WHO WPRO: China Reports 3 More H9N2 Cases On The Mainland

 

#19,024

Although there is no mention of it in today's CHP Weekly Avian flu report, the WHO's WPRO (Western Pacific Region Office) latest avian flu report contains a brief description of 3 new H9N2 cases reported by China. 

Human infection with avian influenza A(H9N2) virus

From 9 to 15 January 2026, three new cases of human infection with avian influenza A(H9N2) virus were reported to WHO in the Western Pacific Region. All three cases were reported from China: The first case is a five-year-old male from Hubei Province, with an onset of symptoms on 30 November 2025; the second case is an eight-year-old female from Jiangsu Province, with an onset date on 4 December 2025; the third case is a one-year-old male from Guangxi Province, with an onset date on 7 December 2025.

The first case had exposure to backyard poultry whereas the other two cases reported no known exposure to live poultry.The parents of the second case visited a store selling freshly slaughtered poultry, and the third case also had indirect exposure to freshly slaughtered poultry. All three cases have now recovered.

Since December 2015, a total of 155 cases of human infection with avian influenza A(H9N2), including two deaths (both with underlying conditions), have been reported to WHO in the Western Pacific Region. Of these, 152 were reported from China, two were from Cambodia, and one was from Viet Nam.

This comes on the heels of 7 cases reported by WHO in the 3rd week of December.  The ECDC summarized those cases as:

The cases were reported in Guangdong (1), Guangxi (3), Henan (1) and Hubei (2) provinces with onset of symptoms in September, October and November 2025. Five patients were children and two were adults. Five of the seven individuals had mild disease, two elderly individuals were hospitalised, of whom one with underlying conditions was hospitalised with severe pneumonia. All but one had exposure to birds either in backyard poultry (4) or live poultry market (2). Investigations are ongoing for one case to determine the source of infection.

As we discussed last month, in HK CHP: Another Cryptic Announcement of H9N2 Cases From the Chinese Mainland, reports out of China are often belated, and many lack critical details. 

And of course, the expectation is that most cases are never detected by surveillance, since most are believed mild, and testing (particularly of adults) in China usually only occurs in hospitalized patients. 

While HPAI H5N1 remains firmly atop our pandemic concerns list - primarily due to its potential severity - the CDC's IRAT List contains 25 influenza A strains across 12 different subtypes (H1N1, H1N2, H3N2, H5N1, H5N2, H5N6, H5N8, H7N7, H7N8, H7N9, H9N2, H10N8).

Arguably, there are several more which could be added to this list, including H3N8, H6N1, and H10N3. Even among this narrow field of influenza A viruses, H5N1 ranks fairly far down the CDC's list (#7).

In terms of likelihood of emergence, the CDC currently ranks a Chinese EA H1N1 `G4' swine virus at the very top of their list of zoonotic influenza A viruses with pandemic potential, with 3 other North American swine variant viruses and H9N2 scoring above H5N1.

While H9N2 has a reputation of being a relatively mild viral infection - primarily reported in children - we've seen changes in its epidemiology of late; including more adult infections (some seriously ill) reported out of China.

H9N2 also easily reassorts with, and often enhances, other novel influenza viruses (including H7N9, H5N1, and H5N6), making it an important viral co-conspirator (see Vet. Sci.: The Multifaceted Zoonotic Risk of H9N2 Avian Influenza).

But, despite all of this,, LPAI H9N2 doesn't get a lot of respect. 

Since it is a low-path virus in poultry, it is not considered `reportable' to WOAH, so surveillance is suboptimal. Some countries vaccinate poultry against it, but existing vaccines have not been very effective (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China), and that may have even helped drive its evolution. 

Last October, in China CDC Weekly: Epidemiological and Genetic Characterization of Three H9N2 Viruses Causing Human Infections, we looked at a local CDC investigation into 3 pediatric cases which were reported last April from Changsha City, Hunan Province, China.

Their report found a number of indicators of increased mammalian adaptation within the virus, including an enhanced ability to infect upper respiratory (α2,6-sialic acid) tract receptors, and a number of HA protein mutations, including; H191N, A198V, Q226L, and Q234L.

Last November, in EM&I: Enhanced Replication of a Contemporary Avian Influenza A H9N2 Virus in Human Respiratory Organoids, we looked at a study which compared two H9N2 isolates (from 2024 and 1999) across several organoid models, and found today's virus to be far better adapted to human hosts.

