Nature Comms Med.: Interactions of SARS-CoV-2, Influenza and RSV Influence Epidemic Timing and Risk

When Epidemic Viruses Collide

#19,086

Since the introduction of the SARS-CoV-2 virus in 2020 there have been perennial concerns we could see a devastating `twin-demic' of influenza A and COVID. While some co-circulation has occurred, for the most part, each virus has peaked while the other was in retreat.

This is not a new observation; 17 years ago (during the 2009 H1N1 pandemic) some European countries that reported rampant rhinovirus outbreaks in the fall saw far less H1N1 activity than expected (see 2009 New Scientist article Common cold may hold off swine flu).

While the exact mechanism behind this blocking of competing viruses is only partially understood, many researchers believe that exposure to one virus activates not only a targeted immune response - but also the body's innate immune response - essentially temporarily raising `shields' against other possible viral invaders.

Some past blogs on this include:

When Epidemic Viruses Collide

Study: Human Rhinovirus Infection Blocks SARS-CoV-2 Replication Within the Respiratory Epithelium 

This heightened immune response is believed to persist for weeks or perhaps even months; an idea that has been dubbed the `temporary immunity hypothesis'.

Last November, in IJID: Short-Term Risks of Influenza and COVID-19 Following Influenza Infection: A Self-Controlled Case Series Study, we looked at a study from Beijing that found that influenza A infection reduces the risk of influenza reinfection by 57% for up to 8 months but increases the risk of COVID-19 infection by 48% within 6 months post-influenza.

Note: they did not study the reverse (and admittedly far more complex) COVID -> Flu scenario. 

Today we've another study from Beijing, that finds that influenza A infection briefly reduces susceptibility to COVID infection, but that protective effect lasts only about 5 weeks post infection. 

They do, however, report finding a slight increase in susceptibility to IAV following COVID infection.  RSV showed no impact on COVID. 

Unlike the IJID study cited above, this study did not attempt to calculate longer-term risks of infection.  I've reproduced the abstract, and summary below. Follow the link to read it in its entirety.

 
Open access
Published: 14 March 2026
Interactions of SARS-CoV-2, influenza and respiratory syncytial virus influence epidemic timing and risk

Yonghong Liu, Xiaoli Wang, Mengyao Li, Eimear Cleary, Zhifeng Cheng, Wenbin Zhang, Ying Shen, Hui Yao, Jiatong Han, Nick W. Ruktanonchai, Andrew J. Tatem, Shengjie Lai, Quanyi Wang & Peng Yang

Communications Medicine , Article number: (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Background

Interactions between SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) at the population level remain poorly understood. This study aimed to quantify potential interactions among these viruses and assess their influence on transmission dynamics.

Methods

We analyzed weekly surveillance data on SARS-CoV-2, influenza A and B viruses (IAV and IBV), and RSV from seven regions from October 2021 to May 2024. Distributed lag nonlinear models within a spatiotemporal Bayesian hierarchical framework were used to assess the exposure-lag-response associations among virus pairs. Additionally, we developed a two-pathogen, meta-population mechanistic transmission model to capture the co-epidemic dynamics of IAV and SARS-CoV-2, and to quantify the strength and duration of their bidirectional interactions.

Results

Among all virus pairs examined, a statistically significant association is identified only between IAV positivity and subsequent SARS-CoV-2 risk. When IAV positive rate percentile is between the 52nd and 88th percentiles, the relative risk (RR) of SARS-CoV-2 infection is significantly reduced. The lowest RR for SARS-CoV-2 (0.58, 95% CrI: 0.40-0.85) occurs at a 5-week lag when IAV positivity reaches the 70th percentile.

The fitted mechanistic model using incidence data in Beijing shows that IAV infection substantially reduces infection to SARS-CoV-2 by 94.24% (95% CrI: 88.50%–99.24%), with the protective effect lasting 38.24 days (95% CrI: 35.50–41.29 days). Conversely, SARS-CoV-2 infection is associated with a slight increase in infection to IAV.

Conclusions

Our findings indicate that IAV circulation may transiently reduce population-level infection to SARS-CoV-2, potential through ecological or immunological mechanisms.

Plain language summary

This study looks at how three common respiratory viruses - SARS-CoV-2, influenza, and RSV, which cause COVID-19, flu and common colds - affect one another when they spread in communities. We used two complementary approaches: advanced statistical model, which identify patterns in real-world data, and mechanistic transmission model, which simulates how viruses spread from person to person. Together, these methods allowed us to measure how strong these interactions are and how long their effects last. 

