PNAS: Reconstructing the Early Spatial Spread of Pandemic Respiratory Viruses in the United States

 
#19,011

Long-time readers are aware of my limited grasp of statistics, and probably suspect I'll drown someday trying to ford a stream that is - on average - 2 feet deep. Which is why I won't even try to dissect the advanced methods used in today's study from Columbia University's Mailman School of Public Health. 

But their findings; that early cryptic spread of pandemic viruses are hard to predict - even when viewed in retrospect - is worthy of deeper discussion.

First, in broad strokes, a brief summary from the press release.

News Release 5-Jan-2026
Study examines how the last two respiratory pandemics rapidly spread through cities
Peer-Reviewed Publication

Columbia University's Mailman School of Public Health
The researchers set out understand the geographic spread of the two pandemics to inform strategies to prevent future pandemics. They applied detailed data on the dynamics of the two infectious diseases to a computer model to simulate their spread using known patterns of air travel and commuting, as well as potential superspreading events. They focused on over three hundred metropolitan areas in the U.S.

In the simulations, both pandemics were widely circulating in most of the metro areas within weeks, before government interventions or early case detection. While the specific transmission pathways across locations were different for the last two pandemics, the spatial expansion was driven by several shared transmission hubs such as the New York and Atlanta metropolitan areas. Their spread was largely driven by air travel rather than commuting, though random dynamics introduced substantial uncertainty in transmission routes, which makes it hard to predict where the outbreaks will happen in real time.

        (SNIP)

Beyond reconstructing the historical spread of the last two pandemics, the study also provides a generalizable framework to infer early epidemic dynamics that may be applied to other pathogens. While mobility, particularly air travel, is a key driver of pandemic spread, the researchers caution that other factors also play a role, including community demographics, school schedules, winter holidays, and weather conditions.

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A link, and some excerpts from the full study, after which we'll look at some of the real-life implications.  

Reconstructing the early spatial spread of pandemic respiratory viruses in the United States
Renquan Zhang, Rui Deng, Sitong Liu , +4 , and Sen Pei  
January 6, 2026
https://doi.org/10.1073/pnas.2518051123
Vol. 123 | No. 2

Abstract

Understanding the geographic spread of emerging respiratory viruses is critical for pandemic preparedness, yet the early spatiotemporal dynamics of the 2009 H1N1 pandemic influenza and severe acute respiratory syndrome coronavirus 2 in the United States remain unclear. 

While mobility and genomic data have revealed important aspects of pandemic spatial spread, several key questions remain: Did the two pandemics follow similar spatial transmission routes? How rapidly did they spread across the United States? What role did stochastic processes play in early spatial transmission?

To address these questions, we integrated high-resolution disease data with a robust, data-efficient inference framework combining air travel, commuting flows, and pathogen superspreading potentials to reconstruct their spatial spread across US metropolitan areas.

The two pandemics exhibited distinct transmission pathways across locations; however, both pandemics established local circulation in most metropolitan areas within weeks, driven by several shared transmission hubs. Early spatial spread was more strongly associated with air travel than with commuting, though stochastic dynamics introduced substantial uncertainty in transmission routes, creating challenges for timely detection and control.

Simulations indicate that broad wastewater surveillance coverage beyond top transmission hubs coupled with effective infection control may slow initial spatial expansion. Our findings highlight the rapid, stochastic spread of pandemic respiratory pathogens and the difficulties of early outbreak containment.

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For those who are as statistically challenged as am I; `stochastic' is just a fancy word for "random" or "probabilistic".  We often talk about the R0 (r-naught) of a virus - how many people one person is likely to infect - but that's just an average. 

Some people may get sick, wisely stay home, and infect no one else. Others may mask their symptoms with OTC cold/flu meds and fly to a convention; becoming a superspreader that infects dozens. 

Individual choices - both good and bad - can affect how quickly a pandemic spreads. As can many external factors, like the weather, holidays, community demographics, and school closures. 

And of course, not all viral threats are created equal. 

The SARS-COV virus of 2022-2023 famously did not spread asymptomatically, which made quarantine of symptomatic individuals effective (see SARS and Remembrance), making containment possible. 