 

The authors wrote:

In summary, we demonstrated that a recent H9N2 virus is more adapted to humans, and is able to replicate to high titres in both upper and lower human respiratory tract which may confer higher person-to-person transmissibility and virulence. Our study underscores the importance of human organoid-based phenotypic monitoring and inter/intrahost genotypic monitoring for assessing the zoonotic risk of avian influenza viruses.

These, and other recent studies (see here, here, and here) have elevated concerns over the trajectory of LPAI H9N2 viruses. While trying to predict the source of the next pandemic is a mug's game, H9N2 certainly deserves our attention. 

The Lancet: Prenatal Paracetamol Exposure and Child Neurodevelopment: A Systematic Review and Meta-Analysis

Photo Credit – Wikipedia

#19,023

Last September the WHO & Other Major Medical Stakeholders Pushed Back On A Suggested Acetaminophen/Autism Link after the White House issued an announcement suggesting that such a link existed. 

Acetaminophen/Paracetamol have long been considered the safest analgesic & antipyretic drugs for pregnant women and their unborn child, with few safe alternatives currently available.  

While a few studies have claimed a statistical link between acetaminophen use during pregnancy and autism (Link), none have found a causal link, and one of the most robust recent (2024) studies (see Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability) found:

Conclusions and Relevance  Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

We've previously looked at potential drivers of increased autism, and after genetics, environmental exposures, and increased recognition of those on the spectrum, fevers during pregnancy are frequently cited (see Molecular Psy.: Increased Autism Risk Linked To Prenatal Fever).

The concern is that discouraging the use of the only `presumed safe' option to reduce fevers could actually end up increasing the incidence of autism, instead of decreasing it.

Admittedly, no medication is 100% safe for 100% of the population 100% of the time. As with everything in life, there there is always a risk-reward calculation involved: Is the risk (no matter how slight) worth the benefit? 

While absolute statements on the absolute safety of any drug are impossible to make, over the weekend The Lancet has published a Systematic Review and Meta Analysis on Paracetamol/Acetaminophen exposure and child neurodevelopment.  

This review incorporated 43 studies (17 of which were combined in the meta-analysis), and they report:

Current evidence does not indicate a clinically important increase in the likelihood of autism spectrum disorder, ADHD, or intellectual disability in children of pregnant individuals who use paracetamol as directed, supporting existing recommendations on its safety.

While additional research is still needed to better understand heavy or prolonged usage, these findings should be reassuring to anyone who chooses to use these drugs during pregnancy. 

Under Implications of all the available evidence, the authors write:

Taken together with large-scale sibling-controlled studies from Sweden and Japan published in 2024 and 2025, our findings support the safety of paracetamol when used appropriately during pregnancy. They reinforce the guidance of major professional and regulatory bodies, including the American College of Obstetricians and Gynecologists, the Royal College of Obstetricians and Gynaecologists, and the European Medicines Agency, which continue to recommend paracetamol as the first-line analgesic and antipyretic in pregnancy.

Avoiding paracetamol based on inconclusive or biased evidence might increase the risk of maternal fever or untreated pain, both of which can harm pregnancy outcomes. Future research should focus on improving exposure measurement, standardising outcome definitions, and integrating mechanistic and family-based designs to clarify any residual uncertainties.

I've posted the link and the abstract from the open-access meta-analysis below.

Prenatal paracetamol exposure and child neurodevelopment: a systematic review and meta-analysis
Francesco D'Antonio, PhDa,† ∙ Maria Elena Flacco, PhDb,† ∙ Lorenza Della Valle, MBBSc ∙ Smriti Prasad, MRCOGd ∙ Lamberto Manzoli, PhDf ∙ Athina Samara, PhDg,h,i ∙ et al.  

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Summary

Background

Concerns have emerged about the impact of paracetamol use in pregnancy on child neurodevelopment, particularly in relation to autism spectrum disorder. We aimed to synthesise available evidence to investigate associations between prenatal paracetamol exposure and autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), and intellectual disability.

Methods

For this systematic review and meta-analysis, we searched MEDLINE, Embase, ClinicalTrials.gov, and the Cochrane Library from inception to Sept 30, 2025, for cohort studies reporting adjusted estimates of the risk of autism spectrum disorder, ADHD, and intellectual disability. Eligible studies used validated questionnaires or medical records to define outcomes, reported maternal comorbidities and treatments, and compared pregnancies with and without paracetamol exposure, whereas unadjusted studies were excluded. Quality assessment of the included studies was conducted using the Quality In Prognosis Studies (QUIPS) tool. The primary outcomes were the associations between prenatal paracetamol exposure and the likelihood of autism spectrum disorder, ADHD, and intellectual disability. Analyses were restricted to sibling-comparison studies with adjusted estimates, and odds ratios (OR) were calculated. Random-effects meta-analyses used the generic inverse variance method. Subgroup analyses were performed when possible (trimester, duration of use, offspring sex, and follow-up length). This study was registered with PROSPERO, CRD420251156690.

