China: National Influenza Center Reporting Increased Oseltamivir Resistance in Seasonal H1N1

Credit NIAID

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Although our primary seasonal influenza concern right now revolves around the newly emerging subclade (K) of H3N2, we continue to see sporadic reports of low - but increasing - resistance to the antiviral drug oseltamivir among H1N1 viruses.  

While spontaneous `resistance' to oseltamivir (aka `Tamiflu') develops in roughly 1%-2% of treated patients, for the past 20 months we've been watching a slow rise in the number of antiviral resistant H1N1 viruses around the world.

In 2008 - before the arrival of a new, and still susceptible swine-origin H1N1 pandemic virus in 2009 - the old H1N1 virus had rapidly grown nearly 100% resistant to oseltamivir in less than a year (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

Although that crisis was averted, since then we've been closely watching for signs of increased antiviral resistance in seasonal flu - and while a few isolated pockets have occurred - none have managed to established a foothold. 

But in March of 2024 we saw a worrisome report in The Lancet - Global Emergence of Neuraminidase Inhibitor-Resistant Influenza A(H1N1)pdm09 Viruses with I223V and S247N Mutations - which reported a much higher incidence of oseltamivir resistance among samples tested in Hong Kong in 2023.

Unlike the near total collapse of oseltamivir effectiveness in 2008 - which was due to a an H275Y mutation in the NA - this was due to I223V and S247N, and was not as profound of a loss in effectiveness.

Since then we've seen a number of studies (see Viruses: Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases and Virus Research: A 15-year Study of Neuraminidase Mutations and the Increasing of S247N Mutation in Spain) from around the world finding similar patterns. 

While most of these increases have been modest, just over 2 months ago Taiwan's CDC reported that 6.5% of the H1N1 viruses they have characterized in 2025 have shown signs of oseltamivir resistance. 

In recent days the Chinese press has been warning about an increase in oseltamivir resistant viruses, and the most recent influenza report (Dec 3rd) from China's National Influenza Center cites a 3.9% resistance rate in H1N1 since March 31st, 2025. 

(Translation)

Overview of the Influenza Epidemic Situation in China (as of November 30, 2025 )

Monitoring data shows that influenza activity has increased in both southern and northern provinces this week. A total of 1,541 outbreaks of influenza-like illness have been reported nationwide .

The National Influenza Center conducted antigenic analysis on a subset of influenza virus strains collected between March 31, 2025 and November 30 , 2025 ( based on experimental dates) . The results showed that 98.0% ( 1054/1076 ) of the A(H1N1)pdm09 subtype influenza virus strains were similar to strain A/Victoria/4897/2022 ; 49.9% (415/832) of the A(H3N2) subtype influenza virus strains were similar to strain A/Croatia/10136RV/2023 ( chicken embryo strain), and 82.8% ( 689/832 ) were similar to strain A/District of Columbia/27/2023 (cell strain); and 97.5 % ( 313/321 ) of the B(Victoria) lineage influenza virus strains were similar to strain A /District of Columbia/27/2023 (cell strain) . () is a similar strain to B/Austria/1359417/2021 .


The National Influenza Center conducted drug resistance analysis on some influenza virus strains collected since March 31 , 2025. The results showed that 3.9% ( 31/792 ) of the A(H1N1)pdm09 subtype influenza virus strains had reduced or highly reduced sensitivity to neuraminidase inhibitors, while the remaining A(H1N1)pdm09 subtype influenza virus strains were sensitive to neuraminidase inhibitors; all A(H3N2) and type B influenza virus strains were sensitive to neuraminidase inhibitors; and all A(H1N1)pdm09 , A(H3N2) , and type B influenza virus strains were sensitive to polymerase inhibitors .

While not horrendous, this is roughly double the expected rate, making it a trend very much worth watching.  

