Nature Sci Reports: The effect of the time of day of influenza vaccination on antibody and T-cell responses in older adults

Photo Credit - CDC PHIL

#19,407

Ten years and just over 8,000 blogs ago, in Vaccine: Taking Your Best Shot, we looked at a study published in the Journal Vaccine which suggested the time of day one is vaccinated may make a difference in the body's immune response.

The cluster-randomized trial followed 276 adults (over 65) across 24 GP practices in the West Midlands, UK who - between 2011 and 2013 - were assigned to receive their flu shots either in the morning or afternoon.

Follow up blood work showed higher antibodies against H1N1 and Influenza B (but not H3N2) in the morning vaccination cohort. (note: a follow-up Corrigendum - published several months later - weakened the evidence, finding that the influenza B result was no longer statistically significant).

Last week, a new study published in Nature Scientific Reports, revisits the idea and reports: 

Individuals vaccinated in the early morning (09:00) showed an approximately 32% stronger antibody response compared to individuals vaccinated in the afternoon (14:00)

That said, their results were mixed. Their main analysis found no statistically significant differences between vaccination periods, but a secondary analysis favored morning vaccination over early afternoon.

But curiously, not over late afternoon. 

Whether this effect actually results in improved vaccine protection hasn't been established, and the reasons behind the purported `afternoon trough' - assuming it is more than just a statistical variation - remains unclear. 

It is possible our internal body clocks may play a role. Some people (like myself) are early risers, so the same appointment time may fall at different points in our `biological day'.  

The researchers explored that possibility using patient's sleep schedules, but those results were inconclusive as well.  

Make of it what you will.  

I've posted the abstract and a snippet from the discussion. Follow the link to read the study in its entirety.

The effect of the time of day of influenza vaccination on antibody and T-cell responses in older adults 
 
Published: 05 November 2026
  
Download PDF 

Tamara M. J. Brouwers, Koen Vink, Martijn Vos, Harry van Dijken, Marijn E. Snik, Jan van de Kassteele, Lisa Beckers, Debbie Smit, Deborah Oomen, Teun Guichelaar, Tobias N. Bonten, Laura Kervezee, Jacco Wallinga & Debbie van Baarle

Abstract

Increasing evidence suggests that time of day of vaccine administration affects immune responses. We aimed to determine the optimal time of day for influenza vaccination by characterising temporal patterns in vaccine-induced immune responses. Additionally, we assessed the effect of vaccination time relative to an individual’s circadian phase on immune responses.

 A randomised controlled trial was conducted with 278 participants aged 60–85 years, who received influenza vaccination at a randomised time between 09:00 and 17:00. 

Antigen-specific antibody titers and T-cell responses to three vaccine strains (A/H1N1, A/H3N2 and B/Victoria) were measured pre- and one month post-vaccination. A permutation-based test was used to determine differences in strain-specific immune responses between the three randomisation time blocks (09:00–11:40, 11:40–14:20, 14:20–17:00). 

As a secondary analysis, strain-specific immune responses were jointly analysed in a single generalised additive mixed-effects model (GAMM) to assess the overall impact of influenza vaccination timing. The permutation-based test found no significant differences in immune responses between the three vaccination time blocks. A GAMM revealed that morning vaccination resulted in significantly higher antibody responses across strains than early afternoon vaccination(p = 0.045), but not late afternoon vaccination (p = 0.498). 

Antibody responses displayed a non-significant non-linear pattern from 09:00 to 17:00, with the model suggesting highest responses in participants vaccinated at 09:00. A similar trend was observed for T-cell responses.

Irrespective of chronotype, vaccinations administered at the start of an individual’s day tended to elicit the strongest vaccine-induced immune responses. Although statistical evidence for a time-of-day effect was limited, numerically higher antibody and T-cell responses were consistently observed in the morning group.

        (SNIP)

Discussion 

This study showed a consistent trend toward stronger strain-specific antibody and T-cell responses among older adults vaccinated in the morning compared to those vaccinated in the afternoon. However, the differences between vaccination time groups did not reach statistical significance in our primary analysis. After adjustment for variation in baseline antibody titers using GAMM analyses, overall antibody responses differed significantly between the morning and early afternoon vaccination groups, but not between the morning and late afternoon vaccination groups. An important strength of the study is its assessment of temporal patterns in vaccine-induced immune responses across a continuous vaccination window from 09:00 to 17:00. A trend was observed toward stronger vaccine-induced immune responses following vaccination in the early morning (at 09:00).

       (SNIP)

In conclusion, we consistently showed that morning influenza vaccination tended to result in stronger vaccine induced immune responses than (early) afternoon vaccination in adults aged 60–85 years. Our results contribute to the growing evidence on the effect of vaccination timing on vaccine-induced immune responses and suggest potential clinical relevance in older adults. Optimising the timing of vaccine administration may therefore offer a safe and cost-effective strategy to enhance immunogenicity of current influenza vaccines, although further investigation into clinical outcomes is warranted. 

