mutations That Favor Human Transmission, we looked at early reports of ambiguous mutations at several key sites (Q226 and E190 (H3 numbering)) in the HA gene. The NEJM report also mentioned the PB2-E627K mutation was detected (52% allele frequency).

All of which raised concerns that this particular patient might have been infected with a more efficient human-adapted virus.  But, as we've seen with most H5 human infections, there was no indication of human-to-human transmission.

Since then we've also seen studies suggesting that Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13, along with at least two North American deaths (here & here). 

All of which brings us to a study, published yesterday in Nature Communications, which unexpectedly finds that two mutations (Q226H and E190D) detected in the British Columbia case did not enhance human-type α2,6 binding.

In fact, they did the opposite. 

These mutations were detected 8 days post symptom onset in a minority (≤ 35%) of viral sequences detected in the patient's lower respiratory tract, and may have arisen after the patient was infected. Together, and/or separately, they produced almost-undetectable binding to α2,3 (avian-like) and α2,6 (human-like) sialoside receptors.

Despite this, the patient's lungs were clearly infected, producing severe - even life-threatening - illness. 

This is a lengthy, highly technical, and (for me, at least) daunting research paper which raises a lot of unanswered questions. 

While that may seem like `good news', it doesn't tell us much about the wild-type virus that originally caused this girl's infection, or where or how that virus entered the body.  

This is a sample of one, which suggests the Q226H and E190D mutations appear less alarming than originally thought. It does not, however, change the evaluation of the Q226L mutation, which has been shown to enhance human-type (α2,6) receptor binding.  

Less reassuringly, the authors note that severe disease occurred despite the lack of α2,6 receptor binding signatures. They note that human infection "is not always dependent" on α2,6 binding.

One potential alternative the authors propose is the virus may still attach well enough to fuse, through many weak contacts or through receptors they didn't test, though this is only a hypothesis.

Due to its length, I've only posted the abstract and an excerpt from the study. Follow the link to read it in its entirety.  I'll have a brief postscript after the break. 

Diminished sialoside binding in novel H5N1 influenza hemagglutinin variants identified in a human patient
John H. Ni, Saeid Malek Zadeh, Alison M. Berezuk, Ryan Lynam, Peter Axerio-Cilies, Xing Zhu, Katharine S. Tuttle, Gethin Rh. Owen, Maria Tokuyama & Sriram Subramaniam

Nature Communications volume 17, Article number: 9972 (2026) 

Abstract

In 2024, an adolescent female in British Columbia was hospitalised presenting with severe symptoms including respiratory failure due to infection with a novel H5N1 influenza strain (BC24). Using cryogenic electron microscopy, we show here that the N169 α2,3-linked auto-glycan that is found in the sialic acid binding site of previously studied H5 hemagglutinin (HA) proteins is absent in purified BC24 HA protein, suggesting greatly reduced affinity for α2,3-linked sialosides.

Glycan microarray and enzyme-linked immunosorbent assay analyses show that HA variants identified in the BC24 case display severely reduced or no binding to both α2,3-linked sialosides and α2,6-linked sialosides. Full-length BC24 HA expressed in A549 alveolar carcinoma cells drives membrane fusion, albeit at lower levels than previous H5 HA proteins, and post-infection sera from the patient display strong binding to BC24 HA and HA proteins from other influenza subtypes.

As each of the two mutations of interest, independently and in conjunction, severely reduce sialoside binding, there appears to have been in this case multiple populations of virus with the diminished receptor binding phenotype. The substantial minority prevalence of weakly binding HA variants in this BC24 case reveals further complexity in the factors that may be present in severe avian influenza infection.

(SNIP)

The cryo-EM structural analyses demonstrate that the combined effect of the E190D and Q226H mutations sequenced from BC24 HA alters the glycan-binding behavior of this HA. Subsequent experiments through glycan microarray analyses, ELISA, and fusion assays in A549 cells support the hypothesis that the BC24 HA has severely reduced affinity for both α2,3-linked and α2,6-linked sialosides. In particular, ELISA experiments show that both the E190D and Q226H mutations reduce sialoside affinity in isolation, as well. Therefore, multiple distinct minority variants in the BC24 case are expected to have a reduced binding phenotype.

We show that the virus likely retains the ability to drive membrane fusion, adding complexity to our understanding of avian influenza’s paths to generating severe disease in humans. Several important conclusions are suggested by our analyses. The lack of binding to α2,6-linked sialosides by HA variants in the BC24 case implies that human infection is not always dependent on such binding. Moreover, generally reduced binding of HA to sialosides, including both α2,3- and α2,6-linked sialosides, can be a phenotype of fit viruses in a severe human disease context.

We speculate that such a reduction in binding may enable deeper penetration into the lung and potentially contribute to a more severe infection; however, further study will better elucidate how differences in receptor-binding sites influence the infectivity of this influenza strain.

(Continue . . . )

While the original reports of two mutations - E190D and Q226H - were seen as potential red flags for human adaptation, today's report found the opposite; these mutated HA proteins barely bound to either avian-type or human-type receptors - yet the patient became critically ill.