So far - based on 302+ H1N1 viruses tested since May - we aren't seeing signs of  increased detections reported by the U.S. CDC (see FluView Week 47 Report below), but > 2/3rds of those tests (n=219) were conducted before the start of this fall's flu season 

One A(H1N1)pdm09 virus had amino acid substitutions NA-I223V and NA-S247N and showed reduced inhibition by oseltamivir. One A(H1N1)pdm09 virus had PA-K34R amino acid substitution associated with reduced susceptibility to baloxavir.

High levels of resistance to the adamantanes (amantadine and rimantadine) persist among influenza A(H1N1)pdm09 and influenza A(H3N2) viruses (the adamantanes are not effective against influenza B viruses). Therefore, use of these antivirals for treatment and prevention of influenza A virus infection is not recommended and data from adamantane resistance testing are not presented.

While oseltamivir continues to be effective against the vast majority of seasonal flu viruses currently in circulation - and we don't appear to be anywhere near a repeat of the 2008 collapse - we are seeing some cracks in the veneer.

A reminder that evolution never stops, making our pharmacological victories over viruses, bacteria, and fungal pathogens often temporary. 

Stay tuned. 

ECDC Pre-pandemic Guidance: Strategies to Fight Avian and Swine flu in Humans

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Today the ECDC has released an impressive 71-page operations framework for European countries to use when dealing with outbreaks of novel swine or avian influenza. This comes just 8 months after releasing ECDC Guidance: Recommendations for Preparedness Planning for Public Health Threats. 

This operations support guide includes 14 scenarios (see chart below) that are `. . . based on specific epidemiological and virological factors, including animal origin, characteristics of human cases (number and exposure context), severity signals, that are then further defined based on the presence of virus mammalian adaptation, antiviral resistance and mismatch with available pre-pandemic vaccines and/or candidate vaccine viruses.'

They describe this framework as being for ` . . . EU/EEA national public health authorities, in particular those involved in preparedness plan updating, risk assessors and managers, and policy-makers in EU/EEA countries. It is also relevant to clinical and laboratory stakeholders involved in zoonotic influenza surveillance, risk communication, and outbreak response.'

Due to its length and complexity, I'll simply post the press release and a link and a few excerpts from the framework.  This is a remarkably detailed framework, and you'll definitely want to download and review at length. 

ECDC defines strategies to fight avian and swine flu in humans
Press release
4 Dec 2025
 
Unprecedented outbreaks in birds highlight the need for early detection and preparedness.

This autumn, Europe has seen a sharp increase in avian influenza A(H5N1) cases in wild birds and poultry. Its wide circulation among birds increases the risk of human exposure to infected animals and the virus subsequently spilling over to humans.

The European Centre for Disease Prevention and Control (ECDC) has today released a guide and tools to help European countries detect and respond to possible animal-related influenza threats, including pandemics.

‘Although the current risk for the European people is low, avian influenza is still a serious public health threat due to widespread outbreaks among animals across Europe.’ says Edoardo Colzani, ECDC Head of Respiratory Viruses. ‘We need to make sure that early warning signs don’t go unnoticed and that public health actions are timely, coordinated, and effective. This document provides countries with a clear and adaptable framework to prepare for and respond to animal-to-human influenza transmission.’

This new guide sets out practical response scenarios ranging from the current situation - where no human cases have been reported in the European Union (EU)/European Economic Area (EEA) but avian influenza viruses are circulating widely in animals - to more serious scenarios involving human infections and even potential transmission human-to-human that could lead to a pandemic.

The framework is designed to help countries act quickly and proportionately as risks evolve. It includes a range of public health response measures, from enhancing surveillance and laboratory testing to ensuring protective equipment is available and communicating clearly with the public. It also highlights the importance of genomic surveillance, laboratory capacity building, and real-time data sharing.

Crucially, the guidance embraces a ‘One Health’ approach, recognising that human health is closely connected to the health of animals and the environment. Close collaboration between veterinary services, agriculture, and public health, is essential to detect and contain threats early and protect people across Europe.

The guide was developed in close collaboration with the European Food Safety Authority (EFSA), the European Medicines Agency (EMA), the European Agency for Safety and Health at Work (EU-OSHA), the European Reference Laboratory for avian influenza and national experts. These materials are designed to help countries integrate the recommendations into their national preparedness plans.