       (Continue . . . )  

IJID Review Article: The H5N1 avian influenza threat: a European Perspective on Research Gaps and State of Preparedness

 

#19,406

While the next pandemic could arise from a wide variety of sources (see WHO 2024 Pathogens Prioritization Report), the most obvious contender today is HPAI H5Nx, which continues to expand its host range as it spreads around the globe. 

Despite the near-inevitability of another pandemic crisis, the world remains slow to embrace that stark reality, and prepare seriously. 

Three years after the start of the last pandemic, in 2023's Lancet Preprint: National Surveillance for Novel Diseases - A Systematic Analysis of 195 Countries, the authors found that the self-reported 66% readiness score for detecting and dealing with novel viruses was not supported by the available evidence.  They wrote:

`A minority of countries have public evidence of novel disease consideration, and significant geographical heterogeneity exists in where this is located.'

Today, most surveillance is passive, and much of what is detected, isn't readily shared. There are often long delays in submitting viral sequences (see Nature: Lengthy Delays in H5N1 Genome Submissions to GISAID) - averaging 7 months - but sometimes taking 1 to 2 years. 

We've also seen repeated warnings from public health agencies that our surveillance systems are not designed to detect novel viruses. 

In 2024 the ECDC issued guidance for member nations on Enhanced Influenza Surveillance to Detect Avian Influenza Virus Infections in the EU/EEA During the Inter-Seasonal Period., which cautioned:

Sentinel surveillance systems are important for the monitoring of respiratory viruses in the EU/EEA, but these systems are not designed and are not sufficiently sensitive to identify a newly emerging virus such as avian influenza in the general population early enough for the purpose of implementing control measures in a timely way.

Similarly, in 2023's analysis from the UKHSA (see TTD (Time to Detect): Revisited), they estimated there could be dozens or even hundreds of undetected human H5N1 infections before public health surveillance would likely detect them, potentially over a period of weeks or months. 

While we've seen a steady chorus of voices from the scientific community calling for more aggressive surveillance and testing (see here, here, here, here, and here) - the world seems content to don blinders and hope for the best.

Today we've a review article in the International Journal of Infectious Diseases (IJID) that examines the current H5N1 threat, and Europe's readiness to deal with it. 

While they cite progress, they urge that Europe strengthen preparedness now, because an emerging human outbreak would likely far outpace our ability to manufacture and deploy vaccines. 

I've only posted some brief excerpts, so follow the link to read the review in its entirety.  I'll have a brief excerpt after the break.

The H5N1 avian influenza threat: a European Perspective on Research Gaps and State of Preparedness

Lone Simonsen 1, Tyra Grove Krause 2 3, Anders Gorm Pedersen 4, Lars E Larsen 5, Marlies Jilles Francine Goedknegt 1, Ramona Trebbien 2, Olav Hungnes 6, Preben Aavitsland 6, Otto Helve 7, Richard J. Webby 8, Marc-Alain Widdowson 9, Bolette Søborg 2, Marion Koopmans 10 11 12, Eskild Petersen 1

10.1016/j.ijid.2026.109220 

Highlights

•  Surveillance must strengthen One Health with closer collaboration between human and veterinary public health.

• Functional assays measuring H5N1 binding to α2,3- or α2,6 sialic acid will help.

• Detect early receptor switching.

• Novel vaccine platforms like the mRNA and Adenovirus must be developed to seasonal influenza to be available for rapid manufacture in a pandemic situation.

Abstract

H5N1 influenza clade 2.3.4.4b has spread from South East Asia through migratory birds since 2020. The expansion seeded frequent spillovers into wild and domestic mammals including cattle in the United States. While the risk for humans not in direct contact with infected animals is low, the widespread presence and opportunities for evolution constitutes a pandemic threat.

If sustained human-to-human transmission (H2H) would emerge, there is limited time to mount a public health response. Initially, non-pharmaceutical interventions (NPIs) are needed until vaccines are available. Experience with H5N1 viruses since 1997 suggests that infections are seen mostly in people born after 1968, indicating that people under sixty may be at particular risk.

Closely monitoring viral diversity and evolution in wild life, and at the human animal interface, using integrated One Health surveillance and genome-based selection of viruses for further characterization for instance receptor affinity of H5N1 to human receptors is mandatory.

        (SNIP)

An influenza A pandemic in our lifetime is highly likely, given there were four in the last 100 years. However, the severity of a future influenza pandemic remains uncertain - it could be as devastating as 1918 or as mild as 2009.[73]

A robust European strategy must be developed during “peace time”, with sustained investment in diagnostics, surveillance, and flexible vaccine manufacturing. Additionally, it is crucial to anticipate, address and counter anti-science and anti-vaccine sentiments, which posed significant challenges during COVID-19. Effective mitigation and vaccination efforts depend on public trust in health authorities.