Findings

43 studies were included in the systematic review, and 17 studies in the meta-analysis. When considering sibling comparison studies, paracetamol exposure during pregnancy was not associated with the risk of autism spectrum disorder (OR 0·98, 95% CI 0·93–1·03; p=0·45), ADHD (0·95, 0·86–1·05; p=0·31), or intellectual disability (0·93, 0·69–1·24; p=0·63).

There was also no association between paracetamol intake during pregnancy and autism spectrum disorder (OR 1·03, 95% CI 0·86–1·23; p=0·78), ADHD (0·97, 0·89–1·05; p=0·49), or intellectual disability (1·11, 0·92–1·34; p=0·28) when considering only studies at low risk of bias according to QUIPS. This absence of association persisted when considering all studies with adjusted estimates and those with more than 5 years of follow-up.

Interpretation

Current evidence does not indicate a clinically important increase in the likelihood of autism spectrum disorder, ADHD, or intellectual disability in children of pregnant individuals who use paracetamol as directed, supporting existing recommendations on its safety.

Preprint: Bovine-derived Influenza A virus (H5N1) Shows Efficient Replication in Well-differentiated Human Nasal Epithelial Cells Without Requiring Genetic Adaptation

Flu Virus binding to Receptor Cells – Credit CDC

#19,022

Based on limited surveillance and reporting systems (see NAS : Diagnostic Tools, Gaps, and Collaborative Pathways in Human H5N1 Detection (Rapid Expert Consultation), the available evidence suggests that HPAI H5N1 viruses are not currently transmitting efficiently (or often) among humans. 

While somewhat reassuring, we've also seen evidence to suggest that mild, or asymptomatic cases are likely being missed (see MMWR: Serologic Evidence of Recent Infection with HPAI A(H5) Virus Among Dairy Workers and JAMA Open: Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic Testing).

While the WHO, PAHO, and the ECDC (see ECDC Pre-pandemic Guidance: Strategies to Fight Avian and Swine flu in Humans) have all called for increased vigilance, there appears to be some reluctance among many member countries - and their agricultural interests - to comply.   

Meanwhile, we continue to see studies and preprints that suggest that HPAI H5Nx viruses are continuing to accrue mammalian adaptations (see here, here, here, here, and here).

To this rapidly expanding list we can add a new preprint from researchers in Switzerland who conducted experiments to test the replication of the bovine (B3.13) H5N1 virus in human nasal epithelial cells - and found they replicated remarkably well - even at low temperatures. 

That said, after 24-hours, the human innate immune system was able to substantially reduce replication via IFN-λ (`lambda interferons'), which may explain its relatively mild presentation.

While lengthy, and somewhat technical, this is a fascinating report and many will want to read it in its entirety.  I've reproduced the abstract and some highlights below. 

I'll return with a bit more after the break. 

Bovine-derived influenza A virus (H5N1) shows efficient replication in well-differentiated human nasal epithelial cells without requiring genetic adaptation
Etori A. Moreira,Samuel Constant, Charlene Constant, Lisa Butticaz, Michele Wyler, Teodora David, Peter M. Grin, Charaf Benarafa, Volker Thiel,Marco P Alves, Gert Zimmer
doi: https://doi.org/10.64898/2026.01.16.699876
This article is a preprint and has not been certified by peer review 

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Abstract

Highly pathogenic avian influenza H5N1 viruses of clade 2.3.4.4b have caused widespread avian mortality and sporadic mammalian infections, raising concerns about their potential for efficient replication in the human population. Efficient replication in the human upper respiratory tract is considered a key barrier to transmission.

Here, we demonstrate that an H5N1 virus isolated from bovine milk in Texas in 2024 (H5N1Tex/24) replicates as efficiently as the 2009 pandemic H1N1 virus (H1N1HH4/09) in well-differentiated human nasal epithelial cells.

These cells express both avian- and human-type influenza receptors, indicating receptor adaptation is unnecessary for entry. H5N1Tex/24 replicates effectively at 33 degrees Celsius, reflecting nasal cavity temperature, whereas earlier avian H5N1 strains require 37 degrees Celsius, suggesting that H5N1Tex/24 has acquired another key adaptive feature to the human upper respiratory tract.