Access the guide

 

You'll find two additional supporting documents at:

Scenarios for pre-pandemic zoonotic influenza preparedness and response
Operational support
4 Dec 2025

The aim of this framework is to guide a scalable public health response to influenza of zoonotic origin in EU/EEA countries and provide options for preparing and responding to different possible pre-pandemic scenarios. The European Food Safety Authority (EFSA) reported unprecedented levels of HPAI A(H5N1) circulation in wild birds across Europe during the 2025 autumn migration, highlighting the need for strengthened preparedness and coordinated public health action.

Instructions for using the ECDC publication ’Scenarios for pre-pandemic zoonotic influenza preparedness and response in the EU/EEA' - EN - [PDF-187.84 KB]

Excel tool: Scenarios for pre-pandemic zoonotic influenza preparedness and response in the EU/EEA, version 1.0 - EN - [XLSX-352.93 KB]

While we continue to see calls for enhanced surveillance and reporting, this is the most ambitious and detailed pre-pandemic planning guide I've seen in years.

As with our own CDC - these are not mandates, only recommendations - and it is up to each individual public health entity to decide what to incorporate in their planning.

Hopefully nations - in Europe, and around the globe - are taking notice.  Because while the threat from HPAI to the general public may be deemed `low' today, that could change in a heartbeat. 

France MOH: 2 Travelers Returning From Arabian Peninsula Diagnosed with MERS-CoV

 

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While MERS-CoV has been out of the news cycle for quite some time, it has not gone away, and starting in early 2025 we've seen an increase in the number of  cases reported by Saudi Arabia (see Oct. ECDC Report).

Even when countries aggressively look for cases (and many appear disinclined), detecting MERS-CoV can be difficult. Official case counts are widely assumed to be undercounts (see EID Journal: Estimation of Severe MERS Cases in the Middle East, 2012–2016. 

Overnight the French Ministry of Health has announced the detection of 2 MERS-CoV cases in a tour group recently returned from the Arabian Peninsula.  The details released thus far are disappointingly scant (i.e. no travel dates, onset dates, itineraries, potential exposures, etc.).

(Translation)

Two cases of MERS-CoV, returning from abroad, identified on national territory

Published on 04.12.25
Health alerts Press releases Stéphanie Rist Press releases and dossiers Diseases Health

The Ministry of Health, Families, Autonomy and Persons with Disabilities and Public Health France have been informed of two cases of MERS-CoV in France. These two cases were confirmed following suggestive symptoms and a history of shared travel to the Arabian Peninsula. Management measures have been implemented to limit the risk of virus transmission.

Stéphanie Rist, Minister of Health, Families, Autonomy and Persons with Disabilities, confirms: “These patients are being monitored in hospital as a precautionary measure and their condition is stable. All management measures have been put in place to limit the risk of transmission of the virus to the patients' contacts and healthcare staff: contact tracing to offer them follow-up, barrier gestures, testing, isolation and procedures to follow in case of the appearance of symptoms, even mild ones.”

These two cases occurred in individuals who had participated in the same trip, but no secondary transmission chains have been identified within the country at this stage. The other individuals who participated in the trip have also been monitored since the identification of the first confirmed case.

If you experience these symptoms and have recently traveled to these areas and/or have been in contact with people who have experienced these symptoms, do not hesitate to consult your doctor.

        (Continue . . . )

Prior to SARS-CoV-2's arrival in late 2019, MERS-CoV was the top contender for sparking a coronavirus pandemic, sporting a high mortality rate, and spreading easily through hospitals in the Middle East (and South Korea) (see Ziad Memish: Two MERS-CoV Hospital Super Spreading Studies).

Last June we looked at an editorial in Journal of Epidemiology & Global Health on the importance of continued healthcare preparedness and surveillance (see Al-Tawfiq & Memish On Recurrent MERS-CoV Transmission in Saudi Arabia), with an emphasis on identifying asymptomatic carriers.