The data came from three years of virus activity across seven countries and regions, providing us a broad view across time and places. We found that increases in flu activity, especially influenza A, may reduce the risk of COVID-19 spread in the weeks that follow. However, these virus interactions are complex. They change over time and depend on how much of each virus is circulating.

This means that viruses do not spread in isolation, and one can potentially influence the timing and size of another epidemic. Our study shows why it is important to consider interactions between viruses when forecasting future outbreaks and planning public health interventions, especially since many respiratory viruses tend to circulate at the same time of year.

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In 2017's PLoS Comp. Bio.: Spring & Early Summer Most Likely Time For A Pandemic, researchers used `viral interference' and/or temporary immunity to help explain why pandemics typically emerge in the spring or early summer; after the end of regular flu season.

Of course, COVID was an exception to this pattern, as it emerged in mid-winter in China and spread globally in a matter of weeks. 

All of which is a reminder that while these viruses don't act in a vacuum, there is still much we don't know about how they may impact one another, or any new ones that may appear in the future.

Cambodia MOH Announces 2nd H5N1 Case of 2026

 

#19,085

With thanks for the head's up from @E_A_Karlsson, we have the following announcement from Cambodia's Ministry of Health on their 2nd confirmed HPAI H5N1 human infection of 2026; this time involving a 45 y.o. woman from Banteay Meanchey Province who was hospitalized on March 14th.

The MOH announcement, along with the translation, follows:

A case of bird flu in a 45-year-old woman

The Ministry of Health of the Kingdom of Cambodia would like to inform the public that there is 1 case of bird flu in a 45-year-old woman who was confirmed to be positive for the H5N1 avian influenza virus on March 14, 2026 by the National Institute of Public Health. The patient lives in Ropai village, Chinu Meanchey commune, Preah Net Preah district, Banteay Meanchey province, and there have been reports of sick and dead chickens and ducks in the village. On the same day, the patient was placed in isolation at the hospital and treated with Tamiflu and received close medical care. Upon questioning, it was revealed that the patient raised chickens and ducks, some of which were sick and dead. Three days before testing positive, she had come into contact with the dead chickens.

The emergency response team of the national and sub-national ministries of health has been collaborating with the teams of the provincial agriculture departments and local authorities at all levels to actively investigate the outbreak of bird flu and respond according to technical methods and protocols, find the source of transmission in both animals and humans, and search for suspected cases and contacts to prevent further transmission in the community, as well as distribute Tamiflu to close contacts and conduct health education campaigns among residents in the affected villages.

The Ministry of Health would like to remind all citizens to always pay attention to and be vigilant about bird flu because H5N1 bird flu continues to threaten the health of our citizens. We would also like to inform you that if you have a fever, cough, runny nose, or difficulty breathing and have a history of contact with sick or dead chickens or ducks within 14 days before the onset of symptoms, do not go to gatherings or crowded places and seek consultation and examination and treatment at the nearest health center or hospital immediately. Avoid delaying this, which puts you at high risk of eventual death.

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Just over 3 years ago an older clade of H5N1 (2.3.2.1.x) reemerged in Cambodia's population after a 9 year absence, spilling over into 6 humans in 2023, 10 people in 2024, and 18 people in 2025.   

The majority of these cases have been in children and adolescents, and sadly, > 40% have died. Contact with sick or dead poultry has often been cited as the source of infection. 

Unlike H5N1 cases reported in the United States - which are due to a milder clade 2.3.4.4b - recent Cambodian cases have been caused by a new reassortment of an older clade of the H5N1 virus (recently renamed 2.3.2.1e) - which appears to be spreading rapidly through both wild birds and local poultry.

While we tend to focus primarily on clade 2.3.4.4b H5N1 viruses which have become endemic in North and South America, Europe,and much of Asia - other incarnations of HPAI H5 are circulating around the globe - and new ones continue to emerge; with each on their own evolutionary trajectory.

In addition to this very active Cambodia lineage of H5N1, some of the other HPAI H5 contenders we are following include:

South Korea: H5N9 Rising

Viruses: Novel Reassortant H5N2 Highly Pathogenic Avian Influenza Viruses from Backyard Poultry in Mexico

Preprint: Emergence of a Novel Reassorted HPAI A(H5N2) Virus Associated with Severe Pneumonia in a Young Adult

Washington State DOH: H5N5 Avian influenza confirmed in Grays Harbor County resident

Preprint: HPAI A (H5N1) Clade 2.3.2.1a Virus Infection in 2 Domestic Cats, India, 2025

EID Journal: Influenza A(H5N1) Virus Clade 2.3.2.1a in Traveler Returning to Australia from India, 2024

Exactly where H5Nx goes from here is anyone's guess. Some strains may lose virulence, while others may grow stronger. New variants may emerge, while others will likely fade away. The virus we see tomorrow may look quite different from the virus we see today.