H5N1Tex/24 remains sensitive to interferon-λ (IFN-λ) despite inducing low cytokine levels. Notably, no known mammalian-adaptive mutations such as PB2-E627K were detected. These findings suggest that H5N1Tex/24 possesses intrinsic traits enabling efficient replication in the human upper airways, a critical step toward potential airborne transmission, underscoring the need for vigilant surveillance.

       (SNIP)

Overall, our results show that bovine-derived H5N1Tex/24 replicates at high titers in primary human nasal epithelial cells even though it lacks many canonical markers of adaptation to mammals. This observation contrasts with the currently low number of confirmed human infections. There are several possible explanations for this discrepancy. 

• First, the sensitivity of H5N1Tex/24 to the antiviral effects of MxA may limit virus dissemination to the lower respiratory tract and thus disease severity. 
• Second, human infections may go undetected because they are completely asymptomatic or because they are associated with only mild symptoms.
• Third, efficient airborne transmission of H5N1 requires that HA induces membrane fusion at pH values significantly lower than pH 6.076,77. However, the HA protein of bovine H5N1 retains typical avian characteristics, with fusion triggered at approximately pH 6.046,78. 
• Finally, pre-existing immunity to influenza viruses may provide some partial protection against bovine H5N1. Cross-reactive antibodies against the NA protein of human H1N1 viruses can particularly inhibit avian N1 sialidase activity, thereby potentially limiting replication of clade-2.3.4.4b viruses. 

The recent fatal human case caused by a H5N5 HPAI virus in the United States is alarming, as there is probably no pre-existing immunity to the N5 antigen in the human population.

Overall, our results show that H5N1Tex/24 has a remarkable ability to replicate in primary human nasal epithelial cells. Since well-differentiated nasal epithelial cells represent a relevant model for the human upper respiratory tract, it is not unlikely that the virus can also replicate efficiently in vivo in humans

       (Continue . . . )

This study confines itself primarily to the milder B3.13 `bovine' H5N1 virus (with a brief mention of HPAI H5N5), but there are also concerns over other genotypes (and subclades) including the D1.1 genotype, which burst onto the scene in the fall of 2024, and has caused more severe (and 2 fatal) infections in humans. 

The exact number of human infections with the D1.1 genotype is unknown, since not all of the (now, roughly 6 dozen) North American human cases have been fully characterized.  

A study, published 2 months ago (see J.I.D.: Avian influenza virus A(H5N1) genotype D1.1 is better adapted to human nasal and airway organoids than genotype B3.13) described this ambiguity:

A total of 53 strains were identified, of which 6 strains had 2 sequences deposited. These 53 strains were collected from patients between March 28, 2024 and February 12, 2025 (Supplementary Table S3). Of these 53 strains, 22 (41.5%) were assigned to genotype B3.13, 8 (15.1%) were assigned to D1.1, 1 (1.9%) was assigned to D1.3, and 22 (41.5%) could not be assigned to any genotypes according to GenoFLU version 1.06 (https://github.com/USDA-VS/GenoFLU). 

Based on those numbers, it appears that Bovine B3.13 human infections have likely outnumbered D1.1 infections by a factor of 2:1, making the difference in virulence even more striking.

That study attributed D1.1's increased severity to their findings that the D1.1 genotype replicates better in lab-grown nasal and lung tissues than the bovine B3.13 strain, and it binds more tightly to human‑type (α2,6-linked SA) receptors.

While direct comparisons between these studies are difficult due to differences in methods and materials, both show that - compared to older H5Nx strains - both the B3.13 and D1.1 genotypes have become much better adapted to the human nasal passage.  

And that's a trend we really shouldn't sneeze at. 

EID Journal: Thrombotic Events and Stroke in the Year After COVID-19 or Other Acute Respiratory Infection

 

#19,021

Six years after the emergence of a novel coronavirus (SARS-CoV-2) the world remains largely in denial over the long-term health impacts of COVID infection, even though the evidence of post-infection sequelae has been strong from the start. 

Originally billed as a primarily SARS-like viral pneumonia, COVID-19 has repeatedly shown that pneumonia is only part of its extensive repertoire (see Nature Med. Review: Extrapulmonary manifestations of COVID-19).

