EID Journal: Influenza A(H1N1)pdm09 Virus with Reduced Susceptibility to Baloxavir, Japan, 2024

Credit NIAID

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Although we spend a good deal of time looking at the risks from novel influenza viruses, seasonal flu kills hundreds of thousands every year around the globe.  Even with somewhere near a billion people getting the flu vaccine every year (which is only moderately effective), that leaves a lot of people at risk of serious illness or death. 

Influenza antivirals have been around for nearly 50 years (Amantadine was approved in the US in 1976), while oseltamivir (aka Tamiflu) was approved in 1999, and Baloxavir in 2018.  

But very much like we see with antibiotics and bacteria, antivirals are susceptible to resistance developing over time in targeted viruses. By the end of 2005 our oldest class of flu antivirals - M2 ion channel blockers (e.g. Amantadine, Rimantadine) - had become largely ineffective against seasonal H3N2, and in early 2006 were no longer recommended for use. 

Luckily we had oseltamivir -- an NAI (neuraminidase inhibitor) - to fall back on. It was, however, far more expensive and difficult to produce in quantity. While occasional instances of Oseltamivir resistance (1%) were reported prior to 2007, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’).

Studies suggested that these resistant strains suffered a `fitness penalty', and were therefore unlikely to spread from human-to-human.

An optimistic view that lasted just over 2 years, as by 2008 seasonal H1N1 picked up `permissive mutations' (Cite) that enabled resistant seasonal H1N1 viruses to spread  rapidly around the globe. By the end of 2008, the CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

This resistance was due primarily to the acquisition of an H275Y mutation, and had seasonal H1N1 not been supplanted by a (still NAI susceptible) pandemic swine H1N1 virus in the spring of 2009, oseltamivir might still be off the table. 

We've been watching ever since 2009 for any signs that the replacement pH1N1 virus has been gaining resistance to oseltamivir, but for the most part, the news has been pretty good.  And in 2018 a new (albeit more expensive) class of antivirals (Baloxavir) was added to our armamentarium. 

But recently we've seen some cracks in the veneer.  While 99% of wild-type seasonal flu viruses remain susceptible to Oseltamivir/Baloxavir, we follow reports of resistant strains with considerable interest. A few of many include:

Eurosurveillance: An outbreak of A(H1N1)pdm09 Exhibiting Cross-resistance to Oseltamivir & Peramivir in an Elementary School in Japan, Sept 2024

Viruses: Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases

EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024

Eurosurveillance: A community Cluster of Influenza A(H3N2) Virus infection with Reduced Susceptibility to Baloxavir - Japan 2023

EID Journal: H-2-H Transmission Of A(H3N2) with Reduced Susceptibility to Baloxavir, Japan

This week we have a new dispatch, published in the CDC's EID Journal, that describes another instance of Baloxavir resistance in Japan (where the drug is mostly widely used).  While only one case is reported, it was in a child who had not been treated with the antiviral, and it was due to a previously unassociated mutation. 

I've posted the link, abstract, and some excerpts, but many will want to read the full dispatch.  I'll have a bit more after the break. 

Dispatch

Influenza A(H1N1)pdm09 Virus with Reduced Susceptibility to Baloxavir, Japan, 2024

Emi Takashita, Hiroko Morita, Shiho Nagata, Seiichiro Fujisaki, Hideka Miura, Tatsuya Ikeda, Kenichi Komabayashi, Mika Sasaki, Yohei Matoba, Tomoko Takahashi, Naomi Ogawa, Katsumi Mizuta, Sueshi Ito, Noriko Kishida, Kazuya Nakamura, Masayuki Shirakura, Shinji Watanabe, and Hideki Hasegawa

Abstract

Influenza A(H1N1)pdm09 virus carrying an I38N substitution was detected in an untreated teenager in Japan. The I38N mutant virus exhibited reduced susceptibility to baloxavir but remained susceptible to neuraminidase inhibitors and showed reduced growth capability. Monitoring antiviral drug susceptibility of influenza viruses is necessary to aid public health planning and clinical recommendations.

(SNIP)

The PA I38T substitution is the most frequent substitution and has the greatest effect on baloxavir susceptibility (5). Influenza A(H1N1)pdm09 (pH1N1) and A(H3N2) viruses with the PA I38T substitution isolated from baloxavir-treated patients show similar replication fitness and pathogenicity to wild-type isolates tested in hamsters and efficiently transmit between ferrets by respiratory droplets (6). 