Although this review focused on the H5N1 threat, the next pandemic could be caused by another influenza A subtype, a coronavirus, or an entirely different pathogen. Given this uncertainty, preparedness efforts should prioritize surveillance anticipating a broad range of pathogens.

       (Continue . . . ) 


While it remains to be seen how the world responds to growing calls for pandemic preparedness (see UN High-Level Meeting on Pandemic Prevention, Preparedness and Response (PPPR)), there are things you can do as an individual to reduce your risk from a pandemic.

As we discussed in  #Natlprep 2025: Personal Pandemic Preparedness, buried in the CDC's archives are a number of useful documents for individuals, schools, and employers on dealing with a pandemic.:

• Get Your Household Ready For Pandemic Flu {PDF - 16 pages]
• Get Ready for Pandemic Flu: Educational Settings [PDF – 16 pages]
• Get Ready for Pandemic Flu: Workplace Settings [PDF – 16 pages]  

I also recommend getting (and being) a Flu Buddy, availing yourself of the vaccines that are available now (Flu/COVID/RSV, Pneumonia, etc.), stockpiling OTC meds and PPE, and being prepared to shelter in place. 

Even if a pandemic doesn't come in the near future, these are all things that would benefit you and your family during any prolonged emergency. 

And those, sadly, appear to be increasingly common.  For more on that, you may wish to revisit:

The UK's `Be Ready' Preparedness Campaign

September Is National Preparedness Month (#NPM26)

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

UK National Risk Register 2026 - Urges Citizen Preparedness

Washington State Adds 3 More H5N1 Infected Herds - HPAI North American Roundup

 

#19,405

Since last Monday, Washington State has reported 3 more infected dairy herds (2 in Yakima County, 1 in Benton), bringing to 43 the number of herds reported since the first week of October.

The number of human infections remains at 3 (1 fatal), with the CDC posting the following brief description in yesterday's FluView. 

Novel Influenza A Virus Infections

Two confirmed human infections with avian influenza A(H5) virus were reported to CDC this week, including one death. To date, human-to-human transmission of avian influenza A(H5) virus has not been identified in the United States.

Both cases were reported by the Washington State Department of Health and occurred in adults aged ≥18 years who worked at commercial dairy cattle farms where highly pathogenic avian influenza (HPAI) A(H5N1) virus has been detected in cows.

One individual developed respiratory symptoms during the week ending October 24, 2026 (Week 42). The patient presented to an emergency department the following week, was hospitalized, and has died. A respiratory specimen collected at the healthcare facility tested positive for influenza A and was presumptive positive for influenza A(H5) at the University of Washington. The specimen was sent to the Washington State Public Health Laboratory where influenza A(H5) was confirmed using the CDC influenza A(H5) assay. Additional testing conducted by the University of Washington determined this was an avian influenza A(H5N1) virus.

The second individual developed conjunctivitis and sought healthcare. Specimens were collected from the individual and tested at the state public health laboratory using the CDC influenza A(H5) assay during the week ending October 31, 2026 (Week 43). Influenza A(H5) virus was confirmed by the state public health laboratory. The specimen has been shipped to CDC for additional testing.

There has been a total of three influenza A(H5) cases in dairy workers in Washington.

The USDA continues to report a sharp uptick in backyard and commercial poultry outbreaks of HPAI H5 across the nation, with 18 states reporting spillovers. California is currently hardest hit, with > 1,300,000 birds affected.

Canada has reported 27 outbreaks since bird flu activity resumed in mid-September, with 6 reports filed over the past week.

And lastly, Mexico's Senasica is reporting a large outbreak of H5N1 in Yucatán. While Mexico has reported H5N1 in wild birds recently, this appears to be the first poultry outbreak since 2024.

        (Translation)

Agriculture promptly addresses avian influenza case in Yucatán

Senasica is conducting a diagnostic assessment to determine if there are more affected farms and will analyze the appropriateness of authorizing emergency vaccination.

National Service for Agrifood Health, Safety and Quality | November 5, 2026 | Press Release

The Ministry of Agriculture emphasizes that the consumption of eggs and chicken is completely safe and that there is no risk to the national poultry industry.

In a timely response of less than 24 hours, the Ministry of Agriculture and Rural Development (Agriculture) confirmed and activated international health protocols for the control of a case of highly pathogenic avian influenza (HPAI) AH5N1, detected in a commercial Poultry Production Unit (UPA) for table eggs in Umán, Yucatán.

The affected farm had a population of 225,860 laying hens, a figure that represents only 0.09 percent of the national inventory, so the event does not impact the supply in the market.

The Ministry of Agriculture reiterates to the public that this case does not pose a risk to the national poultry industry. The supply of poultry products nationwide is fully guaranteed, and the consumption of poultry meat and eggs is completely safe.