Also last June, in JEGH: Epidemiological Characteristics of MERS-CoV Human Cases, 2012- 2025, we looked at the changing epidemiology of MERS-CoV cases since 2012, as well as substantial gaps in our current understanding of the disease.

Over the past year we've seen a small, but noticeable, uptick in cases reported by Saudi Arabia. In March KSA reported 4 cases (2 from late 2024), and in May a WHO DON report added 9 more.  In October the ECDC published an account of the 12th case in KSA. 

Update: Since the previous update on 1 September 2025, and as of 6 October 2025, one new MERS fatality in Saudi Arabia with date of onset in July 2025 has been reported by the World Health Organisation Eastern Mediterranean Region (WHO EMRO).

The case reported no contact with camels, had comorbidities, and resided in the Riyad province. All close contacts are being followed up with no secondary cases reported so far.

Summary: Since the beginning of 2025, and as of 6 October 2025, 12 MERS cases have been reported in Saudi Arabia with date of onset in 2025, including three fatalities.

Since April 2012, and as of 6 October 2025, a total of 2640 cases of MERS, including 958 deaths, have been reported by health authorities worldwide. 

Although dromedary camels are the primary animal reservoir for MERS - and direct or indirect contact are viewed as a major risk factor for infection - sporadic cases continue to show up in the community without any known exposures (camels, camel products, or known MERS cases).

A 2020 Perspective published in the EID Journal (see Middle East Respiratory Syndrome Coronavirus Transmission) reported that `. . . among 1,125 laboratory-confirmed MERS-CoV cases reported to WHO during January 1, 2015–April 13, 2018, a total of 157 (14%) had unknown exposure.'

Compared with the hundreds of cases reported each year in KSA during the last decade, this 2025 surge in activity is hardly earthshaking, but it does represent a noticeable uptick.  

And given its continued evolution, and past performance, it is still very much worth keeping our eye on. 

WPRO Table-Top Exercise Crystal: A `Bovine' Novel Flu Outbreak Scenario

 

Credit Hong Kong CHP

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Nearly two decades ago - during the first ominous flare up of H5N1 in Southeast Asia - pandemic drills were quite common, and were held at international, national, state, and local levels. 

Every nation (and every U.S. state and Federal Agency) crafted a pandemic plan, and table top exercises were held regularly (see CIDRAP  HHS includes online services in pandemic communication drill).

 

Drills were held by both the public and private sector, and ranged from multinational exercises all the way down to events held by local hospitals, and city governments. A few (out of scores of) blogs from that `golden age' of pandemic preparedness include:

Singapore To Begin 2-Week Financial Sector Pandemic Drill

Merced County California Flu Drill

Scottsdale Arizona: Pandemic Drill

Idaho BlogEx : July 28th

UK: Lessons Learned From Winter Willow 

UK Exercise: PPE Usage In A Pandemic

While not all of these drills were terribly realistic (i.e. practicing for rapid delivery of a vaccine that was unlikely to exist for months), they did serve to increase awareness - both for those taking part, for the public who heard about them in the media.

By the middle of the last decade, the number and size of these exercises began to wane, following a relatively mild 2009 H1N1 pandemic and the attenuation of the HPAI H5 threat.  

But since COVID, and the growing realization that a HPAI H5 had reinvented itself, we've seen a resurgence in pandemic planning and exercises, particularly in Asia. 

• Earlier this fall South Korea: MAFRA Conducted A Preemptive Virtual Quarantine Exercise (CPX), which came just days after staging a 19-day, Nationwide, Mock-Training Exercise to Prepare for Zoonotic Influenza.

• A year ago Hong Kong held a Coordinated Avian Flu Drill `Amazonite'.

• And over the summer of 2024, Japan's Ministry of Health Unveiled Revised Pandemic Plans

Since 2008 the WHO Western Pacific Regional Office (WPRO) has sponsored a multinational Exercise Crystal, which (most years) has revolved around respiratory virus outbreaks.  

Participants have ranged from as few as 10 nations in 2014 to as many as 35 in 2024 (cite Exercise Crystal: simulations that drive National IHR Focal Point capacity strengthening).