We have monitored baloxavir susceptibility of seasonal influenza viruses in Japan since the 2017–18 season and reported human-to-human transmission of PA I38T mutant H3N2 viruses in children <10 years of age (7,8).

Researchers detected a PA I38N substitution in a pH1N1 virus isolated from a patient during a phase 3 clinical trial of baloxavir. That substitution conferred a 24-fold reduction in baloxavir susceptibility in recombinant A/WSN/33(H1N1) and a 10-fold reduction in recombinant A/Victoria/3/75(H3N2) and reduced growth capability in both viruses (3,9). However, its effect on pH1N1 virus has not been reported. 

During our 2023–24 surveillance, we detected a PA I38N mutant pH1N1 virus in a 14-year-old patient not treated with baloxavir. Here, we report the in vitro characterization of the PA I38N mutant pH1N1 virus.

Conclusions

In this study, we showed that the PA I38N mutant pH1N1 virus had reduced susceptibility to baloxavir but remained susceptible to NA inhibitors. Our results indicate that the PA I38N substitution in the pH1N1 virus contributed to a reduction in baloxavir susceptibility, but the reduction in susceptibility was less than that caused by the PA I38T substitution (3,9).

PA I38 is highly conserved in influenza A and B viruses (1). During October 2023–March 2024, medical institutions that serve ≈3.7 million persons in Japan received baloxavir to use for antiviral treatment. The PA I38N substitution may negatively affect the growth capability of the virus in vitro; however, our findings suggest possible transmission of the PA I38N mutant pH1N1 virus from another host harboring the mutant virus, which may have emerged under the selective pressure of baloxavir or as a result of a rare spontaneous mutation.

In Japan, influenza activity was low throughout the COVID-19 pandemic; the first influenza outbreak occurred in the 2022–23 season (13). The influenza outbreak in the 2023–24 season was larger than that of 2022–23 (Figure 1). Influenza pH1N1 virus activity peaked in November 2023 and then declined.

The PA I38N mutant pH1N1 virus in this study was detected in March 2024. By March, the pH1N1 outbreak was almost over, and no regional spread of the PA I38N mutant pH1N1 virus was observed.

We reported a community cluster of influenza A(H3N2) viruses with reduced susceptibility to baloxavir caused by a PA E199G substitution in Japan in February–March 2023 (13). In addition, researchers reported widespread community clusters of pH1N1 viruses with cross-resistance to oseltamivir and peramivir in Australia and Japan (14,15). Monitoring of antiviral drug susceptibility of influenza viruses is necessary to aid public health planning and clinical recommendations for antiviral drug use.

Dr. Takashita is a virologist with the National Institute of Infectious Diseases, Tokyo, Japan. Her research interests include antiviral drug susceptibilities of influenza viruses. 

 

While a loss of one (or both) of our main classes of antivirals would be a disaster for seasonal flu, it could have even greater impact during a pandemic.  For most people, a novel flu vaccine would only be available 6 months or more into an outbreak (see Referral: SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).

Just over 2 weeks ago, St. Jude Researchers warned Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk, and 6 weeks ago we learned from Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms.

Although we've not seen any reports of H275Y in D1.1 samples collected in the United States, last November the CDC did report finding a far-less impactful mutation (NA-S247N) in 3 poultry workers from Washington State, which they stated may slightly reduce the virus's susceptibility to antivirals.

While other studies (conducted 2022-2024) have reported relatively little resistance in HPAI H5 viruses tested in the United States (see here, and here), the one thing you can count on with influenza viruses is they are always changing. 

Although I remain hopeful our antiviral stockpiles (mostly oseltamivir) can help `take the edge off' the opening months of the next pandemic, it is by no means assured.

To be most effective, antivirals ideally need to be given early (< 48 hours) into an infection. Stockpiles are finite, and even during moderately severe seasonal flu epidemics we've seen difficulties in rapidly dispensing these drugs (see 2022's CDC HAN #0482: Prioritizing Antiviral Treatment of Influenza in the Setting of Reduced Availability of Oseltamivir).

Any way you cut it, our first line of defense will - once again - rely heavily on NPIs (non-pharmaceutical interventions), like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.