H1N1 and COVID, however, could be spread asymptomatically and via aerosols, and that made them virtually unstoppable.   

The reality is, it doesn't take a super virus to spread uncontrollably. Even a (relatively) mild H1N1 virus swept the world in 2009, and supplanted the old H1N1 virus, all in a matter of weeks.

While many countries implemented border closings, passenger screenings, and airport thermal scanners to try stop H1N1 and COVID; at best they only delayed entry by a matter of days or weeks.   

Most viruses take days - up to a week or longer - to incubate. And with 7 million airline passengers each day, any attempts to identify and isolate infected passengers are probably doomed from the start.

Today's study is a reminder that once a respiratory pandemic virus is transmitting efficiently in the community, our ability to stop it is laughably small. 

The authors of today's study do suggest airport wastewater surveillance at key transmission hubs (testing sewage from aircraft, airport terminals, and related infrastructure) would be a cost effective early warning system. 

This would not only pick up asymptomatic carriers, or tell us where to deploy medical assets, it might even alert us to emerging threats before they become fully transmissible.

As much merit as that idea has - given our current level of pandemic denial, and unwillingness to test and share data -  I'm not particularly hopeful.

Arch. Pub. Health: Excess Primary Healthcare Consultations in Norway in 2024 Compared to Pre-COVID-19-pandemic Baseline Trends

#19,010

From very early on in the SARS-CoV-2 pandemic, we saw concerns raised over the potential long-term impact of COVID infection; often centered around cardiac or neurological involvement.

In early April 2020, the New York 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).

In June, JAMA published an original investigation which found a huge increase in out-of-hospital cardiac arrests in New York City during the peak of their COVID-19 epidemic, writing:

From March 1 to April 25, 2020, New York City, New York (NYC), reported 17 118 COVID-19–related deaths. On April 6, 2020, out-of-hospital cardiac arrests peaked at 305 cases, nearly a 10-fold increase from the prior year.

Admittedly, most of these cases were never tested for COVID-19, making any link circumstantial. The following month, however, in JAMA: Two Studies Linking SARS-CoV-2 Infection To Cardiac Injury, we saw physical evidence of cardiac injury due to COVID infection, even among a relatively young cohort of previously healthy adults.

By mid-summer, it was becoming apparent that COVID was far more than just an acute respiratory infection (see Nature Med. Review: Extrapulmonary manifestations of COVID-19), and could produce blot clots, along with neurological, renal, and cardiovascular damage.

 In late July we saw this cautionary editorial published in JAMA.

Coronavirus Disease 2019 (COVID-19) and the Heart—Is Heart Failure the Next Chapter?
Clyde W. Yancy, MD, MSc1,2; Gregg C. Fonarow, MD3,4
JAMA Cardiol. Published online July 27, 2020. doi:10.1001/jamacardio.2020.3575

Since then, studies showing post-acute impacts of COVID infection have exploded, with many citing repeated COVID infections as increasing the risk of long-term health damage. A few (of many) include:

Nature: Long-term Cardiovascular Outcomes of COVID-19

AHA: COVID-19 May Trigger New-Onset High Blood Pressure

NIH: Study Shows SARS-CoV-2 Infects Coronary Arteries, Increases Plaque Inflammation

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

Terms like `Long COVID' and PASC (Postacute Sequelae of COVID) are now officially recognized, but their impact remains poorly quantified (and often disputed).

Much of the evidence is anecdotal, or inferential, because 90% of the world stopped testing, and reporting on ICU admissions and deaths, more than 3 years ago (No News Is . . . Now Commonplace).

The world desperately wanted to move on from COVID, and it decided the best way to do so was by touching up the X-rays.  But of course, the health burden of COVID - recognized or not - remains. 

Today we've a study from the Norwegian Institute of Public Health and others, that looks at the trajectory of primary care consultations in Norway both before - during - and after the COVID pandemic.

What they found was the number of consultations in 2024 were about 7% above pre‑pandemic expectations (see graphic at top of this blog). Most of these were coded as being for respiratory, fatigue, psychological, cognitive, and some infectious/gastrointestinal complaints.

Patterns that have often been associated with PASC or `Long COVID', but remain exceedingly difficult to establish a causal link.  