The authors speculate that weak binding may have helped these variants reach the lower airway, but the belated retrieval of viral samples can't show when the mutations arose or what the original virus looked like. 

All of which makes these findings only partly reassuring. These two mutations now look less alarming than originally feared, but the patient's infection still flourished, causing severe, life-threatening illness. 

A reminder that - even after years of research - there's still a lot we don't know about how viruses in general - and H5N1 in particular - interact with their hosts. 

#NPM26: Making Preparedness a Priority

 

Note: This is the 29th day of National Preparedness Month. Follow this year’s campaign on Twitter by searching for the #NatlPrep #BeReady or #PrepMonth hashtags

.

This month, as part of NPM26, I’ll be rerunning some updated preparedness essays, along with some new ones.

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Over the summer - and most particularly the past 4 weeks -  we've looked at a number of personal preparedness scenarios (see links below), covering topics such as earthquakes, severe weather, prolonged power outages, and even pandemics. 

#NPM26: It's a 12 Volt Life

#Natlprep 2026: Pandemic Planning At Both Ends of the Spectrum

#NPM26: Preparing For An El Niño Winter

#NatlPrep: 75% of Americans At Risk Of Experiencing A Damaging Earthquake

September Is National Preparedness Month (#NPM26)

We've also looked at a number of governmental concerns and/or reports; with an emphasis on this winter's El Niño, an increasingly stressed power grid, risks to the global food supply, and a plethora of other threats. 

California Declares State of Emergency to Bolster Statewide El Niño Preparedness

FAO: Expect The Unexpected - Guidelines on Emergency Response Preparedness in Agriculture in Europe and Central Asia

NERC Reliability Report: Large Computational Load Risks Due to Voltage Sensitivity

UK National Risk Register 2026 - Urges Citizen Preparedness

NERC Issues Level 3 Alert As Grid Faces `Unprecedented Challenges' Due to Surge In Large Power Consumers

 
While I can't tell you what untoward events may happen in the months ahead, or when or where they might occur, it is a pretty safe bet that some - potentially large - number of people will be affected by one or more local or regional disasters. 

How they will cope with whatever comes will depend in large part on how well they've prepared. 

While I'm a huge proponent of having a good first aid kit (or three), emergency power options, and a full pantry, I can think of no prep more valuable than having one or more `disaster or flu' buddies on whom you can rely in an emergency.

Simply put, a network of family, friends, and neighbors to whom you can turn for help in a emergency, who can turn to you for if they need it. My disaster buddy and I have saved each other's bacon more than once. 

Most disasters boil down to unscheduled camping - for days, or sometimes weeks - in your home, in a community shelter, or possibly even in your backyard. So having the right gear - before an emergency arises - can make life far easier.

Every year I publish a long list of preparedness items that I've either bought for myself, or as gifts for other people. While I'll update that list for the holidays, you'll find my most recent list at The Gift of Preparedness 2025.

Since being sick with the flu, of COVID, during an emergency can seriously degrade your ability to cope, I've long recommended staying current with yearly vaccines (see #NatlPrep: Giving Your Preparedness Plan A Shot In The Arm).

Which is why later today I'll be getting both the fall flu and COVID shots from my local pharmacy. I'm also current with my tetanus shot, and pneumonia vaccines. 

Long time readers know I love to tinker with solar panels and emergency power options, and I've put together some low cost systems for myself, and for a couple of friends (see Emergency Solar Power: Revisited).

For as little as $100, you can buy off-the-shelf plug-and-play components to keep phones charged, and a couple of LED lights powered.  Double that, and you can have comms, fans, and an emergency shortwave radio.

My older (circa 2019) basic $200 kit

While solar generators are the preparedness rage, a system capable of running refrigerators, TVs, and other appliances for more than a few hours can run into the thousands of dollars.  For me, that isn't an option. 

In 2024 I described building a rudimentary LiFePo4 power station (see picture below), which packs a whopping 600 Watt/hour capacity. LiFePo4 batteries are lighter than lead/acid, are far less dangerous, and can be charged and discharged (fully) thousands of times.

My system featured dual 12V Car Cigarette Lighter Sockets, 2 USB outlets, and I added a small 110v inverter (which I will probably never use).  I have both a wall charger and a 100 watt solar panel to keep it charged. 

I now have 3 of these battery systems, and 2 solar panels. They won't run my fridge or big-screen TV, but they will keep lights, radios, MP3 player, fans, DVD player, and other creature comforts going for weeks or even months.  

And most importantly, there is enough redundancy built into these systems than if one (or even two) should fail, I'm not left in the dark.  The old prepper's adage, that `one is none, and two is one' applies. 

I've also got 60 gallons of water stored, water filters, a full pantry, a propane stove, and enough books (audio & physical), MP3 radio shows/podcasts, and DVDs to keep me from going stir crazy for months if need be. 

While my investments have been small, they have already paid off, since I've been without power twice in the past 10 years - each time for several days - thanks to Hurricanes Irma (2017) and Helene & Milton (2024).  