ECDC Guidance: Recommendations for Preparedness Planning for Public Health Threats

 

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Eighteen years ago - after H5N1 managed to spread rapidly out of Southeast Asia into Europe, Africa, and the Middle East for the first time - pandemic planning suddenly became a global priority. Nearly every nation (and every U.S. state and Federal Agency) crafted a pandemic plan, and table top exercises and drills were held regularly.

Some of these plans, and drills, were better conceived than others, of course. Far too many envisioned a `mild' pandemic, or focused on delivering unlikely-to-be-available vaccines (see No Such Thing As A `Planacea').

A few (out of hundreds of) examples include:

• Hong Kong : Exercise Redwood - 2009
• UK Exercise: PPE Usage In A Pandemic –2008
• Singapore: Public Involvement In Financial Sector Pandemic Drill –2008
• Florida's Pandemic Simulation – 2008
• Idaho BlogEx : July 28th –2008
• UK: Lessons Learned From Winter Willow – 2007

 When an influenza pandemic finally did emerge in 2009, it came from a swine H1N1 virus, and was relatively mild (except for those who died from it). 

Critics of pandemic planning (which was, admittedly expensive and time consuming) insisted the age of severe pandemics was over (pointing to 3 successively weaker pandemics since 1918), and that modern medicine could more than cope with anything that might emerge. 

Having dodged a bullet, interest in pandemic planning, and drills, gradually declined and most existing pandemic plans gathered dust on the shelf.  While there were constant concerns raised that the `world was ill prepared' for a pandemic, little actual progress in preparing for the next pandemic occurred. 

Although once again from an unexpected source, COVID in 2020 reaffirmed that severe pandemics still happened, and that 10 years after the last pandemic, we were still woefully unprepared to deal with one (see The Most Predicted Global Crisis of the 21st Century).

A few, of many challenges included:

NIOSH Update: More Fake/Counterfeit N95 Masks Entering Market

JAMA: A Framework for Rationing Ventilators & ICU Beds During the COVID-19 Pandemic

Contemplating A Different `Standard of Care'

HHS ASPR-TRACIE: COVID-19 Crisis Standards of Care Resources

Rather than learn from these mistakes, five years after the start of the COVID pandemic we've dismantled much of our surveillance and reporting systems, in order to declare the emergency ended (see No News Is . . . Now Commonplace).

Worse, the international sharing of emerging disease information is - as near as I can tell - the most dysfunctional its been since I began this blog nearly 20 years ago (see The Wrong Pandemic Lessons Learned).  

While the world appears to be sleepwalking towards the next global health crisis, we've seen some movement.  Last summer both South Korea and Japan issued revised pandemic plans, and last November Hong Kong held a Coordinated Avian Flu Drill `Amazonite'.

A number of countries and regions have purchased (or arranged to purchase) limited quantities of H5N1 vaccine.

• In 2023 Japan announced plans to stockpile about 10 million doses.
• The United States ordered about 4.8 million doses last summer, enough for about 2.4 million people.
• The EU announced plans to acquire 650,000 doses  
• Last December the UK announced plans to purchase 5 million doses, 
• Six weeks ago Canada PHAC Announces Plans To Purchase 500,000 doses Of H5N1 Vaccine.

Over the past year the ECDC has been busy issuing guidance documents to its member nations.  Like 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. 

While most of this recent surge in preparedness is likely inspired by the continued spread of H5N1, the reality is we could easily be blindsided (again) by something other than avian flu with the next pandemic. 

Just over a year ago (March 20th, 2024) we looked at the first part of this 2-part plan (see  ECDC Guidance: Public Health and Social Measures for Health Emergencies and Pandemics in the EU/EEA), which was published less than a week before the announcement of H5N1 in American livestock. 

I've only included the link and executive summary of this 49-page installment.  Follow the link to read it in its entirety.  I'll have a bit more after you return.

Recommendations for preparedness planning for public health threats

Public health guidance
2 Apr 2025

This document aims to provide public health authorities in European Union and European Economic Area (EU/EEA) countries with guidance for improved preparedness planning taking the lessons that have been identified through various activities in the context of recent public health crises (e.g. COVID-19 pandemic, mpox multi-country outbreak 2022–23) and translating them to concrete advice.

Executive summary


This document, together with the ECDC recommendations on the implementation of public health and social measures (PHSMs) for health emergencies and pandemics published in 2024, form a package of concrete recommendations for preparedness planning for the EU/EEA countries.