While last year's scenario revolved around an outbreak of Oropouche virus, an emerging arbovirus (see CDC HAN Advisory: Increased Oropouche Virus Activity and Associated Risk to Travelers), but this year a novel flu was once again front and center. 

And as we learn from the following Hong Kong CHP report, this year's scenario envisioned  `. . . a novel influenza A infection related to dairy farms, with sustained human-to-human transmissions and further spread to many countries.'

This is, as far as I can tell, the first large-scale international acknowledgement that a mammalian livestock driven novel flu epidemic was plausible.  First the report, after which I'll have a postscript.

DH participates in WHO's large-scale Western Pacific Region exercise to enhance emergency preparedness and cross-sectoral collaboration for public health emergencies (with photo)

The Department of Health (DH) today (December 3), together with the Food and Environmental Hygiene Department and the Agriculture, Fisheries and Conservation Department, participated in a large-scale annual table-top exercise, Exercise Crystal, organised by the Regional Office for the Western Pacific (WPRO) of the World Health Organization (WHO). The exercise aims to enhance emergency response mechanisms and cross-sectoral collaboration capabilities between Hong Kong, China and neighbouring regions to jointly tackle public health emergencies.

This year, the exercise simulated a scenario on human outbreaks of a novel influenza A infection related to dairy farms, with sustained human-to-human transmissions and further spread to many countries. More than 30 countries and areas in the WPRO region participated in the exercise. During the exercise, the WHO provided information on the scenario to the representatives of the participating countries and areas via videoconferencing and email.

Representatives from the DH and other government departments thoroughly discussed the scenario, including the immediate responses, prevention and control measures, and the relevant co-ordination required in Hong Kong, rapidly adjusting the planning according to the evolving scenario. The exercise host of the WPRO concluded the exercise with a debriefing to review the exercise's achievements and explore with participants how to further enhance cross-regional emergency response and collaboration mechanisms.

"Emerging infectious diseases have long posed significant public health threats worldwide. With frequent international population mobility today, emerging respiratory viruses can spread across regions in a short period of time through contact with patients’ secretions or droplets, potentially causing a global pandemic. As a major international transportation hub, Hong Kong faces a significant risk of importation of emerging respiratory infectious diseases. The exercise provided us with a valuable opportunity to strengthen communication and information sharing mechanisms between Hong Kong, China and the WHO WPRO, as well as national focal points of various countries. It also further enhances the cross-departmental collaboration mechanism against emerging respiratory diseases. The Centre for Health Protection (CHP) will consolidate the experience gained from this exercise, to opportunely review existing mechanisms in a timely manner, and make more forward-looking arrangements to comprehensively safeguard public health,” the Head of the Communicable Disease Branch, the CHP of the DH, Dr Albert Au, said.

Since 2008, the WPRO has conducted the Exercise Crystal annually to help member countries and regions prevent and respond to cross-regional public health risks affecting population worldwide. Meanwhile, the WPRO maintains close communication with focal points responsible for enforcing the International Health Regulations to ensure that the regions are familiar with the response mechanism to public health emergencies. Being one of the focal points between Hong Kong, China and the WHO, the CHP has actively participated in the exercise for years.

Ends/Wednesday, December 3, 2025
Issued at HKT 17:00

In the opening months of the 2024 H5N1 outbreak in dairy cattle in the United States many countries believed that this was a uniquely `American' problem - unlikely to spread internationally - because the genotype involved (B3.13) was rarely seen in birds. 

But since then we've seen a second genotype (D1.1) turn up in American dairy cows, along with serological evidence of HPAI exposure in goats and sheep in Pakistan, a report last March from the UK's Defra on H5N1 Detected In Domestic Sheep with Mastitis, and in May we saw serological evidence of H5N1 in sheep in Norway.

Six weeks ago, in WOAH Statement (Oct 22nd): High Pathogenicity Avian Influenza (HPAI) in Cattle, the reporting of HPAI H5 in cattle was finally made mandatory by the World Organization for Animal Health. 