The only thing we can say with any certainty is these viruses continue to evolve, and that their current trajectory is still on the ascendent.

Which is a trend we ignore at our own considerable risk.

USDA Report 9 More Live Bird Markets Infected With HPAI H5

Credit USDA

#19,084

A little over 3 weeks ago, in When You're in the Market For Bird Flu, we looked the USDA's reports of  9 HPAI H5 outbreaks in live bird markets around the country (5 in NYC, 4 in PA) since late December 2025.

Since then, the pace has increased, with 9 more outbreaks (8 in NYC, 1 in Fl) reported over the past 16 days (see USDA chart above).  

Less than halfway through the month, and already March 2026 is tied for the 2nd highest number (n=8) of outbreaks (see below), only exceeded by the March 2025 total of 15 outbreaks.   

Based on USDA Data - Graph created with Gemini

As the following graphic illustrates, New York leads the nation with lion's share of of live market outbreaks (44 of 73, or just over 60%), followed by Florida (18%), and Pennsylvania and New Jersey each at 9.6%.

Based on USDA Data - Graph created with Gemini

These outbreaks tend to get far less publicity today than they did even a year ago, but on March 12th the New York State Department of Agriculture and Markets issued the following Health Alert.

Health Alerts

Highly Pathogenic Avian Influenza

Detections in New York

March 12, 2026 - To date, 78 flocks in New York State have tested positive for HPAI since February 2022. The Department is working closely with the United States Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) on a joint incident response and is also collaborating with partners at the Department of Health and Department of Environmental Conservation.

According to the U.S. Centers for Disease Control and Prevention, the public health risk associated with these avian influenza detections remains low. As a reminder, the proper handling and cooking of poultry and eggs to an internal temperature of 165 ˚F kills bacteria and viruses. Birds from the affected flocks have not entered the food system.

Biosecurity

The detections of HPAI in New York prompt reminders for commercial and hobby poultry farmers to increase their biosecurity measures to help prevent the spread of the disease. The Department encourages all poultry producers, from small backyard to large commercial operations, should review their biosecurity plans and take precautions to protect their birds. Poultry biosecurity materials and checklists can be found on the USDA’s “Defend the Flock” website. Best practices include:

• Discourage unnecessary visitors and use biosecurity signs to warn people not to enter buildings without permission.
• Ask all visitors if they have had any contact with any birds in the past five days.
• Forbid entry to employees and visitors who own any kind of fowl.
• Require all visitors to cover and disinfect all footwear.
• Lock all entrances to chicken houses after hours.
• Avoid non-essential vehicular traffic on-farm.
• After hauling birds to processors, clean and disinfect poultry transport coops and vehicles before they return to the farm.
• Report anything unusual, especially sick or dead birds, to AGM.

In addition to practicing good biosecurity, poultry owners should keep their birds away from wild ducks and geese and their droppings. Outdoor access for poultry should be limited at this time.

To report sick birds, unexplained high number of deaths, or sudden drop in egg production, please contact the Department’s Division of Animal Industry at (518) 457-3502 or the USDA at (866) 536-7593.

While government agencies are quick to reassure the public that the risk of contracting avian influenza remains low in the United States, exposure to live birds is a known risk factor (see CDC graphic below).

It was just over a year ago that the United States reported its first human H5N1 fatality in a Louisiana Man who kept live poultry in his backyard.  

LDH reports first U.S. H5N1-related human death

Current general public health risk remains low

Baton Rouge, Louisiana, Jn 06, 2025 - The Louisiana Department of Health reports the patient who had been hospitalized with the first human case of highly pathogenic avian influenza (HPAI), or H5N1, in Louisiana and the U.S. has died. The patient was over the age of 65 and was reported to have underlying medical conditions. The patient contracted H5N1 after exposure to a combination of a non-commercial backyard flock and wild birds.

Over the past couple of years somewhere in excess of 30 people have been infected from exposure to poultry or wild birds in North America (2 fatal). Most were agricultural workers, but some had undetermined exposures.

As we've discussed previously (see Mixed Messaging On HPAI Food Safety), there is some degree of risk in the slaughtering of live birds and preparation of raw poultry; especially from birds raised at home or purchased from live markets.

PAHO (the Pan-American Health Organization) mentions this on their Avian Influenza landing page:  Plucking, handling infected poultry carcasses, and preparing poultry for consumption, especially in domestic settings, may also be risk factors.