Lessons learned primarily from the response to the COVID-19 pandemic, but also from the response to the multicountry mpox outbreak in 2022–23, were collected through various activities from Member States, the European Commission, the World Health Organization (WHO) and the WHO Regional Office from Europe. We have then presented these in the form of specific recommendations for planners within each phase of the continuous cycle of preparedness (Anticipation, Response and Recovery), following a prototype structure of a preparedness and response plan. In each section, we have presented a relevant example from a Member State or international organisation to illustrate their practice or attempt to implement lessons after COVID-19 or the mpox outbreak. These examples were identified either through literature review or communication with representatives of the countries within ECDC’s network for Preparedness and Response.

Annex 1 includes an overview of the main lessons for the public health sector and Annex 2 includes a compiled catalogue of documents, tools and other resources for public health preparedness planning.

Download

Recommendations for preparedness planning for public health threats - EN -

[PDF-2.82 MB

Over the past year, PAHO (Pan American Health Organization) has repeatedly urged its member nations to proactively prepare to deal with a potential influenza pandemic. While H5N1 is assumed, it could certainly be from another coronavirus (or something entirely unexpected).

Just over 4 months ago, in A Personal Pre-Pandemic Plan, I wrote about the practical things you and your family can do now to prepare for a possible pandemic in the months or years ahead.

While I still hope we can avoid (or at least delay) that eventuality, the simple truth is, preparedness is always easier before the next emergency starts. 

And the clock is always ticking.

NOAA/NWS SPC: Another `High Risk' Severe Storm Day

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While we sometimes can go a year or longer without seeing a `High Risk' forecast from the Storm Prediction Center (SPC), today they've issued their second in just over 2 weeks (see previous).  Although the High Risk region is relatively small, the moderate and enhanced risk areas for today are substantial.  

Somewhere between 1000 and 1200 tornadoes are reported each year in the U.S., although that number has been going up in recent years, possibly because of better detection methods. Roughly half occur between March and May, making the spring - particularly in the South and Central states - prime time for these storms. 

 During the summer, the focus for severe weather moves away from the south (Dixie Alley), and into the mid west (aka `Tornado Alley'). 

For most Americans, a severe weather event is their biggest regional disaster threat; hurricanes, tornado outbreaks, blizzards, Derechos, and ice storms affect millions of people every year. Having a good (and well rehearsed) family emergency plan is essential for any disaster.

It is important for your plan to include emergency meeting places, out-of-state contacts, and individual wallet information cards - before you need it (see #NatlPrep : Create A Family Communications Plan).

Together with adequate emergency supplies, a solid first aid kit, and an emergency battery operated NWS Weather Radio, these steps will go a long ways to protecting you, and your family, from a wide variety of potential disasters.

Because it's not a matter of `if' another disaster will strike . .  . 

It's only a matter of where, when, and how bad. 

Media Reports Of Fatal H5N1 Case in Child In Andhra Pradesh, India

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Overnight the India press has lit up with multiple reports (hat tip FluTrackers and @vinodscaria​) on the death - two weeks ago - of a 2-year-old child from H5N1 in Andhra Pradesh. A quick tour of the local AP MOH website and twitter account, however, turns up no confirmation of the story.

The Indian press, admittedly, has a history of `jumping the gun' when it comes to reporting H5N1 cases (see 2007's India Admits 8 Boys to Hospital With `Bird Flu' Symptoms) - while the government is often slow to confirm - but this one sounds plausible. 

While we've seen many false alarms, there are precedents.  

In the summer of 2021, after several days of unconfirmed newspaper reports, we saw India: MOH Statement On Investigation Of 1st Human H5 Avian Flu Infection. The patient, an 11-year-old boy with acute myeloid leukemia, was infected with the clade 2.3.2.1a virus, and died after a week in the hospital.

According to a 2022 EID Journal Report:

An in-depth interview with family members indicated that the patient often frequented a family-owned poultry business and may have been exposed to birds with undetected infection, although no infected domestic or wild avian sources or any environmental contamination had been reported in or around the residence of the child.

Last May Australia reported their first H5N1 case (see Australia: Victoria Reports Imported H5N1 Case (ex India)) in a 2 year-old child who recently traveled from India. The virus was originally identified as  clade 2.3.2.1a virus, which is known to circulate in poultry in Bangladesh and India.