The authors - who cite (and are critical of) Norway’s national COVID strategy which `. . . emphasizes the assumed benefits of sustaining population immunity through repeated SARS-CoV-2 infections' - hypothesize that repeated COVID infections have led to population‑level health impacts, with PASC and post‑COVID immune dysfunction driving much of the cited excess primary care consultations.

The authors note, in particular, the impact this has had on women, children, adolescents, and young adults.

I've reproduced the abstract below, but you'll want to follow the link and read the full article.  I'll have a brief postscript when you return.

Excess primary healthcare consultations in Norway in 2024 compared to pre-COVID-19-pandemic baseline trends

Research
Open access
Published: 02 January 2026
article number , (2026)

Download PDF

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

The risk of post-acute sequelae of COVID-19 (PASC) is estimated at 3–6% per infection in 2024. We hypothesized that widespread SARS-CoV-2 infections could lead to population-level consequences. Our previous study identified substantial increases in Norwegian primary healthcare consultations in 2023—compared to pre-pandemic levels—for conditions associated with acute COVID-19 and PASC. This study extended that analysis to 2024. We then assessed whether observed patterns were compatible with our hypothesis.

Methods

We used data from the Norwegian Syndromic Surveillance System, which captures nationwide primary healthcare consultations for 102 ICPC-2 codes (out of a possible 710) that are relevant for infectious disease surveillance and some post-acute infection syndromes. Bayesian linear regression models were fitted to 2010–2019 trends, adjusting for population changes, to estimate expected values for 2024. Excess consultations were calculated by age and sex. A COVID-19 community spread was proxied by vaccination-adjusted weekly hospitalization rates.

Results

In 2024, there were 17,800,365 consultations, corresponding to an absolute excess of 1,185,231 consultations, or a 7.1% relative excess, compared to the modelled baseline. The 10 code combinations with largest absolute excess in 2024 were respiratory infections (325,726 excess consultations; 20% relative excess), fatigue (205,381; 70%), psychological symptom/complaint other (188,978; 87%), acute stress reaction (182,079; 76%), feeling depressed (126,783; 133%), hyperkinetic disorder (112,763; 116%), abdominal pain/cramps general (84,544; 29%), memory disturbance (39,177; 63%), conjunctivitis (34,643; 59%), and infectious disease other/NOS (33,556; 81%). COVID-19 community spread showed the strongest correlations with conjunctivitis, strep throat, respiratory infections as a group (R**), fatigue, infectious disease other, memory disturbances, and pneumonia. Deviations from pre-pandemic trends varied: respiratory and psychological disorders worsened from 2020 onward and several conditions showed dramatic excess from 2022–2024. Females 15–29, children, adolescents, and young adults had disproportionately large relative excesses for consultations for memory disturbances.

Conclusions

Primary healthcare consultations in 2024 significantly exceeded pre-pandemic expectations, especially for conditions linked to acute COVID-19 and PASC, though the two cannot be differentiated in these data. While other factors undoubtedly also play a role, findings are compatible with ongoing population-level health impacts associated with repeated SARS-CoV-2 infections, particularly among women, children, adolescents, and young adults. These results emerged under a national COVID-19 strategy that does not account for post-acute consequences of SARS-CoV-2 infection.

(Continue . . . )

The author's hypothesis, and findings, certainly resonate with what I've seen, and written extensively about, for the past 6 years. But proving causality is always difficult, even when the patterns neatly `fit' the hypothesis. 

A task that is made even more onerous by the deliberate dismantling of COVID surveillance, testing, and reporting around the world.  

Society has used this lack of data to trivialize COVID infection (and reinfection) to the point that vaccine uptake has plummeted, and mask-wearing - and other protective measures - have become anathema. 

Meanwhile, COVID continues to exact a heavy toll, while the public remains oblivious to - or highly skeptical of - other threats that may be in the pipeline. 

While ignorance may yield temporary bliss, we risk a very rude awakening down the road. 

South Korea MAFRA: Special Quarantine Measures Implemented for one Month to Prevent the Spread of HPAI

19,009

Like many other countries, this fall South Korea has been hit particularly hard by this fall's return of avian flu, and over the past 30 days we've seen 3 major declarations from MAFRA and local authorities regarding their response. 