And in 2024 the WHO published  Interim Guidance to Reduce the Risk of Infection in People Exposed to Avian Influenza Viruses, which lists a number of `risk factors', including:

• keep live poultry in their backyards or homes, or who purchase live birds at markets;

• slaughter, de-feather and/or butcher poultry or other animals at home;

• handle and prepare raw poultry for further cooking and consumption;

These risks go far beyond just human exposure, of course,  as live markets also bring together different types of birds which may also silently carry LPAI viruses like H3N2 and H6N2, which could reassort with HPAI H5. 

As we discussed last year in J. Virology: Zoonotic Disease Risk at Traditional Food Markets (Minireview), live animal markets present special risks.

While strict regulation and better biosecurity can substantially reduce the risks, LBMs remain a source of concern. 

CDC MMWR: Interim Estimates of 2025–26 Seasonal Influenza Vaccine Effectiveness — United States, September 2025–February 2026

 
2025-2026 Flu Season - Credit CDC

#19,083

While the 2025-2026 flu season still continues (albeit on a downward trajectory), yesterday the CDC released their first estimate of this year's flu vaccine VE (Vaccine Effectiveness).  A final, revised, report should be issued in a few months.

In early November it became apparent that a new `drifted' H3N2 virus (subclade K) had recently emerged on the world stage, one which was antigenically distinct from this year's H3N2 vaccine strain. 

Early estimates (see UKHSA Preprint: Early Influenza Virus Characterisation and Vaccine Effectiveness in England in Autumn 2025, A Period Dominated by Influenza A(H3N2) Subclade K) suggested that the fall vaccine wasn't a total bust, but that it's VE would suffer. 

This is a scenario we've seen play out before - particularly with the H3N2 subtype (see 2017's The Enigmatic, Problematic H3N2 Influenza Virus) - which is more mutable, and more genetically diverse, than H1N1. 

The CDC Seasonal Flu Vaccine Effectiveness Studies webpage shows some of the variability of the flu vaccine VE over the years. While the dominant flu strain each year isn't shown, the lowest VE years were dominated by H3N2.

While most years we get a breakdown in VE between influenza A subtype (H1N1 and H3N2), this year H3N2 overwhelmed the flu season, and there was apparently insufficient data on H1N1 to break out those numbers. 

I've reproduced the summary and abstract of the MMWR interim report below. Follow the link to read it in its entirety.  

I'll have a bit more when you return.

Interim Estimates of 2025–26 Seasonal Influenza Vaccine Effectiveness — United States, September 2025–February 2026

Weekly / March 12, 2026 / 75(9);116–123

Patrick Maloney, PhD1,2; Emily L. Reeves, MPH1; Kristina Wielgosz, MPH1; Ashley M. Price, MPH1; Karthik Natarajan, PhD3,4; Malini B. DeSilva, MD5; Kristin Dascomb, MD, PhD6; Nicola P. Klein, MD, PhD7; Sara Y. Tartof, PhD8,9; Stephanie A. Irving, MHS10; Shaun J. Grannis, MD11,12; Toan C. Ong, PhD13; Zachary A. Weber, PhD14; Jennifer E. Schuster, MD15; Danielle M. Zerr, MD16; Marian G. Michaels, MD17; Julie A. Boom, MD18; Natasha B. Halasa, MD19; Mary A. Staat, MD20; Geoffrey A. Weinberg, MD21; Stacey L. House, MD, PhD22; Elie A. Saade, MD23; Krissy Moehling Geffel, PhD24; Manjusha Gaglani, MBBS25; Karen J. Wernli, PhD9,26; Vel Murugan, PhD27; Emily T. Martin, PhD28; Natalie A. B. Bontrager, MPH29; Marie K. Kirby, PhD1; Amanda B. Payne, PhD30; Fatimah S. Dawood, MD30; Ayzsa Tannis, MPH30; Heidi L. Moline, MD30; Sifang Kathy Zhao, PhD1; Katherine Adams, DrPH1; Jennifer DeCuir, MD, PhD1; Samantha M. Olson, MPH1; Jessie R. Chung, MPH1; Nathaniel Lewis, PhD1; Brendan Flannery, PhD1; Carrie Reed, DSc1; Shikha Garg, MD1; Sascha Ellington, PhD1; CDC Influenza Vaccine Effectiveness Collaborators (VIEW AUTHOR AFFILIATIONS)View suggested citation

Summary

What is already known about this topic?