Last December the CDC's EID Journal published a dispatch which revealed this older clade was actually a new genotype, with contributions from newer clade 2.3.4.4b viruses.

And given the number of confirmed human cases in neighboring Bangladesh (n=8) and Pakistan (n=3) over the years - which are likely undercounts - it seems likely that some actual cases in India have been missed.  

According to the following English Language report from the Deccan Chronical (see AP Reports First Bird Flu Death as 2-Year-Old Succumbs to H5N1) the child was admitted to the hospital on March 4th after falling ill after consuming a small piece of raw chicken. 

The child died 12 days later. Swab samples initially tested positive for Influenza A, but were later confirmed to be H5N1 by AIIMS and the National Institute of Virology (NIV), in Pune.  So far, we have no indication of the clade. 

It is worth noting that India has been reporting as surge in H5N1 in recent months, in poultry, wild birds, and even cats.   Last week Andhra Pradesh reported 8 outbreaks (see WOAH report) in poultry, although none appear to be near to where this child was infected.  

Hopefully we'll get some better information in the next few days. 

Stay tuned. 

Preprint: Population Immunity to HPAI 2.3.4.4b A(H5N1) Viruses in the United States and the Impact of Seasonal Influenza on A(H5N1) Immunity

 

Note: Those already familiar with immune imprinting may wish to skim, or skip, my rather lengthy intro. 

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A little over 18 years ago, in A Predilection For The Young, I wrote about the disturbing (but curious) skewing of H5N1 cases (and deaths) among younger individuals (see WHO Chart above). 

While there are no records of humans ever having dealt with an H5 influenza pandemic (going back 130+ years), those who were born before before 1967 appeared far less susceptible to the virus - and those born before 1958 - even more so. 

 A lot of theories were proposed, but answers were elusive. Then, in 2013 an equally novel avian H7N9 virus emerged in China - sparking 5 years of seasonal infections - which skewed dramatically toward those over 40 (see comparison chart below).

Since both H5 and H7 virus exposures had been equally rare, it was obvious that there was more than just prior exposure to - and acquisition of specific antibodies against - these viruses at work. 

While most influenza pandemics see the greatest impact on the elderly, during the 1918 Spanish flu, the death rates among those in their teens, 20s, and 30s was reportedly much higher those in their 50's and 60's.  

In 1977-78, the H1N1 seasonal flu virus - which had been absent for 20 years, suddenly appeared in the Far East, and caused a pseudo-pandemic, primarily affecting those born after 1957. 

And during the  2009 H1N1 pandemic, we saw a similar age shift, where people in their 40's were hardest hit.  Here is what the CDC had to say about the impact of the virus in 2012's First Global Estimates of 2009 H1N1 Pandemic Mortality Released by CDC-Led Collaboration.

2009 H1N1 Pandemic Hits the Young Especially Hard

This study estimated that 80% of 2009 H1N1 deaths were in people younger than 65 years of age which differs from typical seasonal influenza epidemics during which 80-90% of deaths are estimated to occur in people 65 years of age and older.

By early in the last decade many researchers were convinced that the first flu you are exposed to early in life `primes' your immune system to preferentially fight similar influenza infections.  

Over time, this theory was refined to say that the HA Group type (I or II) you are exposed to first could substantially affect your immune response to influenza A (see Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting).

The idea is that if your first influenza exposure was to H1N1 or H2N2 (Group 1), you may carry some limited degree of immunity to H5 viruses (H5N1, H5N6, etc.), while if your first exposure was to H3N2 (Group 2), you may carry some degree of protection against H7 viruses instead (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).

• Those born prior to the mid-1960s were almost certainly first exposed to Group 1 flu viruses (H1N1 or H2N2)

• Those born after 1968 and before 1977 would have been exposed to Group 2 (H3N2) 

• After 1977, both Group 1 and 2 viruses co-circulated, meaning the first exposure could have been to either one. 

Other research suggests exposure to H1N1 (or the seasonal flu shot) may provide some limited degree of protection, since the the NA gene segment in seasonal H1N1 virus is antigenically similar to the NA in the clade 2.3.4.4b H5N1 virus (see EID Journal: A(H5N1) NA Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09).

While none of this is likely to make one fully immune to H5 infection, it could reduce the severity of infection, and decrease mortality. 