South Korea: MAFRA Reports Increased Infectivity & Pathogenicity of This Year's Avian Flu Strains

South Korean City (Naju) Orders Extraordinary Emergency Measures Due to HPAI

South Korea: MAFRA Identifies Biosecurity Breaches On HPAI Infected Poultry Farms

While South Korea has dealt with avian flu off and on for 2 decades - including the disastrous arrival of H5N8 in early 2014 - this year they have been unusually wary; with their CDC holding a 19-day Nationwide, Mock-Training Exercise to Prepare for Zoonotic Influenza in early September.

Six weeks ago, South Korea's MAFRA Ordered Strengthened Quarantine Measures After 3 HPAI H5 Subtypes (H5N1, H5N6, H5N9) Detected In Wild Birds, and last month they announced a 10-fold increase in infectivity of this year's returning virus. 

While we've seen strong responses by South Korea to HPAI outbreaks in the past,  today MAFRA has announced unusually stringent nationwide quarantine and biosecurity measures; even for them. 

Few countries have been as open about their concerns over - and their response to - HPAI, and so other governments, agencies, and poultry producers may want to take note. 

First, the translated announcement, after which I'll have a brief postscript on a curious aspect to today's announcement.

       (Translation)

Special quarantine measures implemented for one month in January to prevent the spread of highly pathogenic avian influenza.

2026.01.05 15:38:20 Avian Influenza Prevention and Control Division

The Central Disaster and Safety Countermeasures Headquarters for Highly Pathogenic Avian Influenza ( Chief: Minister of Agriculture, Food and Rural Affairs Song Mei - ling , hereinafter referred to as the Central Disaster and Safety Countermeasures Headquarters ) announced that as the risk of additional outbreaks has increased due to the recent increase in the occurrence of highly pathogenic avian influenza (AI), it will hold a quarantine countermeasures meeting chaired by Minister of Agriculture, Food and Rural Affairs Song Mei- ling on Monday , January 5 to review the situation of highly pathogenic avian influenza outbreaks and quarantine measures and further strengthen quarantine management .

1. Situation

This winter ('25/'26 season ) , there have been 30 cases of highly pathogenic avian influenza in poultry farms and 22 cases in wild birds .

* Poultry farm outbreak status ( 30 cases in total ): Gyeonggi 9 cases ( Anseong 3, Paju 1, Hwaseong 2, Pyeongtaek 3), Chungbuk 7 cases ( Goesan 1, Yeongdong 1, Jeungpyeong 1, Jincheon 2, Eumseong 2), Chungnam 5 cases ( Boryeong 1, Cheonan 3, Asan 1), Jeollabuk-do 2 cases ( Gochang 1, Namwon 1), Jeollanam-do 6 cases ( Naju 4, Yeongam 2), Gwangju Metropolitan City 1 case

** Status of wild bird detection ( total 23 cases ): Gyeonggi 1, Chungbuk 1, Chungnam 6, Jeonbuk 4, Jeonnam 4, Gyeongbuk 3, Gyeongnam 1, Busan 1, Gwangju 1, Seoul 1

This winter season, for the first time in Korea , three types of viruses ( serotypes : H5N1, H5N6, H5N9) were detected in wild birds and poultry farms , and in particular, the highly pathogenic avian influenza virus ( serotype H5N1) confirmed in Korea this winter season was confirmed to be more than 10 times more infectious than in previous years, making the situation very serious with a higher risk of additional outbreaks than ever before .

As seen in the past when the most cases occurred in December and January , the number of cases of highly pathogenic avian influenza has been increasing since December during this winter season as well , and the cases are particularly concentrated in the Gyeonggi , Chungcheong , and Jeolla regions where chicken and duck are raised. In order to minimize damage, all poultry farms and related personnel must be on alert and implement more thorough quarantine management than before, such as entry control and disinfection .

* Monthly occurrence : (September ) 1 case → (October ) 1 case → (November ) 4 cases → (December ) 22 cases → ( January '26 ) 2 cases

* Occurrence by region : 9 cases in Gyeonggi , 12 cases in South and North Chungcheong , 8 cases in South and North Jeolla , 1 case in Gwangju Metropolitan City

2. Special quarantine measures

The Central Disaster and Safety Countermeasures Headquarters will strengthen quarantine measures as follows to prevent and control highly pathogenic avian influenza .