CDC routinely monitors influenza vaccine effectiveness (VE). Annual influenza vaccination is available for all eligible persons aged ≥6 months.

What is added by this report?

Interim 2025–26 seasonal influenza VE estimates were derived from three U.S. VE networks. Among children and adolescents, VE was 38%–41% against influenza-associated outpatient visits and 41% against influenza-associated hospitalization. Among adults aged ≥18 years, VE was 22%–34% against influenza-associated outpatient visits and 30% against influenza-associated hospitalization.

What are the implications for public health practice?

Receipt of a 2025–26 influenza vaccine reduced the risk for influenza-associated outpatient visits and hospitalizations. These findings support CDC’s influenza vaccination recommendations.

Article PDF 

Abstract

In the United States, annual influenza vaccination has been recommended for all persons aged ≥6 months, including during the 2025–26 season. Interim influenza vaccine effectiveness (VE) estimates were calculated for patients with acute respiratory illness–associated outpatient visits and hospitalizations from three U.S. respiratory virus VE networks during the 2025–26 influenza season, using a test-negative case-control design.

• Among children and adolescents aged <18 years, VE was 38%–41% against influenza outpatient visits and 41% against influenza-associated hospitalization.
• Among adults aged ≥18 years, VE was 22%–34% against influenza outpatient visits and 30% against influenza-associated hospitalization.
• Among children and adolescents, VE against influenza A ranged from 37% (against outpatient visits) to 42% (against hospitalization) across settings; among adults, VE against influenza A ranged from 30% (against hospitalization) to 34% (against outpatient visits) across settings.
• Among children and adolescents, VE against influenza A(H3N2)–associated outpatient visits was 35% and against influenza A(H3N2)–associated hospitalization was 38%. VE against influenza B outpatient visits ranged from 45%–71% among children and adolescents and was 63% among adults.

Other estimates of VE were not statistically significant or were not reportable. Although interim influenza VE is lower during the 2025–26 influenza season than it was during recent influenza seasons, these findings demonstrate that influenza vaccination still provides protection against influenza. CDC recommends influenza vaccination; U.S. influenza vaccines remain available for persons aged ≥6 months.

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Yesterday the FDA followed the WHO's lead and announced their recommendations for next fall's flu vaccine (see CIDRAP report FDA vaccine advisers recommend adding subclade K to fall shots), which swaps out all 3 flu strains. 

Despite offering only moderate protection, and being vulnerable to late-arriving `drifted' flu strains, I've gotten the flu shot every year for the past 20+ years, and have only once contracted the flu (summer 2009). 

Admittedly, I take other precautions, including wearing a mask in crowded indoor venues and using hand sanitizer.  But when combined with the flu vaccine, it has proven to be a very effective combination. 

Everyone has to make their own risk-reward calculation, of course. 

But given everything we've learned about influenzas' extrapulmonary impacts on the body (see Risk of Cardiovascular Events After Influenza), it seems a reasonable enough trade off to me. 

CDC Preprint: A Newly Emergent N1 Neuraminidase Associated with Clade 2.3.4.4b HPAI A(H5) Viruses in North America

 

#19,082

In the fall of 2024 - barely six months after the discovery of the `Bovine' B3.13 genotype of H5N1 circulating in U.S. dairy cattle - another genotype of H5N1 appeared in Canada and the Pacific Northwest - dubbed D1.1 - which very quickly became dominant in wild birds and rapidly swept eastward across the United States and Canada.

Although both B3.13 and D1.1 have spilled over into dozens of (primarily) agriculturally exposed humans, the bovine strain has produced mostly mild symptoms, while a few D1.1 patients saw severe (and even fatal) illness (see here, here, and here). 

The exact cause of B3.13's mild presentation remains unclear, but many researchers have posited that - since its N1 Neuraminidase gene is similar to that found in seasonal H1N1 -  many people may have some preexisting (albeit, limited) immunity to that genotype.

A few examples include:

Preprint: Cross-Reactive Human Antibody Responses to H5N1 Influenza Virus Neuraminidase are Shaped by Immune History

Preprint: Neuraminidase Imprinting and the Age-related Risk of Zoonotic Influenza

Two EID Journal Articles On Prior Immunity From A(H1N1)pdm09 Infection Against H5N1 (in Ferrets)

The D1.1 genotype, however, carries a different (North American lineage) N1 Neuraminidase, which may account for its ability to cause more severe illness. 

And in its opening months, it displayed brief, but worrisome, signs of antiviral resistance. 