Upon receiving notification of the unusual mortality of 862 birds from the farm's veterinarian, official personnel from the National Service for Agrifood Health, Safety and Quality (Senasica) immediately went to the site. Following strict biosecurity protocols, samples were taken and tested positive for HPAI subtype H5 at the Official Biosafety Level 2 Laboratory in Mérida.

Subsequently, the samples were transferred to the Biosafety Level 3 Laboratory of the Mexico-United States Commission for the Prevention of Foot-and-Mouth Disease and Other Exotic Animal Diseases (CPA) in Palo Alto, Mexico City, for further virus isolation and sequencing tests.

Therefore, he stated that specialists from CPA-Senasica delimited a risk area of ​​10 kilometers in radius and immediately implemented international counter-epidemic measures:

• A definitive quarantine was applied to the UPA and the total depopulation of the farm was carried out, sanitary disposal of the birds, destruction of waste and contaminated materials, as well as the cleaning and disinfection of the facilities.
• After the sanitary break period is completed, sentinel birds will be introduced to verify the absence of the virus before authorizing restocking.
• CPA technicians deploy sampling in all fattening, commercial egg-laying and breeding UPAs located within the risk perimeter. 

The diagnosis will determine if there are more affected farms and, according to the results, the General Directorate of Animal Health of Senasica will analyze the appropriateness of authorizing emergency vaccination of the birds that are in the farms surrounding the detected case.

As part of the origin analysis, authorities also inspect nearby bodies of water, where migratory wild birds from the north of the continent usually arrive during the winter season.

In addition, he reported that an expert group in wildlife epidemiological surveillance will soon arrive to intentionally and systematically search for cases of the disease in free-living birds and thereby confirm whether the source of infection is associated with infected migratory species.

During the winter season, the Ministry of Agriculture intensifies epidemiological surveillance throughout the country and invites producers to reinforce biosecurity measures on their farms and to report any suspicion immediately through the Senasica service channels: telephone line 800 751 2100, WhatsApp 55 3996 4462 and email gestioncpa.dgsa@senasica.gob.mx .

South Korea: MAFRA Reports 2 Outbreaks of HPAI H5N9 in Poultry & Ducks

 

#19,404

Over the 2024-2026 flu season, South Korea's MAFRA Reported Increased Infectivity & Pathogenicity of last Year's Avian Flu Strains, which - for the first time - included 3 HPAI subtypes (H5N1, H5N6, and H5N9).

Notably, their Animal and Plant Quarantine Agency also reported H5N1's infectivity was more than 10 times higher than in previous years. 

 

Last year MAFRA reported 62 outbreaks in poultry, and 63 detections in wild birds. While details were scant at the time, last September a highly technical report published in Virus Research added considerable detail. Briefly it reported:

• Last year South Korea was visited by a diverse panoply of H5Nx genotypes (n=16), with at least two - H5N9 N9-G2 and H5N1 25G2 - displaying unusually high infectivity in chickens.

• H5N1 25G2 was also deadly to ducks, whereas H5N9 N9-G2 spread efficiently in ducks, albeit without producing serious illness.

• H5N1 25G2 was the source of nearly half (n=30) of last year's 62 South Korean poultry outbreaks, but it was only detected in environmental samples once, making its prevalence in wild birds unknown.

This year's avian flu season has already started in South Korea, with a report of H5N1 In wild leopard cat in Seosan, South Chungcheong Province less than a week ago, and - over the past 4 days - 2 seperate outbreaks of H5N9. 

The first, reported on Nov 4th, is from the north of the country near the DMZ, while the second is in the far south of the country.  

        (translated)

Nationwide disease control measures strengthened following the first outbreak of highly pathogenic avian influenza (AI) at a laying hen farm in Yeoncheon, Gyeonggi Province.

2026.11.04 18:00:00 Quarantine Policy Bureau Avian Influenza Prevention Division

The Central Disaster Management Headquarters for Highly Pathogenic Avian Influenza ( headed by Minister of Agriculture, Food and Rural Affairs Song Mi-ryeong , hereinafter the Headquarters ) announced on Wednesday , November 4 , that highly pathogenic avian influenza (H5N9 type ) was confirmed at a laying hen farm ( approximately 91,000 birds ) located in Yeoncheon-gun, Gyeonggi-do .

Accordingly, it was announced that on November 4 ( Wed ), a meeting of the Central Disaster and Safety Countermeasure Headquarters, presided over by Director General of Food Policy Park Jeong-hun and attended by relevant agencies and local governments, would be held to review the outbreak situation of highly pathogenic avian influenza and quarantine measures, and to strengthen quarantine management .

1. Situation of Occurrence

The owner of a laying hen farm in Yeoncheon, Gyeonggi Province, reported an increase in chicken deaths to the Northern Gyeonggi Animal Health Laboratory, and as a result of a detailed examination , it was confirmed on November 4 ( Wed ) as highly pathogenic avian influenza (H5N9 type ) . This outbreak is the first case at a domestic poultry farm in the '26/'27 season .