The road to preparedness needn't be terribly expensive, but it's a journey you need to start before the next crisis occurs.  

So . . . if a disaster struck your region today, and the power went out, stores closed their doors, and water stopped flowing from your kitchen tap for the next 7 to 14 days . . . do you already have:

• A battery operated NWS Emergency Radio to find out what was going on, and to get vital instructions from emergency officials
• A decent first-aid kit, so that you can treat injuries
• Enough non-perishable food and water on hand to feed and hydrate your family (including pets) for the duration
• A way to provide light when the grid is down.
• A way to cook safely without electricity
• A way to purify or filter water
• A way to stay cool (fans) or warm when the power is out.
• A small supply of cash to use in case credit/debit machines are not working
• An emergency plan, including meeting places, emergency out-of-state contact numbers, a disaster buddy, and in case you must evacuate, a bug-out bag
• Spare supply of essential prescription medicines that you or your family may need
• A way to entertain yourself, or your kids, during a prolonged blackout

If your answer is `no’, then I would suggest the time to start preparing
is now.

Cambodian MOH Announces 6th Human H5N1 Case of 2026

 

#19,352

Cambodia's Ministry of Health has announced their 6th confirmed HPAI H5N1 human infection of 2026 - and 40th since early 2023 - this time involving a 49-year-old man from Oddar Meanchey Province who is hospitalized and was confirmed positive on September 27, 2026. 

The man reportedly worked on a farm and had direct contact with sick and dead chickens which were confirmed positive for H5N1 by the National Animal Health and Production Research Institute on September 23, 2026.

Some translated excerpts from the press release, after which I'll  have a bit more. 

   

(Translation)
Kingdom of Cambodia
Nation, Religion, King
Ministry of Health

Press Release

A Case of Bird Flu in a 49-Year-Old Man

The Ministry of Health of the Kingdom of Cambodia wishes to inform the public of a confirmed case of bird flu (H5N1) in a 49-year-old man. The case was confirmed positive for the H5N1 virus on September 27, 2026, by the National Institute of Public Health and the Institut Pasteur du Cambodge. The patient resides in Tuol Kruos Village, O'Svay Commune, Trapeang Prasat District, Oddar Meanchey Province. Currently, the patient is in isolation at the hospital and is receiving attentive care and treatment from the medical team. Inquiries revealed that the patient raised and cared for chickens at a farm and had direct contact with sick and dead chickens; the latter were confirmed positive for the H5N1 avian influenza virus by the National Animal Health and Production Research Institute on September 23, 2026.

National and sub-national Ministry of Health rapid response teams are collaborating with provincial agricultural departments and local authorities at all levels to actively investigate the avian influenza outbreak. They are responding in accordance with established technical protocols and methods to identify sources of transmission—in both animals and humans—and to locate suspected cases and contacts in order to prevent further community spread. Additionally, they are distributing Tamiflu to close contacts and conducting health education campaigns for residents in the affected village. The Ministry of Health wishes to once again remind all citizens to remain vigilant regarding bird flu, as the H5N1 virus continues to pose a threat to public health. If you experience symptoms such as fever, coughing, a runny nose, or difficulty breathing—and have had contact with sick or dead poultry within the 14 days prior to the onset of symptoms—please avoid gatherings or crowded public places. Instead, seek immediate consultation and medical treatment at the nearest health center or hospital to avoid delays that could lead to a high risk of fatal consequences.

Transmission: H5N1 bird flu is an influenza virus that typically spreads among birds; however, it can sometimes be transmitted from birds to humans through close contact with sick or dead poultry. Bird flu in humans is a serious illness that requires timely hospital treatment. Although it does not easily spread from person to person, if it mutates, it could become transmissible—much like seasonal influenza.

Address: Plot No. 80, Samdech Pen Nouth Blvd (289)

Sangkat Boeung Kak II, Khan Tuol Kork, Phnom Penh

1/2

Telephone: (+855) 23 885 970
Email: info@moh.gov.kh
Website: www.moh.gov.kh
Telegram: t.me/MOHCambodia

In February of 2023 an older clade of H5N1 (2.3.2.1.x) reemerged in Cambodia's population after a 9 year absence, spilling over into 6 humans in 2023, 10 people in 2024, and 18 people in 2025.

Most of these recent Cambodian cases have been due to a new reassortment of an older clade of the H5N1 virus (recently renamed 2.3.2.1e) - which appears to be spreading rapidly through both wild birds and local poultry.

Unlike the recent North American H5N1 clade 2.3.4.4b cases - which have proved far less virulent - Cambodia has seen a 40% fatality rate across these 40 cases. 

While we usually focus on the more dominant H5 2.3.4.4b clade, these cases remind us that there are other lineages of HPAI H5 still in circulation around the globe (see Viruses: Zoonotic Implications of the Co-Circulation of Clade 2.3.4.4b and 2.3.2.1a H5N1 Avian Influenza Viruses in Nepal in 2023), and each is on their own evolutionary trajectory.