In light of the impact on animal and public health, the Scientific Commission for Animal Diseases considered at its February 2025 meeting that ‘infection of bovines (Bos taurus) with influenza A viruses high pathogenicity’ meets the Terrestrial Code glossary definition for ‘emerging disease’. Accordingly, Members are required to notify the occurrence of HPAI in cattle to the World Animal Health Information System (WAHIS) in accordance with the WOAH Terrestrial Code Article 1.1.4.

While this increased recognition of the threat from bovine H5N1 is encouraging, from far too many countries we see little or no sense of urgency.  Pandemic preparedness is somehow viewed as being either `bad for the economy', politically unproductive, or not worth the expense.

While No Pandemic Plan Survives Contact With A Novel Virus, it is still imperative to have a plan going into any crisis. And that goes for individuals, families, and businesses . . .  as well as for countries. 

While we can't control what others choose to do, there are some simple things we can do now to improve our chances should another novel virus begin its world tour (see #Natlprep 2025: Personal Pandemic Preparedness).

The following quote is nearly 20 years old, but it is every bit as true today as it was in 2006:

“Everything you say in advance of a pandemic seems alarmist. Anything you’ve done after it starts is inadequate." - Michael Leavitt, Former Secretary of HHS

Denk Vooruit: The Netherlands National Citizen Preparedness Drive

 

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`Denk Voruit' is Dutch for `Think Ahead', and over the next few weeks every household in the Netherlands is expected to receive a government sponsored booklet on how to survive an emergency (e.g. extreme weather, cyberattacks, terrorist attack, even armed conflict, etc.). 

While this sort of messaging is fairly common here in the United States (see September is National Preparedness Month), until recently it has been rarely discussed in Europe. 

But in the aftermath of the deadliest pandemic in a century - and with a major war continuing in Europe, increasingly severe weather, and escalating cyber threats - suddenly the safety net provided by local governments seems less reliable.  

Eight months ago the EU made headlines after calling for all households to prepare for a wide array of disasters (see excerpts below).

What type of crises is the EU preparing for? 

The EU is preparing for a broad spectrum of risks and threats, encompassing both natural and human-induced disasters. This includes:

• Natural disasters: floods, wildfires, earthquakes, and extreme weather events exacerbated by climate change.
• Human-induced disasters: industrial accidents, technological failures, and pandemics.
• Hybrid threats: cyberattacks, disinformation campaigns and foreign information manipulation and interference (FIMI), and sabotage of critical infrastructure.
• Geopolitical crises: armed conflicts, including the possibility of armed aggression against Member States.

       (SNIP)

In which areas will the EU focus its efforts to enhance population preparedness?

The EU will focus its efforts on enhancing population preparedness working with Member States, with a particular emphasis on fostering a culture of resilience at national and local level. This includes improving public awareness of risks through targeted information campaigns, educational programs, and accessible online resources.

Efforts will also concentrate on empowering citizens to take proactive measures to prepare for crises, such as developing household emergency plans and stockpiling essential supplies. The EU will also support the development of effective public warning and crisis communication systems by Member States to reach all citizens, regardless of their location, language, or circumstances.

Many of the EU's recommendations for household preparedness mirror longstanding advice by FEMA for Americans, but despite seeing dozens of regional disasters each year, many Americans remain underprepared. 

 

The Denk Vooruit website has both Dutch and English versions available. I've posted the English links below.  

• Information booklet: prepare for an emergency situation

• This booklet will help you to prepare. So you can manage for the first 72 hours at home, should an emergency situation.

• Prepare yourself

• That way, you’ll know what you need and what to do in an emergency.

• Risks in the Netherlands

• Know what emergency situations may arise and how to prepare for them.

In the Netherlands, we almost always have electricity, water and internet. But in an emergency, such as extreme weather, war or a major outage, those supplies could suddenly fail. It might take a little while for help to arrive. So it’s smart to be properly prepared. That requires action from everyone: from the government, but also from you and those around you. By preparing properly, you can help yourself and others if the need arises. This website and the 'Information booklet: prepare for an emergency situation' tells you how to do that.