Considering the recent continued detection of highly pathogenic avian influenza in wild birds and the high incidence of outbreaks in laying hen farms last season, thorough disease control management, such as adherence to biosecurity protocols and strengthened disinfection, is required at poultry farms nationwide .

Of the 62 cases that occurred in the '25/'26 season, 31 were at laying hen farms ( 17 were at large laying hen farms with over 100,000 birds ).

In particular , it is a serious situation requiring intensive management, such as disinfection , surveillance , and inspection, centered on large-scale laying hen farms and densely populated areas that suffer significant damage in the event of a highly pathogenic AI outbreak .

       (Continue . . . .)

Quarantine management strengthened following the confirmation of highly pathogenic avian influenza at a broiler duck farm in Jangheung, Gwangju, Jeonnam.

2026.11.06 18:50:00 Quarantine Policy Bureau Avian Influenza Prevention Division

The Central Disaster Management Headquarters for Highly Pathogenic Avian Influenza ( headed by Minister of Agriculture , Food and Rural Affairs Song Mi-ryeong , hereinafter the Headquarters ) announced on November 6 (Fri) that highly pathogenic avian influenza (H5N9 type) was confirmed at a broiler duck farm ( approximately 22,000 ducks) located in Jangheung , Gwangju , South Jeolla Province .

Accordingly, it was announced that on November 6 ( Fri ), a meeting of the Central Disaster and Safety Countermeasure Headquarters was held under the chairmanship of Director of the Disease Control Policy Bureau Lee Dong-sik, with the participation of relevant agencies and local governments , to review the situation regarding the outbreak of highly pathogenic avian influenza and disease control measures, and to strengthen disease control management .

1. Situation of Occurrence

At a broiler duck farm in Jangheung, Gwangju, Jeollanam-do, the farm owner reported an increase in mortality to Jangheung-gun , and as a result of a detailed inspection , it was confirmed on November 6 ( Fri ) as highly pathogenic avian influenza (H5N9 type ) . Including this outbreak, two cases of highly pathogenic avian influenza have occurred at domestic poultry farms during the winter of '26/'27 .

* Status of outbreaks at poultry farms this winter ('26.11.3.~): 1 case ( Laying hens in Yeoncheon, Gyeonggi-do )

With additional outbreaks occurring just two days after the first outbreak at a poultry farm on November 3 , and the risk of further outbreaks being very high in farms with inadequate quarantine measures , all poultry farms nationwide need to strengthen biosecurity and report any suspected symptoms to the quarantine authorities without delay .

In particular , as the first outbreak of the season has been confirmed at a duck farm, thorough disease control management is required for duck farms under the jurisdiction of affiliates .

        (Continue . . . )

While two outbreaks does not a flu season make, for South Korea to kick off their avian flu season with back-to-back H5N9 outbreaks (hundreds of miles apart) is worthy of mention.

Last year, H5N9 made up just 5 of 62 (8%) of South Korea's poultry outbreaks and 10% of wild bird (environmental) samples.  It will be of great interest to see if H5N9 continues to spread.

Also worth mentioning, last year H5N9 was described as highly lethal in chickens, but without producing serious illness in ducks. Friday's announcement cites `an increase in mortality' on the affected duck farm.

Of course, the H5N9 subtype returning this fall could be a different genotype than was seen last year.   

As we discussed as recently as yesterday (see EM&I: Emergence of a Distinct Evolutionary Cluster of Clade 2.3.4.4b H5 Viruses in China during 2024-2025 with Rapid Evolution and Antigenic Divergence), HPAI is constantly reinventing itself.

In addition to H5N9 in South Korea, H5N5 is making moves (see HPAI H5N5: A Variation On A Theme) in high latitude regions of the Northern Hemisphere, and H5N6 continues to simmer in China. 

Although it seems unlikely that today's H5N1 juggernaut could be toppled by any of these competing subtypes, it wasn't all that long ago (2020) that H5N8 was the dominant subtype.

A reminder that HPAI is highly unpredictable, and its threat can change over time. 

EM&I: Emergence of a Distinct Evolutionary Cluster of Clade 2.3.4.4b H5 Viruses in China during 2024-2025 with Rapid Evolution and Antigenic Divergence

 

Antigenic Distance Map

#19,403

As we've discussed often over the years, there are scores of genotypes of HPAI H5 clade 2.3.4.4b viruses circulating around the world, and many genetic variations may exist within each genotype. 

Beyond that, there are other subclades of the HPAI H5 virus circulating in places like Cambodia, Bangladesh, and India (see 2025's WHO: Influenza at the Human-Animal Interface Report - Identifies New H5 Clade 2.3.2.1e Infections in Cambodia & Vietnam). 

Simply put, the H5Nx virus currently infecting cattle and humans in Washington state is closely related to - but genetically distinct from - numerous H5 viruses circulating in Europe, Australia, or South Korea. 