ARDS and pneumonia are often associated with severe SARS-CoV-2 infection, but other organs - including the brain, heart, and kidneys - may be involved as well. Thrombotic events (blood clots, strokes, etc.), in particular, were linked to COVID-19 in the opening months of the pandemic, including:

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

The Lancet: Yet Another Study On Neurological Manifestations In Severe COVID-19 Patients

JAMA Neurology: Elevated Risk of Ischemic Stroke With COVID-19

In early April 2020, the NYC Fire Department reported a 400% increase in sudden cardiac arrest death calls beginning in late March (see NBC affiliate Massive Spike in NYC ‘Cardiac Arrest’ Deaths Seen as Sign of COVID-19 Under counting).

Two months later, JAMA published an original investigation which found  10-fold increase in out-of-hospital cardiac arrests in New York City during the peak of their COVID-19 epidemic.

A year into the pandemic (April 2021)  FIOCRUZ Researchers Made The Case That COVID-19 Should Be Considered A `Thrombotic Viral Fever', and in 2022 the BMJ published a Swedish study (BMJ: Elevated Risk Of Blood Clots Up To 6 Months After COVID Infection) which reported:

• a 5-fold increase in the risk of DVT (deep vein thrombosis)
• a 33-fold increase in risk of a PE (pulmonary embolism)
• and an almost doubled risk of bleeding in the first month following infection.

And all of this barely scratches the surface of the post-acute impact of COVID infection, with nearly 20% of the adult population reporting `long COVID' symptoms persisting for months or sometimes even years.  

All of which brings us to a new study, published yesterday in the CDC's EID Journal, which finds a strong signal that even mild COVID infection significantly increases your risk of stroke and other thrombotic events for up to a year post-infection.

While many studies have focused on the more severe Delta wave of COVID, this study covers a period when a milder Omicron variant had already supplanted Delta, yet non-hospitalized COVID patients still had a 73% increased risk of stroke of thrombotic event (compared to other ARIs).  

I've only posted the Abstract, and some excerpts, so follow the link to read the report in its entirety.  I'll return after the break with a bit more. 

Volume 32, Supplement—February 2026

Thrombotic Events and Stroke in the Year After COVID-19 or Other Acute Respiratory Infection
 
Caroline Q. Pratt , Alexandra F. Dalton, Emily H. Koumans, Abraham Agedew, Fatima Coronado, Elizabeth A. Lundeen, Rebecca C. Woodruff, Jason P. Block, Mark Weiner, Lindsay Cowell, Jonathan D. Arnold, Sharon Saydah, and PCORnet Network Partners

 
Abstract

Previous studies have documented an increased risk for thrombotic events 30 days after COVID-19 infection, but less is known about this risk beyond 30 days or compared with risk after other infectious acute respiratory illnesses (ARIs).

By using PCORnet data from April 1, 2022–April 30, 2023, we compared the incidences of thrombotic events in the year after COVID-19 illness with other ARI diagnoses in hospitalized and nonhospitalized patients. Overall, the risk for any thrombotic event was higher among patients with COVID-19 compared with patients with other ARIs (incidence ratio 1.63; p<0.05). 

Nonhospitalized patients with COVID-19 had a 73% increased risk for a thrombotic event in the year after acute illness compared with nonhospitalized patients with ARI (p<0.05). The increased risk for thrombotic events in the year after COVID-19 emphasizes the need for stroke awareness for patients and healthcare professionals.


Stroke and thrombotic events are known sequelae of respiratory viral illnesses, including influenza and COVID-19 (1–5). Since the onset of the COVID-19 pandemic, studies have documented an increased risk for embolic events, including ischemic stroke, in the first 30 days after a COVID-19 infection, with a >2-fold greater risk compared with people without COVID-19 (6,7). Several studies have found the risk for ischemic stroke is higher in those with severe acute illness (8,9). Among children, who have fewer strokes and thromboembolic events, 2 studies found an increased risk for stroke after COVID-19 (10,11). 

Although the mechanisms remain under investigation, the hypothesized pathophysiology that leads to increased stroke and thromboembolic events among patients with COVID-19 include endothelial cell damage (12,13), a viral-triggered exaggerated immune response and cytokine storm (14), and persistent microthrombi formation and fibrin amyloid microclots (15,16).

        (SNIP)

Of note, the risk ratios for all events in COVID-19 versus ARI patients were higher among the nonhospitalized group in this analysis, with a risk ratio of 1.73 (95% CI 1.71–1.76) for 31–365 days among nonhospitalized patients versus 1.14 (95% CI 1.10–1.18) in hospitalized patients. Many earlier studies focused on the initial phases of the COVID-19 pandemic, primarily during the pre-Delta and Delta variant periods (19,20).