What you do today makes us stronger tomorrow. Thinking ahead isn't a fearful reaction; it prevents panic. Those who are prepared are stronger, keep a cool head, and can also make a difference for others. And that starts at home: make an emergency kit, make an emergency plan, talk about it, and help each other. 

The sobering reality is - even in Europe - during a major disaster a government's response may be limited, and you and your loved ones may be on your own for the first few days (possibly longer).

 

Having ridden through more than a few hurricanes, my `standard advice' is that everyone should strive to have the ability to withstand 7 to 10 days without power and water. 

Recommended preps include:

• 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 handle basic sanitation and waste disposal. 
• 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

Being prepared doesn't guarantee you and your loved ones will come through a major disaster unscathed. But it is relatively cheap insurance, and when things do go sideways, it can substantially improve your chances.

For some past blogs on personal and household preparedness, you may wish to revisit:

Emergency Preparedness: A Medicine For The Melancholy

The Gift of Preparedness 2024

Instead of Cursing The Darkness

ASM Spectrum: Characterization of H5N1 HPAI Virus Belonging to Clade 2.3.4.4b Isolated from Ezo Red Fox in Japan in a Mouse Model

Credit NIAID

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In May of 2024 we looked at plan by Japan's MOH To Stockpile 10 Million Doses of H5N1 Vaccine, enough to vaccinate about about 8% of their population.  

Over the past 2 decades more than 4 dozen H5Nx candidate vaccine viruses (CVVs) have been selected by WHO for development. 

Admittedly, many of these older CVVs are for viruses that no longer circulate in the wild, having been supplanted by newer versions.

In a follow-up report last April (see Japan: Updated HPAI H5 Risk Assessment & Pre-pandemic Vaccine Selection), we looked at Japan's decision to go with a locally detected H5N1 virus; a strain isolated from an infected fox with viral meningoencephalitis collected on Hokkaido in 2022.

What makes this choice interesting is this isolate did not carry the amino acid markers (PB2-E627K or PB2-D701N) that we typically associate with increased virulence and replication in mammals. 

Today's report, however, finds that even though lacking these `red flag' mutations -  this isolate produced high virulence and robust replication in mice - suggesting other gene factors may drive pathogenicity.

While the murine model has known limitations in influenza research, it can be useful; particularly in virulence studies (see Animal Models for Influenza Research: Strengths and Weaknesses). 

First, a link and some excerpts from the study, after which I'll return with a postscript. 

Characterization of H5N1 high pathogenicity avian influenza virus belonging to clade 2.3.4.4b isolated from Ezo red fox in Japan in a mouse model
Authors: Shintaro Shichinohe  Takahiro Hiono, Yasushi Itoh , Kosuke Takada, Yurie Kida, Pei Wang, Daisuke Motooka, Norikazu Isoda, Ayato Takada, Yoshihiro Sakoda , Tokiko Watanabe tokikow@biken.osaka-u.ac.jpAuthors Info & Affiliations
https://doi.org/10.1128/spectrum.01097-25

PDF/EPUB

ABSTRACT

H5N1 high pathogenicity avian influenza virus (HPAIV) has spread in wild birds and poultry worldwide. H5N1 HPAIV belonging to the currently predominant clade 2.3.4.4b has infected not only birds but also mammals (wild and domestic animals), with several human infections also being reported, raising concerns for public health.

 In 2022, a clade 2.3.4.4b H5N1 HPAIV strain, A/Ezo red fox/Hokkaido/1/2022 (H5N1; Fox/Hok/1/22), was isolated from an Ezo red fox (Vulpes vulpes schrencki) in Hokkaido, Japan; this was the first reported case of clade 2.3.4.4b H5N1 HPAIV isolation from a mammalian species in Japan. Several amino acid substitutions in the PB2 protein play an important role in the adaptation of avian influenza viruses to mammals, but Fox/Hok/1/22 PB2 does not have any of these well-known mammalian-adapting PB2 substitutions. 