Since 2022 more than 100 different genotypes have been identified in the United States alone.  Some are more pathogenic in birds or mammals - while others are more benign - but more are expected to emerge over time. 

Most of these variants are destined to become evolutionary failures; ultimately unable to compete with more biologically `fit' variants already in circulation. 

Over the past 20+ years we've seen hundreds of them appear - sometimes only briefly - before fading away.  Occasionally, however, a new variant will bring something new to the party.

In early 2014 an emerging H5N8 virus in South Korea improved its ability to be carried long distances by migratory birds. In less than a year it had crossed the Pacific and sparked the first major North American epizootic with HPAI H5, and the following year (2016) conquered Europe. 

In 2021 a new and improved H5N1 emerged in Europe and quickly supplanted H5N8, winging its way first to North America, then South America, and then the Antarctic. In 2026, it reached Australia and New Zealand. 

This new H5N1 has shown an increased affinity for infecting mammals, and a much wider avian host range (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK).

Since then, we've seen HPAI H5 increase its ability to infect dairy cattle, sheep, goats, and other ruminants, even as it continues to occasionally spill over into humans. 

Although H5's evolutionary trajectory is both erratic and unpredictable, as long as they circulate, these avian influenza viruses will undoubtedly continue to reinvent themselves. 

All of which bring us to a new research article, published yesterday (Nov 5th) in Emerging Microbes & Infections, which describes the detection of an antigenically distinct cluster of HPAI H5 viruses which appeared in China in 2024-2025 (see distance map at top of blog).

While the authors didn't report any immediately alarming red-flags (e.g. increased virulence or transmissibility, mammalian markers, etc.), this is a reminder that HPAI H5 viruses continues to evolve, and what we say about their threat today may not hold true tomorrow. 

Much of this report is highly technical, and of interest primarily to virologists. Those desiring a deeper dive will want to follow the link to read it in its entirety.  

Research Article

Emergence of a Distinct Evolutionary Cluster of Clade 2.3.4.4b H5 Viruses in China during 2024-2025 with Rapid Evolution and Antigenic Divergence

Xinkui Zhang ,Yujia Yang , Xirong Huang, Shunyin Fang ,Xinyu Han ,Dandan Wei , show all
Article: 2760125 | Accepted author version posted online: 05 Nov 2026
Cite this article https://doi.org/10.1080/22221751.2026.2760125

Abstract

Clade 2.3.4.4b H5 viruses have undergone continuous evolution since their emergence in China, but the extent of genetic and antigenic diversification among recently circulating viruses remains unclear. 

Here, we characterised 18 H5 viruses isolated through routine surveillance in China during 2024-2025, together with publicly available clade 2.3.4.4b H5 sequences collected since 2020. 

Phylogenetic analysis revealed that these isolates formed a distinct evolutionary cluster within clade 2.3.4.4b, designated the G2-derived emerging cluster (G2-EC), which emerged around mid-2024 and exhibited clear genetic divergence from previously circulating H5N1 viruses. 

G2-EC viruses accumulated a characteristic set of hemagglutinin amino acid substitutions, most of which were located in antigenic regions. Across the clade 2.3.4.4b H5 virus population, the estimated mean HA evolutionary rate was higher during 2024-2025 than during preceding periods. 

These genetic changes were accompanied by marked antigenic divergence from the Re14 vaccine strain, with 4- to 32-fold reductions in HI titres. Genomic analysis revealed acquisition of PB1 segment from a distinct genetic background in G2-EC H5N1 viruses, followed by the emergence of H5N6 viruses sharing a highly similar genetic backbone but carrying a distinct NA segment, indicating sequential reassortment. 

Animal experiments showed that representative G2-EC viruses retained high pathogenicity and efficient direct-contact transmission in SPF chickens, while exhibiting relatively limited lethality in mice. Collectively, these findings document a recent evolutionary transition of clade 2.3.4.4b H5 viruses in China, characterised by genetic and antigenic divergence accompanied by sequential reassortment, underscoring the need for continued genomic and antigenic surveillance.

        (SNIP)

Evolutionary rate analysis further suggested that the estimated mean evolutionary rate of the HA gene of clade 2.3.4.4b H5 viruses was higher during 2024–2025 than during the preceding two periods. Together with the emergence of the new evolutionary cluster and the accumulation of multiple characteristic substitutions in its HA protein, this observation suggests that 2024–2025 may represent an important phase of enhanced genetic divergence within the clade 2.3.4.4b H5 virus population in China.

However, the number of HA sequences available for evolutionary rate estimation during this period was relatively limited, which may have increased uncertainty in the posterior estimates and resulted in partial overlap of the 95% HPD intervals among different periods. Therefore, although the estimated mean evolutionary rate was higher during this period, this trend still requires further validation using larger-scale surveillance datasets.