Our first inkling of all of this came just over a year ago in Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms, where Canada's PHAC and CFIA wrote:

Abstract

We report the detection of a clade 2.3.4.4b A(H5N1) reassortant virus with a neuraminidase surface protein derived from a North American lineage low-pathogenic avian influenza virus. This virus caused a widespread and ongoing outbreak across 45 poultry farms in British Columbia, Canada.

Isolates from 8 farms reveal a mutation in the neuraminidase protein (H275Y) that is exceptionally rare among clade 2.3.4.4b viruses (present in 0.045% of publicly available clade 2.3.4.4b isolates). NA-H275Y is a well-known marker of resistance to the neuraminidase inhibitor oseltamivir. We demonstrate that this substitution maintains its resistance phenotype on the genetic background of H5N1 clade 2.3.4.4b viruses.

Since then we've seen multiple spillovers of D1.1 into dairy cattle (Nevada, Arizona & Wisconsin), and some studies (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) have suggested D1.1 may be better suited to human biology than the `bovine'  strain. 

At this point it's worth noting that there are scores of other HPAI H5 genotypes in circulation  - both in North America and around the globe - many of which have yet to be fully (or even partially) characterized. 

But, of the H5 genotypes currently on our radar, D1.1 ranks pretty high on our watch list.  All of which brings us to a preprint from researchers at the CDC, which looks at what we currently know - and don't know - about this emergent genotype. 

I've reproduced the abstract, and an excerpt from the discussion. Follow the link to read the preprint in its entirety.  I'll have a postscript after the break.

A newly emergent N1 neuraminidase associated with clade 2.3.4.4b highly pathogenic avian influenza A(H5) viruses in North America

Matthew J Wersebe, Nicole M Paterson, Norman Hassell, Xiao-yu Zheng, Benjamin J Rambo-Martin, Julia C Frederick, Kristine K Lacek, Amanda H Sullivan, Marie Kirby, Rebecca Kondor, Yunho Jang, Sabrina Schatzman, Han Di, C. Todd Davis
doi: https://doi.org/10.64898/2026.03.09.26347929
This article is a preprint and has not been certified by peer review

Preview PDF

Abstract

We investigated the evolutionary history of the newly emergent neuraminidase (am4N1) associated with the D1.1 and D1.2 genotypes of highly pathogenic avian influenza A(H5N1) viruses in North America. 

Phylogenetic inference places am4N1 in a sister clade to Eurasian avian, swine, and human A(H1N1)pdm09 viruses and distinct from 1918, pre-2009 human seasonal, and classical swine A(H1N1) lineages. 

Am4N1 descends from diverse avian N1 genes endemic to the Americas. Phylodynamic analysis indicates a monophyletic am4N1 lineage with numerous introductions of viruses carrying the am4N1 gene likely originating from western Canada into the United States during emergence of the D1.1 and D1.2 genotypes.

The lineage has diversified and accumulated deletions in the stalk domain. Despite amino acid divergence, structural modeling shows conserved neuraminidase architecture in the globular head. Given its distinct ancestry and amino acid sequence, further studies are needed to assess cross-reactivity of antibodies from prior human A(H1N1)pdm09 infections.

(SNIP)

Pandemic preparedness countermeasures such as vaccines typically rely on comparing host antibody recognition via Hemagglutinin inhibition assays (HAI) as the HA mediates viral attachment and host cell entry and is the primary surface antigen. However, the NA plays a key role in influenza viral replication as well - allowing the release of progeny virions from infected cells [27, 36].

Neuraminidase activity is targeted by numerous pharmaceutical countermeasures including the widely prescribed oseltamivir which inhibits its enzymatic activity [37]. Currently, Neuraminidase inhibiting pharmaceuticals are stockpiled for the event of an influenza pandemic. 

Signore et al. [8] showed that am4N1 NAs isolated from Canadian chickens harbored an amino acid substitution at NA:H275Y, a known marker for resistance to oseltamivir and showed that the isolate with NA:H275Y had decreased  susceptibility to oseltamivir. 

This clade has not shown onward transmission in the samples analyzed here but continued surveillance for NA:H275Y is needed. Most am4N1 NAs do not carry this amino acid substitution and human isolates tested to date are inhibited well by NAI pharmaceuticals [38].

Another critical aspect of pandemic preparedness is fully understanding the genetic makeup and evolutionary history of pathogen threats. Here we provide a description of the phylogenetics and evolution of am4N1 NAs which have contributed to the ongoing epizootic in wild birds, infected numerous mammals, and caused two human fatalities to date. 