Here, we investigated the biological properties of Fox/Hok/1/22 in a mouse model and found that this virus was highly virulent in mice and replicated well in multiple organs, including the lungs and brain. We then examined whether viruses isolated from these organs acquired known mammalian-adapting PB2 amino acid substitutions, such as PB2 E627K. 

Deep sequencing analysis of viral RNA from mouse brain and lungs revealed that virus with PB2-627E was predominant in three of four mice, whereas the PB2-627K substitution was predominant in one mouse. These results indicate that Fox/Hok/1/22 is highly virulent in mice despite lacking known PB2 substitutions involved in mammalian adaptation.

IMPORTANCE

The H5N1 avian influenza virus has caused severe disease in birds worldwide and is now spreading to mammals, including humans. In 2022, this virus was detected for the first time in an Ezo red fox in Japan. To understand its potential impact on mammals, we studied this virus in mice and found that it caused severe illness, spreading to multiple organs, including the lungs and brain. 

Surprisingly, despite lacking genetic mutations typically associated with mammalian adaptation, the virus was highly virulent in mice.

This finding suggests that the H5N1 virus may pose a greater threat to mammals, including humans, than previously thought. Given their continued spread among wild and domestic animals, our findings underscore the urgent need to monitor how recent H5N1 viruses behave in mammals.

        (SNIP)      

DISCUSSION

Clade 2.3.4.4b H5N1 HPAIV has caused tremendous damage worldwide, especially in poultry and wild birds, as well as many cases of infection in mammals, including carnivores, such as red foxes, in Asia, Europe, and the USA (1). It has been reported that foxes can be infected with H5N1 HPAIV by feeding on HPAIV-infected birds (14).

Previously, Hiono et al. isolated clade 2.3.4.4b H5N1 HPAIV (Fox/Hok/1/22) from a dead Ezo red fox in Hokkaido, Japan (10). This was the first clade 2.3.4.4b H5N1 HPAIV isolation from a mammal in Japan. Phylogenetic similarity between virus isolated from the fox and that from birds suggests that infection can be caused by fox predation on virus-infected birds (15). 

Here, we investigated the biological properties of Fox/Hok/1/22 in a mammalian model. We found that the MLD50 of Fox/Hok/1/22 was 100.5 PFU, and that Fox/Hok/1/22, like other H5N1 HPAIVs, grew in multiple organs, including the brain and respiratory tract of the virus-infected mice (Table 1). These results indicate that Fox/Hok/1/22 efficiently replicates and is highly virulent in the mouse model.

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Although efficient transmission among humans has not yet occurred, further outbreaks in various wild mammals should be carefully monitored, and proactive measures should be taken to prevent and treat infections with these viruses.

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This isn't the first time we've seen evidence that HPAI H5N1 can be virulent in mammals without these notorious PB2 mutations.  Eleven months ago, the CDC published  Genetic Sequences of Highly Pathogenic Avian Influenza A(H5N1) Viruses Identified in a Person in Louisiana (who later died), which found:

The genetic sequences of the A(H5N1) viruses from the patient in Louisiana did not have the PB2 E627K change or other changes in polymerase genes associated with adaptation to mammals and no evidence of low frequency changes at critical positions.

And, like other D1.1 genotype viruses found in birds, the sequences lack PB2 M631L, which is associated with viral adaptation to mammalian hosts, and which has been detected in >99% of dairy cow sequences but is only sporadically found in birds.  

Interestingly, the CDC also noted that the HA of this Louisiana isolate was closely aligned with the Ezo fox isolate discussed above. 

Overall, the hemagglutinin (HA) sequences from the two clinical specimens were closely related to HA sequences detected in other D1.1 genotype viruses, including viruses sequenced from samples collected in November and December 2024 in wild birds and poultry in Louisiana. The HA genes of these viruses also were closely related to the A/Ezo red fox/Hokkaido/1/2022 candidate vaccine virus (CVV) with 2 or 3 amino acid changes detected.  

These reports complicate matters, because they suggest we can't automatically assume that just because an HPAI virus doesn't carry these PB2 mutations, that it is guaranteed to be less of a public health threat.