       (Continue . . . )
 

Whether we are seeing the start of a new (and potentially important) branch in HPAI H5Nx's evolution - or simply a flash in the pan - is hard to say. This study is based on just 18 sequenced viruses (15 H5N1, 3 H5N6) acquired from routine surveillance in China. 

The authors wrote:

To date, viruses belonging to this cluster have been detected predominantly in China. Apart from a small number of highly similar sequences identified in environmental samples from Japan in November 2025, no evidence of widespread detection of G2-EC-related viruses has been observed among publicly available H5N1 virus sequences from other countries or regions.

Limited surveillance, along with delays in depositing sequences (see Nature: Lengthy Delays in H5N1 Genome Submissions to GISAID), mean that we are only catching glimpses of H5's evolution.

Which is why we should be prepared for surprises going forward. 

EID Journal: Serologic Evidence of Avian Influenza Virus Exposure in Livestock, Egypt, 2024–2026

#19,402

In the spring of 2024 a mysterious illness spreading among Texas, Kansas, and New Mexico dairy cattle was identified as avian H5N1, an outbreak that has now spread to at least 21 states, and has affected > 1200 herds.  

At that time cattle were believed poorly susceptible to influenza A (see A Brief History Of Influenza A In Cattle/Ruminants), and so testing for H5N1 was delayed.   

The immediate global reaction was that this was an `American problem', caused by a new (and presumably unique to North America) strain (B3.13) of H5N1 (see DEFRA Risk Assessment Of HPAI H5N1 Occurring in Cattle In the UK), and unlikely to occur in Europe. 

This strain has not been detected in the UK, and none of the viruses detected in the UK over the 2020 to 2024 HPAI outbreak period have contained genetic material originating from North or South American viruses. 

 The risk to GB of H5N1 in livestock is assessed at very low. 

That assumption was challenged in June of 2024 (see Germany: FLI Statement On Experimental Infection Of Dairy Cows With European H5N1 Virus) when researchers demonstrated that a German virus isolate could replicate in a cow's udder after experimental infection.

Over the summer of 2024 the USDA reassuringly suggested that B3.13 entered dairy cattle via a single spillover from birds - and was subsequently spread by the interstate transport of infected dairy cows. That assumption held until early 2025 when another genotype (D1.1) turned up in dairy cattle in two states (Nevada & Arizona).

In March of 2025, the UK's Defra reported H5N1 Detected In Domestic Sheep with Mastitis, and over the previous year we'd seen reports of other non-B3.13 H5N1 in goats and sheep in Pakistan, horses in Mongolia, and pigs in Oregon.

Also in the spring of 2025, Chinese scientists warned that Clade 2.3.4.4b HPAI H5N1 influenza Viruses from Birds in China Replicated Effectively in Bovine cells.

Last April, in Preprint: Infection of the Bovine Mammary Gland by Avian H5N1 Subclade 2.3.4.4b Influenza viruses. we saw even more evidence that diverse HPAI H5 strains could infect dairy cattle. The authors wrote:

Our findings show that mammary tissue from common cattle breeds is permissive to clade 2.3.4.4b H5N1 infection. These results support the view that bovine mammary epithelium represents a susceptible tissue environment and suggest that IAV infection in cattle may be more widespread than previously assumed.

Four months ago, in Eurosurveillance: Detection of antibodies against avian influenza in European dairy cattle, the Netherlands, January 2026), we saw additional evidence of HPAI spillover into dairy cattle outside of the United States. 

A little over a a year ago, WOAH embraced an 11-page OFFLU technical document (see OFFLU Guidelines for High Pathogenicity Avian Influenza Virus Risk Mitigation in Cattle) which - among other things - finally made HPAI in cattle a `reportable disease'.

But surveillance remains passive, and testing largely up to the discretion of the livestock owner. Something that many farmers find unappealing, fearing the quarantining of their herds and the stigma of infection.

Today we've an EID Journal research letter which reports compelling serological evidence not only of HPAI H5 infection in Egyptian cattle, but LPAI H9N2 as well.  The authors write:

Our findings indicate that spillover of avian influenza viruses to cattle and other livestock is not geographically restricted or caused by certain genotypes of H5N1 virus.

Testing included both hemagglutination inhibition (HI) and microneutralization (MN) assays, and positive results weren't confined to cattle.  Sheep and goats tested positive for LPAI H9N2 as well.  

I've only posted some excerpts from this letter. Follow the link to read it in its entirety. I'll have a postscript after the break.