In contrast, this study provides more recent data from the Omicron-dominant period, characterized by high population immunity because of extensive vaccination and prior infections. Those updated findings could provide valuable insights for future studies and enhance early recognition and effective management of DVT and stroke, while informing the long-term cardiovascular consequences of COVID-19.

This study underscores the importance of COVID-19 vaccination and other prevention and treatment efforts to reduce risk for severe illness and subsequent adverse outcomes and conditions (38). In addition, given the higher risk for post-COVID conditions with more severe COVID-19 acute illness (39,40), our data provide yet another reason to increase efforts targeted at prevention and improved management of chronic conditions that increase the risk for severe COVID-19, stroke, and thrombotic complications.

Comprehensive chronic disease management, combined with COVID-19 and ARI prevention strategies, can help reduce the incidence of postillness DVT and stroke, ultimately benefiting those most vulnerable to complications. Patient education is also crucial, particularly an emphasis on the benefits of vaccinations for those with underlying risk factors or comorbidities.

        (Continue . . . .)

This week I spent about 30 minutes in a Dr's waiting room with about 20 other (mostly elderly) people - during the height of one of the worst flu seasons in years - and I was conspicuously the only one wearing a mask. 

We've trivialized COVID and flu to the point that people are oblivious to the potentially life-altering (or ending) risks of infection.  

Seasonal flu vaccinations have plummeted by roughly 30% since 2019, COVID booster shots are down 70% since 2022, and mask wearing has become anathema for many. 

At the same time applications for COVID-related disability continue to rise, and Postpandemic Cardiac Mortality Rates remain elevated for the 5th year in a row.

While many now consider COVID infection to be no worse than a `common cold', the evidence suggests otherwise, including these 2025 studies: 

European Society of Cardiology: Major Consensus Statement Released on Long-Term Cardiovascular Impact of COVID Infection

EHJ: Accelerated Vascular Ageing After COVID-19 Infection: The CARTESIAN Study

BMC Neurology: Long-term Neurological and Cognitive Impact of COVID-19: A Systematic Review and Meta-analysis in over 4 Million Patients

Brain, Behavior & Immunity: COVID-19 may Enduringly Impact Cognitive Performance and Brain Haemodynamics in Undergraduate Students

Preprint: Occupationally Exposed & General Population Antibody Profiles to Influenza A Viruses Circulating in Swine as an Indication of Zoonotic Risk

#19,020

While there are legitimate concerns over the potential for HPAI H5, or H7 viruses to spark a human pandemic, as we've discussed often over the years (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), the progression of human influenza pandemics over the past 130 years has been H2, H3, H1, H2, H3, H1, H1 . . .

Novel H1, H2, and H3 flu viruses appear to have fewer barriers to overcome in order to jump to humans - and while they might not prove as virulent as H5 & H7 avian subtypes - that puts them at or near the top of our pandemic threats list.

Every year since 2010 we've seen anywhere from a handful to several hundred swine-origin influenza cases detected in humans, primarily connected with state and local agricultural fairs. Less well documented, we've also gotten reports of swine-origin influenza jumping to humans in Europe and Asia.

Spillovers of swine variant viruses to humans are thought to be significantly under-reported, with some estimates suggesting fewer than 1% of cases are ever ever confirmed (see CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012).

Results. We estimate that the median multiplier for children was 200 (90% range, 115–369) and for adults was 255 (90% range, 152–479) and that 2055 (90% range, 1187–3800) illnesses from H3N2v virus infections may have occurred from August 2011 to April 2012, suggesting that the new virus was more widespread than previously thought. 

The CDC's IRAT (Influenza Risk Assessment Tool) lists 3 North American swine viruses as having at least some pandemic potential (2 added in 2019).

H1N2 variant [A/California/62/2018]  Jul   2019   5.8  5.7 Moderate

H3N2 variant [A/Ohio/13/2017]          Jul   2019   6.6  5.8 Moderate

H3N2 variant [A/Indiana/08/2011]      Dec 2012   6.0  4.5 Moderate 

In addition to the 3 North American swine-variant viruses on the CDC's IRAT list, we continue to watch the evolution of China's EA H1N1 `G4' virus, Brazil's H1N2v virus, and emerging variants (and spillovers) in Europe (see ANSES Reports A `New' Swine Flu Virus Has Taken Over Other Genotypes in France).

But the reality is, most of the world isn't bothering to test for - or to share reports on - swine influenza.