All of which brings us to a preprint- published yesterday - from researchers at the CDC and the University of Wisconsin - on potential preexisting population immunity against the HPAI H5 2.3.4.4b virus.  

The good news is this research seems to support previous studies which have suggested that past (age related) H1N1/H2N2 exposure and seasonal flu vaccines may provide some limited protection against severe H5 infection.

This is a lengthy and detailed report, and so I've just posted the link, abstract, and some excerpts.  I'll have a brief postscript after the break. 

Population Immunity to Hemagglutinin Head, Stalk and Neuraminidase of Highly Pathogenic Avian Influenza 2.3.4.4b A(H5N1) viruses in the United States and the Impact of Seasonal Influenza on A(H5N1) Immunity
zhu-nan Li, Feng Liu, Yu-Jin Jung, Stacie Jefferson, Crystal Holiday, F Liaini Gross, Wen-pin Tzeng, Paul Carney, Ashely Kates, Ian York, Nasia Safdar, C Todd Davis, James Stevens, Terrence Tumpey, Min Levine
doi: https://doi.org/10.1101/2025.03.30.25323419

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
 
Preview PDF

Abstract

The unprecedented 2.3.4.4b A(H5N1) outbreak in dairy cattle, poultry, and spillover to humans in the United States (US) poses a major public health threat. Population immunity is a critical component of influenza pandemic risk assessment. 

We conducted a comprehensive assessment of the population immunity to 2.3.4.4b A(H5N1) viruses and analyzed 1794 sera from 723 people (0.5-88 yrs) in multiple US geographic regions during 2021-2024. Low pre-existing neutralizing and hemagglutinin (HA) head binding antibodies and substantial cross reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1) were detected in US population. 

Antibodies to group 1 HA stalk were also prevalent with an age-related pattern. A(H1N1)pdm09 infection and influenza vaccination did not induce neutralizing antibodies but induced significant rise of NA inhibition (NAI) antibodies to N1 of 2.3.4.4b A(H5N1), and group 1 HA stalk antibodies. Understanding population susceptibility to novel influenza is essential for pandemic preparedness.

        (SNIP)

Age-stratified scatter plot of antibodies to group 1 HA stalk in 2023-24, 327 sera were collected from 234 participants from 8 age groups. 

Discussion

Population immunity against new emerging novel viruses is a key factor for influenza pandemic risk assessment16. Amid the ongoing A(H5N1) outbreaks in cattle and poultry and the continued spillover to humans, our study provides a timely and comprehensive assessment of the population immunity in the US to 2.3.4.4b A(H5N1) viruses. 

Results from the current study demonstrate that the levels of the pre-existing neutralizing  antibodies and the HA head binding antibodies to 2.3.4.4b A(H5) viruses in the US population are low, consistent with previous reports of low seroprevalence (mostly measured by HI antibodies) even in populations at increased risk of A(H5) exposure (e.g., poultry workers)12.

 However, our study revealed that the population in the US was not completely immunologically naive to the 2.3.4.4b A(H5N1) viruses: there were substantial levels of preexisting antibodies to the N1 NA of 2.3.4.4b A(H5N1) virus, and group 1 HA stalk antibodies in an age-related pattern. 

Furthermore, these pre-existing cross-reactive immunities to A(H5N1) virus (group 1) were mostly likely from past exposures to seasonal A(H1N1)pdm09 (group 1), not A(H3N2) (group 2) viruses.

While neutralizing antibodies targeting the HAs of the influenza virus are the main correlate of protection in reducing the risk of influenza virus infections, multiple immune mechanisms can contribute to protection from influenza13. Although seasonal influenza A(H1N1)pdm09 virus infection and influenza vaccination did not induce neutralizing and HA head binding antibodies to A(H5N1) viruses (Fig 3-4), both could induce significant rise of cross-reactive functional NAI antibodies to the N1 NA of 2.3.4.4b A(H5N1) (Fig 6). 

Sequence analysis showed that there is significant genetic distance between the HA head of the 2.3.4.4b A(H5N1) and A(H1N1)pdm09 viruses, with amino acid homology at approximately only 53%, and differences across multiple antigenic sites (Extended Table S3 and Extended Fig 2). In contrast, there is a higher level of amino acid sequence homology (86-88%) between the N1 NA sequences of 2.3.4.4b A(H5N1) and recent circulating seasonal A(H1N1)pdm09 viruses (Extended Table S4). 