Volume 32, Number 12—December 2026
Research Letter
Serologic Evidence of Avian Influenza Virus Exposure in Livestock, Egypt, 2024–2026

Mokhtar Gomaa, Rabeh El-Shesheny, Ahmed El Taweel, Omnia Kutkat, Hager Emam, Basant Helal, Ayat Swelam, Mohamed GabAllah, Ahmed Kandeil, Pamela P. McKenzie, Richard J. Webby, Mohamed Ahmed Ali, and Ghazi Kayali

Abstract

Spillover of influenza A(H5N1) virus to cattle in the United States sparked global concern. We investigated whether endemic avian influenza viruses are potentially spilling over into domestic livestock in Egypt. We detected influenza H9N2 antibodies in 2.5% and H5N1 antibodies in 2.9%–4.5% of tested animals. Additional surveillance will elucidate host infection dynamics.

       (SNIP) 

Clade 2.3.4.4b H5N1 virus and low-pathogenicity avian influenza A(H9N2) virus are widely and endemically circulating in poultry in Egypt on farms and backyards and at live bird markets (7). Subtype H5N1 was detected in feral rats in poultry production areas (8). In addition, reassortment events between the H5N1 and H9N2 subtypes led to the emergence of novel clade 2.3.4.4b influenza A(H5N2) viruses (9). To determine whether those viruses are spilling over to livestock in Egypt, particularly in mixed-species settings, we conducted a serosurveillance study in northern Egypt.

During October 2024–January 2026, we collected 444 serum samples from 33 conveniently selected small farms (≈10 cattle, no mixed species) and backyards housing cattle (1–3 cattle with mixed species) in 3 governorates (n = 155, n = 59, and n = 230) in northern Egypt, representing common practices in Egypt. Sheep and goats were also sampled if housed in the same backyards as cattle. All sampled animals were apparently healthy adults.

We tested serum samples for antibodies against a 2025 Egyptian clade 2.3.4.4b H5N1 (A/duck/Egypt/BA20361C/2022) virus using hemagglutination inhibition (HI) and microneutralization (MN) assays and against a G1-like Egypt influenza A(H9N2) (A/chicken/Egypt/RA20191OP/2022) virus by HI in accordance with World Health Organization protocols (10). We considered an antibody titer >1:40 as positive for both assays. Data on the number of cows, presence of other mammals (e.g., donkeys and horses), and presence of avian species (poultry and/or wild birds) were available for 271 samples. We performed statistical comparisons with χ2 or Fisher exact tests; we considered p<0.05 statistically significant.

Overall, 11 (2.5%) serum specimens tested positive for influenza A(H9N2) antibodies, 20 (4.5%) were positive for influenza A(H5N1) antibodies by HI, and 13 (2.9%) were positive for influenza A(H5N1) antibodies by MN (Figure, panel A). Positive titers were 40–160 (Figure, panel B). None of the samples tested positive for antibodies against both viruses. Of the 20 H5N1 virus specimens positive by HI, 12 tested positive by MN; 1 specimen was negative by HI and positive by MN. All influenza H9N2-positive specimens were from 3 locations in the same governorate (p = 0.005). Influenza A(H5N1) antibodies were detected in 2 governorates; the differences in detection rates by governorate were statistically significant (0%, 1.3%, and 4.8%; p = 0.049). All H5N1 virus–seropositive specimens were from cattle (Table).

We detected H9N2 antibodies in 6/374 (1.6%) of cattle specimens, 1/31 (3.2%) of goat specimens, and 4/39 (10.3%) of sheep specimens (p = 0.004). Presence of other animals did not predict seropositivity. Small farms had a significantly higher proportion of H5N1 virus–positive animals tested by MN (p = 0.039).

Our findings indicate that spillover of avian influenza viruses to cattle and other livestock is not geographically restricted or caused by certain genotypes of H5N1 virus. Clade 2.3.4.4b H5N1 virus of the EA-2021-AB genotype and G1-like H9N2 virus appear to be spilling over into livestock in Egypt; however, because our evidence is serologic, we could not ascertain whether true infection is occurring and whether the same signs seen in the United States are common in cattle in Egypt. 

Even so, the evidence is a strong indicator that spillover is occurring, similar to that reported in Europe (4,6). Furthermore, spillover is not restricted to cattle; some sheep and goats tested in our study were seropositive for influenza A(H9N2) virus. Surveillance for avian influenza viruses in Egypt and other countries, especially those in which avian influenza is endemic, will verify infection and provide data on frequency, routes of transmission, and factors affecting infection of and transmission to livestock.

       (Continue . . . )
 

Despite the accrued evidence to date -  for a myriad of political, societal, economic, and logistical reasons - governments around the world appear slow to respond to HPAI (and now LPAI) spillover into mammalian livestock.   

We see this same reluctance in investigating HPAI spillover into other species, including farmed mink (see Virological (Referral): Preliminary report on H5N1 highly pathogenic avian influenza in Utah mink, August 2026).

Although this laissez faire approach may work out in the short run, it provides these viruses with ample opportunities to spread, to evolve, and to adapt. 

Admittedly, most of these viruses will likely never pose a serious public health threat. 

But it only takes one overachiever - aided and abetted by inaction on our part - to plunge the world back into another pandemic crisis.