All of which brings us to a preprint by researchers from the USDA's National Animal Disease Center (and others) on the susceptibility of the general populations - and occupationally exposed individuals - to commonly circulating swine influenza A viruses. 

Researchers tested blood samples from 4 cohorts; pig workers, veterinarians, Philadelphia flu-vaccine recipients, and Hong Kong residents for antibodies against seasonal flu and an array of H1/H3 swine-influenza viruses in circulating in U.S. swine. 

While all four groups showed notable gaps in protective antibodies (HI titer ≥40) against specific swine influenza A virus (IAV) strains, swine-exposed workers had the lowest overall seropositivity to several high-risk strains. 

The authors wrote:

Individuals occupationally exposed to swine, such as Veterinarians and Farm Employees, were significantly less likely to have protective antibody levels against contemporary IAV in swine. This group exhibited lower vaccination rates and reduced seropositivity, particularly swine farm employees, underscoring a heightened risk of zoonotic infection.

The authors also report (out of 10 representative swine IAVs tested) - that based on population immunity - 4 strains had even lower R₀ (r-naught) thresholds than the 2009 H1N1 pandemic.

The authors noted:

Swine strains representing HA clades 1A.1.1.3, 1A.3.3.3-c-1, 1B.2.1, and 1B.2.2.2 demonstrated elements of increased pandemic risk, including low population immunity, lack of cross-reactivity to human seasonal vaccine strains, and low thresholds of required human transmissibility.

Due to its length and technical nature, I've just posted the abstract below. Follow the link to read it in its entirety.  I'll have a postscript after the break. 

Occupationally exposed and general population antibody profiles to influenza A viruses circulating in swine as an indication of zoonotic risk
Celeste A. Snyder, Garrett M. Janzen, Giovana Ciacci Zanella, Daniel C. A. Moraes, Gustavo S. Silva, Jefferson J. S. Santos, Elizabeth M. Drapeau, Scott E. Hensley, Tavis K. Anderson, Phillip C. Gauger, Amy L. Baker
doi: https://doi.org/10.64898/2026.01.08.26343691
This article is a preprint and has not been peer-reviewed

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Abstract

Individuals with occupational exposure to swine may have disproportionate risk for zoonosis with swine influenza A virus (IAV). To evaluate human antibody responses, sera or plasma from swine veterinarians, swine farm employees, and the general population were tested by hemagglutination inhibition (HI) assays against representative swine and human seasonal influenza vaccine strains. HI data were analyzed by antigenic cartography to assess strain relationships, and reproduction number modeling to evaluate pandemic potential using age-stratified immunity profiles.

 

Occupationally exposed groups had lower human seasonal vaccine uptake (45.5% vs 70%) and significantly lower odds of seropositivity to several H1 and H3 from swine compared to general population cohorts.

One swine strain exhibited significant antigenic drift (3.62 AU) from its nearest vaccine strain. Multiple strains required lower R₀ thresholds for pandemic spread (1.09-1.35) than recorded pandemic strains (1.46-1.80). This demonstrates that population immunity gaps heighten zoonotic risk to circulating swine H1 and H3 strains.

        (Continue. . . )

Despite campaigns to get agricultural workers to increase their uptake of the seasonal flu vaccine, there is obviously a lot of work to be done in that regard.  As we've discussed previously (see Nature: Reverse Zoonosis of the 2022–2023 Human Seasonal H3N2 Detected in Swine), flu transmission is a two-way street.

There remain huge gaps in surveillance of pigs, both here in the United States and around the world, which leaves us vulnerable to being blindsided (like we were in 2009) by an emerging swine flu virus. 

 And while that might not be as severe as H5N1, there are no guarantees that the next swine-flu pandemic will be as mild, or as short-lived, as the last one. 

Adv. Genetics (Review Article) : Evolution of H5N1 Cross‐Species Transmission - Adaptive Mutations Driving Avian‐to‐Human Infection

#19,019

In the wake of the SARS-CoV-2 pandemic it has become increasingly difficult to find substantive, and verifiable, information on avian flu, COVID, MERS-CoV, (and other) emerging disease outbreaks around the world. 

Many countries simply no longer report outbreaks or incidents. Others do, but only intermittently, and are often parsimonious in the sharing of details.  

Public health organizations - like the WHO, PAHO, and the ECDC - are forced to constantly `remind' countries of their obligation under the IHR to report. But since there are no real penalties for failing to comply, many countries choose silence (see From Here to Impunity).

The public remains largely apathetic (see Two Surveys (UK & U.S.) Illustrating The Public's Lack of Concern Over Avian Flu), and many governments appear more than happy to downplay the threat for political or economic reasons.