(Continue . . . )

As we've discussed previously (see SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1), our options during the opening months of a novel pandemic will be limited. Antivirals may be in short supply (or ineffective), and a well-matched vaccine could be 6 months to a year away. 

While not ideal - and with the caveat that it is always possible that H5 swaps out its NA gene for something less compatible - there may be some value in getting the seasonal flu vaccine in the opening days of an H5 pandemic. 

Although the oft-quoted 50% CFR (Case Fatality Rate) of H5N1 is probably greatly exaggerated (see discussions here and here), even a more reasonable 2%-5% CFR would represent a public health crisis unlike anything we've seen in the modern era.

Making any advantage - even a small one - very much worth having. 

A Geospatial Perspective Toward the Role of Wild Bird Migrations and Global Poultry Trade in the Spread of Highly Pathogenic Avian Influenza H5N1

 

Major bird migration flyways - Credit CDC EID Journal

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Twenty years ago, HPAI H5 was viewed as a regional problem; a poultry virus restricted to Southeast Asia which occasionally spilled over into humans. While it could be carried by waterfowl, most of its spread was chalked up to illicit poultry trade. 

In 2005 a new clade of the virus (2.2) appeared at Qinghai Lake in Tibet, and for the first time managed to escape the confines of Asia (see EID Journal: H5N1 Branching Out), turning up six months later in mute swans in Croatia (cite).  

Changes in the virus appeared to have improved its carriage via migratory waterfowl. By the end 2005, 17 (mostly Asian) countries had reported infections, but in 2006 the virus would appear in an additional 39 countries.

By the end of 2007, the virus was endemic in the Middle East, well established in West Africa, and was a frequent return visitor to Europe. Fortunately, carriage by wild birds was still spotty, and strict culling of infected poultry prevented the virus from getting a solid foothold in Europe.

But repeatedly over the years new clades would emerge - and a new subtype (H5N8) - which incrementally improved the virus's ability to spread via migratory birds.  In early 2014, a clade 2.3.4.4 H5N8 virus abruptly appeared in South Korea, ripping through their poultry industry.  

By the end of that year, this new and improved clade had done what no other H5 had done before; it had crossed from Siberia to Alaska, bringing the first HPAI H5 epizootic to North America. 

While devastating, this epizootic was short-lived, and by summer all traces of the virus had disappeared (see PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl).

 The virus was still not able to maintain itself long-term in wild and migratory birds. 

The following year, another reassortment occurred in Russia (see EID Journal: Reassorted HPAI H5N8 Clade 2.3.4.4. - Germany 2016), which led to the unprecedented 2016-2017 epizootic in Europe, one which saw numerous subtypes (H5N8, H5N5, H5N2, H5N9, etc.) emerge, and an increased host range among avian species. 

Additional reassortments, several new subclades (e.g. 2.3.4.4b), and the emergence of competing subtypes (H5N6 then H5N1) would appear over the next 3 years, with the virus gaining new abilities to infect - and persist - in a growing number of bird species. 

In 2017, the virus pushed south through Central Africa, reaching the Southern Hemisphere for the first time. 

In 2020, H5N1 would re-emerge, and in 2021 the virus would make another great leap - crossing the North Atlantic and arriving first in Eastern Canada - then spreading rapidly across North America, arriving in South America the following fall. 

The H5 virus continues to expand its avian host range (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK), as well as branching out into many more mammalian species (e.g. cattle, sheep, goats, rodents, cats, etc.). 

Today, the H5 has made it to every continent except Australia, and many scientists fear that conquest is only a matter of time (see Australia : Biodiversity Council Webinar on HPAI H5 Avian Flu Threat).

Like a snowball rolling down a mountainside, H5N1 is gaining both mass and momentum. Where that leads is unknowable, but the H5 virus we face today is not your father's avian influenza. 

All of which brings us to an excellent research article, published in GeoHealth, which looks at this decades-long evolution of the HPAI H5 virus, and how its spread by wild and migratory birds has changed over the years.  

The full open-access report is very much worth reading in its entirety. You'll find the link, some excepts, and a link to a press release below. 