In addition, we use bioinformatic analysis to predict the structure of diverse NAs and determine how sequence identity changes may have functional implications for am4N1 NAs. Am4N1-like NAs are highly divergent from those previously associated with HPAI A(H5N1) viruses from clade 2.3.4.4b and are phylogenetically distant from NA genes that humans may have immunity to via vaccination and prior infection. 

Detailed studies describing the human antibody recognition of viruses with the am4N1 protein following seasonal influenza vaccination or infection are needed to fully understand the public health risk posed by D1.1 viruses and its derivate genotypes sharing this NA lineage. 

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We are now 18 months since the first detection of D1.1, yet there is still much we don't know about its impact, prevalence, or pandemic potential. Surveillance is spotty at best, and the public release of WGS (Whole Gene Sequencing) and antigenic characterization data continues to be limited.

Remarkably, the exact number of human infections with the D1.1 genotype is unknown, since only a subset (of the roughly 6 dozen) North American human cases have been fully characterized. 

A year ago, in Nature: Lengthy Delays in H5N1 Genome Submissions to GISAID. we saw the average delay in submitting sequences to GISAID was 7 months (228 days), with some countries taking nearly 2 years. 

And genetic sequences - when they are submitted to GISAID - are often devoid of crucial metadata (i.e. collection date, exact location, host-specific information, etc.), limiting their value to the scientific community.

While I'm sure there are legitimate logistical challenges involved, it is hard to believe this is the best we can do. 

Viruses: Novel Reassortant H5N2 Highly Pathogenic Avian Influenza Viruses from Backyard Poultry in Mexico

 

#19,081

Influenza A's superpower is its ability to simultaneously infect a host with 2 or more strains, swap genetic material, and generate a new `hybrid' virus; a reassortant. This reassortment can generate new genotypes, or - if the HA or NA are swapped - a new subtype.

While flu viruses continually evolve slowly through antigenic `drift' - as we saw with H3N2 subclade K this past winter - truly large evolutionary jumps generally require reassortment (aka `Antigenic Shift').  

Most reassortants end up as evolutionary failures, but when they get it right, they can spark pandemics.  While rare, any virologist will tell you; `Shift happens.'

Twice in my lifetime (1957 & 1968) avian flu viruses did precisely that; reassorted with a seasonal flu virus and launched a human pandemic.

• The first (1957) was H2N2, which according to the CDC `. . . was comprised of three different genes from an H2N2 virus that originated from an avian influenza A virus, including the H2 hemagglutinin and the N2 neuraminidase genes.'

• In 1968 an avian H3N2 virus emerged (a reassortment of 2 genes from a low path avian influenza H3 virus, and 6 genes from H2N2) which supplanted H2N2 - killed more than a million people during its first year - and continues to spark yearly epidemics more than 50 years later.

When H5N1 arrived in North America 4 years ago it immediately began to reassort with local LPAI viruses, and in the first year generated at least 100 distinct genotypes. Since then, we've seen:

• In late 2023 a new B3.13 genotype emerged that could efficiently infect dairy cattle while mildly infecting scores of humans

• In the fall of 2024 we saw 3 new genotypes emerge (D1.1, D1.2, D1.3), with D1.1 producing more severe illness in humans. 

• We continue to see scattered reports of HPAI H5N5 in birds and mammals in Europe & Canada, and the the United States, and last fall we saw the first confirmed (and fatal) human infection.

This growing diversity of HPAI H5 can be seen everywhere the virus goes:

• South Korea is currently battling H5N1, H5N6, and H5N9. 

• Europe has their own distinct set of HPAI genotypes 

• A little over a year ago, in  Emerg. Microbes & Infections: Emergence of a Novel Reassortant HPAI Clade 2.3.4.4b A(H5N2) Virus, 2024, we looked at the emergence of a novel HPAI H5N2 virus in the Middle East. 

Due to limited surveillance and sharing of information, there are undoubtedly far more HPAI H5 reassortants circulating around the globe than we know. 

But today we get details on the recent emergence of HPAI H5N2 viruses - due to the reassortment of LPAI H5N2 and HPAI H5N1 - in backyard poultry across 3 Mexican states: Michoacán, Estado de México, and Ciudad de México.

This follows the announcement of the first known human infection with HPAI H5N2 (also in Mexico) last September. That was the third H5 case reported from Mexico since 2024, and the source of all three remain undetermined.

• The first occurred in April of 2024 (see Mexico announced the death of a 58-year-old man) when a patient - who also suffered from serious comorbidities - tested positive for LPAI H5N2, becoming the first laboratory-confirmed human case of influenza A(H5N2) infection reported globally.