But just because we ignore a threat doesn't make it go away; HPAI H5 continues to evolve at a rapid rate, and over the past 4 years it has increased its affinity for mammalian hosts.

Obviously, no one truly knows what HPAI H5 will do next. 

There could still be some `species barrier' that prevents it from becoming a genuine pandemic threat (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), or it might simply be beaten to the punch by another threat, like H9N2, H3N8, or another coronavirus.

But right now, HPAI H5 remains at the top of our pandemic worry list, for reasons that are covered at length in the following Review/Perspective article  published this week in the journal Advanced Genetics. 

This (12-page) review recounts the evolution of the H5N1 avian influenza virus, with a focus on the 2.3.4.4b clade, and focuses on a number of critical mutations (including HA‐Q226L, HA‐T199I, PB2‐E627K, and NA‐H274Y) which could help enable cross-species transmission or increase NAI resistance.

I've just posted the abstract and a brief excerpt. Follow the link to read the review in its entirety.  I'll have a postscript when you return.

Evolution of H5N1 Cross‐Species Transmission: Adaptive Mutations Driving Avian‐to‐Human Infection
Wenxin Man 1,2, Lin Du 2, Ying Liu 2, Zehan Pang 3, Hongyan Zhu 4,✉, Bixia Hong 2,5,✉, Zhichao Xu 1,2,✉, Huahao Fan 2,✉
PMC Copyright notice
PMCID: PMC12791573 PMID: 41531488

ABSTRACT

First detected in poultry in China in 1996, the H5N1 avian influenza virus has evolved into a significant global public health hazard, primarily owing to its high pathogenicity and potential for interspecies transmission. While primarily affecting avian species, H5N1 has repeatedly breached species barriers, infecting mammals including humans, minks, seals, and cattle. 

This review synthesizes current knowledge on the molecular mechanisms underpinning H5N1's host adaptation, focusing on key mutations in viral proteins‐such as hemagglutinin (HA), neuraminidase (NA), and polymerase subunits (PB2)‐which boost binding affinity to human‐type receptors, increase replicative efficiency in mammalian cells, and facilitate immune evasion. 

Critical mutations, including HA‐Q226L, HA‐T199I, PB2‐E627K, and NA‐H274Y, are discussed in detail, highlighting their roles in altering receptor specificity, promoting antiviral resistance, and expanding viral tropism. The paper also outlines epidemiological trends, global dissemination patterns driven by migratory birds and trade, and current strategies for prevention and control, including antiviral therapeutics and vaccine development. 

Ultimately, this comprehensive analysis underscores the urgent need for continued surveillance, broad‐spectrum countermeasures, and international collaboration to reduce the pandemic risk posed by H5N1.

        (SNIP)

Although the current transmission efficiency of the H5N1 virus among humans remains limited, its highly variable genome provides the molecular foundation for potential evolution toward sustained human-to-human transmission [73].

Significant knowledge gaps remain concerning the key factors that enable efficient human-to-human spread of the virus, its long-term evolutionary trajectory in new mammalian hosts such as cattle, and the impact of continuous surface antigen drift on the efficacy of antibody protection [74-76]. To address these issues, future global surveillance efforts must extend beyond poultry populations to systematically encompass domestic and wild mammalian species, particularly those in outbreak areas, in order to establish a comprehensive ‘One Health’ early warning system [77]. 

Addressing this threat necessitates global collaboration in the integration of resources and technologies to continuously monitor viral evolutionary dynamics, with a particular emphasis on its cross-species transmission tendencies from poultry to humans and other mammals.

By implementing comprehensive strategies that encompass surveillance, research, and international cooperation (Figure 4), we can more effectively mitigate future H5N1 virus threats, reduce the risk of a global pandemic, and safeguard both human health and ecological balance.

       (Continue . . . )

Like with nearly every study or review we've looked at (see here, here, here, here, and here), the authors call for greatly improved surveillance, reporting, and international cooperation.

While a few countries obviously `get it', see (see South Korea CDC Announces A 19-day, Nationwide, Mock-Training Exercise to Prepare for Zoonotic Influenza), most nations seem content to ignore the threat, praying nothing happens during their watch. 

A policy that works well up until the point it doesn't anymore. And by then it is usually too late to do much about it.  As the former Secretary of the HHS Michael Leavitt put it 20 years ago:

“Everything you say in advance of a pandemic seems alarmist. Anything you’ve done after it starts is inadequate."