A Geospatial Perspective Toward the Role of Wild Bird Migrations and Global Poultry Trade in the Spread of Highly Pathogenic Avian Influenza H5N1

Mehak Jindal, Haley Stone, Samsung Lim, C. Raina MacIntyre
First published: 25 March 2025
https://doi.org/10.1029/2024GH001296

Abstract

This study presents the interplay between wild bird migrations and global poultry trade in the unprecedented spread of highly pathogenic avian influenza, particularly the H5N1 clade 2.3.4.4b strain, across the world and diverse ecosystems from 2020 to 2023. We theorized the role of migratory birds in spreading pathogens as various wild bird species traverse major flyways between the northern and southern hemispheres.

Simultaneously, we analyzed the global poultry trade data to assess its role in H5N1's anthropogenic spread, highlighting how human economic activities intersect with natural avian behaviors in disease dynamics. Lastly, we conducted spatial hotspot analysis to identify areas of significant clustering of H5N1 outbreak points over different bird families from 2003 to 2023.

This approach provides a strong framework for identifying specific regions at higher risk for H5N1 outbreaks and upon which to further evaluate these patterns with targeted intervention studies and research into what is driving these patterns. Our findings indicate that both the poultry sector and wild bird migrations significantly contribute to global H5N1 transmission, which helps better understanding of H5N1 transmission mechanisms when combined with ecological, epidemiological, and socio-economic perspectives. The results are intended to inform policy-making and strategic planning in wildlife conservation and the poultry trade to improve public health and animal welfare globally.

Key Points

• We investigated the role of wild bird migration in the inter-continental spread of avian influenza on a global scale

• We analyzed the global poultry trade data to highlight how human economic activities intersect with disease dynamics

• Our findings indicate that both the poultry sector and wild bird migrations significantly contribute to avian influenza transmission

Plain Language Summary

The unprecedented scale and simultaneous infection of avian influenza across multiple species raise concerns about the potential threats to human health, especially in the upcoming years, if not months. The looming increase in bird migrations to the south adds a layer of complexity and urgency to the situation. As we navigate this evolving landscape, it becomes imperative to closely monitor and comprehend the altered dynamics of the virus to implement effective strategies for mitigating the risks associated with human infections.

In this study, we tracked the movement of some wild birds according to their seasonal migration along with the incidence of avian influenza. While the spread patterns revealed that the avian influenza had started in Asian countries, it is not clear how it spread from Asia to Europe because, with the birds we analyzed, it was unable to find a flyway from Asia to Europe. 

However, every spread after the first incidence of avian influenza in Europe can be correlated with the seasonal migration of birds from one country to the other. Europe to Greenland to North America to South America can be established with different wild birds along with the spread from Europe to Africa.

(SNIP)

Analysis from 2005 to 2023 indicated a cyclic occurrence of the H5N1 every 5 years. However, a noteworthy deviation from this established pattern has become apparent in the latest outbreak since 2020. The ecological dynamics of the virus seem to have undergone a significant shift, manifesting in an unprecedented surge in cases compared to previous outbreaks. What distinguishes this event is the simultaneous and extensive infection of poultry, birds, and mammals during the same season—a phenomenon not witnessed in prior instances.

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New carrier birds brought avian flu to Europe and the Americas

Unexpected wild bird species, from pelicans to peregrine falcons, are transporting the virus from poultry to new places around the world and changing where the risk of outbreaks is highest

25 March 2025

         (Excerpt)

Far more bird species than ducks, geese and swans are transporting highly pathogenic H5N1 today, the study found. Cormorants, pelicans, buzzards, vultures, hawks, and peregrine falcons play significant roles in spreading avian flu. That makes them both victims and vectors of the disease and upends traditional approaches to monitoring H5N1 spread and predicting and responding to outbreaks. Culling of poultry birds worked in the past to mitigate burgeoning outbreaks, but it has failed to stop the current outbreak.

“We’ve got to think beyond ducks, geese and swans,” MacIntyre said. “They’re still important, but we have to start looking closely at these other species and other routes and think about what new risks that brings.”

Monitoring wild birds at a global scale is very difficult, so managing poultry bird populations is all the more important, she said. “We can do more about factors in our control — agriculture and farming.” Free-range birds, for instance, are more likely to contact wild birds, so managing them requires more vigilance. And pigs are “an ideal genetic mixing vessel” for viruses, so keeping pigs and poultry in close proximity is dangerous, she said.

“It’s a global problem, and it requires global solutions,” MacIntyre said.

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