• A year later (April 2025), a 3-year old girl from Durango State died following an H5N1 infection (see WHO DON Update On Mexico's Fatal H5N1 Infection).

Notably, this study found two distinct genotypes of HPAI H5N2, which supports the idea that reassortment activity is ongoing. The newer - more complex genotype (from Nezahualcóyotl and Gustavo A. Madero outbreaks) - most closely matches the human H5N2 case mentioned above.

I've only reproduced the abstract and an excerpt from the conclusion. Follow the link to read it in its entirety.  I'll have a bit more after the break.

Novel Reassortant H5N2 Highly Pathogenic Avian Influenza Viruses from Backyard Poultry in Mexico
Mario Solís-Hernández1,*, Guillermo Orta-Pineda1,*, Carlos Javier Alcazar-Ramiro1, Montserrat Amaranta Velázquez-Vázquez1, Claudia Garnica-Rivera1,
Marisol Karina Rocha-Martínez2, Nadia Carrillo-Guzmán1, Ignacio Eliseo Tetla-Zapotitla2, Israel Tiburcio-Sánchez1 … Armando García-López1
Viruses2026, 18(3), 337;https://doi.org/10.3390/v18030337
9 March 2026

Abstract

Highly pathogenic influenza A viruses of the H5 subtype continue to diversify worldwide through mutation and genetic reassortment, generating novel variants with unpredictable consequences under the One Health approach. 

Between 2024 and 2025, five outbreaks of avian influenza A viruses were detected in backyard poultry across Michoacán, Estado de México, and Ciudad de México. We conducted molecular and genetic characterization of five highly pathogenic H5N2 viruses isolated from these events. All cases tested positive for influenza A virus and the H5 hemagglutinin, exhibiting high pathogenicity with intravenous pathogenicity index values ranging from 2.88 to 3.0.

 Whole-genome sequencing revealed novel reassortants containing hemagglutinin from Eurasian H5N1 clade 2.3.4.4b and neuraminidase from the endemic Mexican H5N2 lineage. The viral genome of the isolate from Michoacán contained six segments derived from Eurasian H5N1 viruses introduced into North America in 2021–2022, while nucleoprotein and neuraminidase originated from Mexican H5N2 viruses. 

In contrast, viruses from Estado de México and Ciudad de México contained five H5N1-derived segments and incorporated polymerase basic protein 1, nucleoprotein, and neuraminidase from low-pathogenic H5N2 viruses circulating in 2024. Phylogenetic analyses confirmed the emergence of a distinct H5N2 Mexican sublineage, providing evidence of active viral reassortment and local evolutionary processes in Mexico.

(SNIP)

5. Conclusions

This study reports the emergence of novel H5N2 reassortant viruses in central Mexico, resulting from interactions between highly pathogenic H5N1 clade 2.3.4.4b and endemic low-pathogenic H5N2 lineages. The distinct genomic constellations identified, ranging from early-stage reassortants to more complex combinations involving PB1, NP, and NA, demonstrate active viral ex🔜→→change within backyard poultry systems. 

These findings emphasize the critical role of informal production environments as ecological niches that facilitate reassortment and sustain viral diversity. Mutational patterns in HA and NA further reveal ongoing adaptation and selective pressures consistent with extended regional circulation. 

The emergence of these reassortants underscores the urgent need to strengthen genomic surveillance programs, particularly in regions where influenza lineages overlap and biosafety measures are limited. Continuous monitoring will be essential to assess the evolutionary trajectory, pathogenic potential, and epidemiological impact of these viruses, as well as their implications for poultry health, zoonotic transmission, and pandemic risk.

       (Continue . . . )

The first known human H5N1 infections (n=18) were reported in Hong Kong in 1997. Seventeen years later (in 2014) we saw the 1st Known Human Infection With H5N6 Avian Flu Sichuan Province, China, and 7 after that (2021) we saw the first human infections with H5N8 in Russia.

  

While worrying, this relatively slow progress - averaging > 10 years between each new subtype spillover - has been somewhat reassuring. 

In contrast, over the past 6 months we've seen two new HPAI H5 subtypes spillover into humans for the first time; H5N2 in Mexico and H5N5 in the United States.  

Moreover, the interval between each new H5 subtype spillover (17 yrs ➡ 7 yrs ➡ 4 yrs) continues to shrink.

While all of this could be a coincidence, it's a trend we shouldn't ignore. The greater viral diversity in the wild, the better the chance that one of these novel viruses will crack the code, and spark the next global health crisis. 

And with our continued reliance on limited (and mostly passive) surveillance systems, our first clue may only appear after hospitals begin filling up with patients. 

Again.