First , as a special measure to prevent further outbreaks of laying hens, dedicated officers will be assigned to laying hens nationwide (539 farms with over 50,000 hens ) for two weeks from January 5 to January 16 to control the entry of livestock vehicles into the farms and conduct intensive inspections for any violations of quarantine regulations.

* ① Register the number and company of pre-risk livestock vehicles ( eggs , feed , manure ) , control the entry of other vehicles , ② On-site inspection when registered vehicles enter and exit , ③ Instruct and inform drivers of registered vehicles and related companies on quarantine rules

Second , the Avian Influenza Special Quarantine Team and the Ministry of Agriculture, Food and Rural Affairs field response team ( section chief level, etc. ) will be dispatched simultaneously to three risk areas and 11 regions where there is concern about additional outbreaks to conduct quarantine management, including special inspections .

* 3 special quarantine areas : Gyeonggi ( Hwaseong , Pyeongtaek , Anseong ) , South Chungcheong ( Cheonan , Asan ) , North Chungcheong ( Eumseong , Jincheon )

* Field response team 11 risk areas : Gyeonggi Pyeongtaek and Anseong , Chungcheongnam-do Cheonan , Chungcheongbuk - do Eumseong , Jincheon and Cheongju , Sejong , Jeollabuk -do Buan and Gimje , Jeollanam -do Yeongam and Naju

Third , to eliminate sources of contamination inside and outside poultry farms , livestock facilities, and vehicles, the period until January 14, 2026 will be designated as a “ National Intensive Disinfection Week ,” and roads around migratory bird arrival areas and nearby poultry farms will be disinfected at least twice a day .

Fourth , to strengthen disinfection and prevent transmission through vehicles, we will strengthen management by conducting surprise environmental inspections on high-risk livestock vehicles ( egg and feed transport , manure disposal ) entering and exiting poultry farms nationwide from January 5 to January 16 .

* Collect samples from disinfection facilities (222 locations , 1,100 cases ) and conduct detailed tests.

Fifth , we plan to conduct a comprehensive quarantine strengthening campaign in January in cooperation with producer groups . Poultry farms will be divided into three color-coded quarantine zones , and staff will change into colored boots for each zone and conduct intensive disinfection and rat catching operations .

* Promotion of changing boots when moving from the farm yard - polluted area ( red boots ) ↔ inside the anteroom - buffer area ( yellow boots ) ↔ inside the barn - clean area ( blue boots ) in laying hen farms

Sixth, in order to raise awareness and encourage autonomous quarantine in poultry farms, a special inspection and publicity week ('25.12. 31~'26.1. 13) will be designated for poultry farms nationwide, where daily inspections and guidance and education on key quarantine rules will be intensively provided , and quarantine rules will be delivered to farms within the jurisdiction every week through communication channels of city /county ( director in charge ) .

In addition, we will provide guidance and education on quarantine rules tailored to the language of each country for foreign workers working on poultry farms , and further strengthen publicity through the broadcast of disaster warnings to the public.

4. Requests

Minister of Agriculture, Food and Rural Affairs Song Mei-ryeong said , “ This winter, three types of viruses (H5N1, H5N6, H5N9) have been detected in wild birds and poultry farms , and the infectivity of the viruses has been confirmed to be more than 10 times higher than in the past. Therefore, all poultry farm workers and quarantine officials should further strengthen quarantine measures such as controlling the entry and exit of people and vehicles and disinfection, and do their best by mobilizing all available human and material resources . ”

In addition , “ Local governments in Gyeonggi , Chungcheong , and Jeolla regions, where there have been many recent outbreaks , should actively utilize the 1:1 poultry farm manager system through the local disaster response headquarters, which includes quarantine and disaster departments, to prevent the spread to surrounding areas , and intensively inspect quarantine area management and whether poultry farms are following quarantine rules . ”

In addition , he emphasized, “January is the month with the most avian influenza cases following December, so poultry farms should thoroughly follow basic quarantine rules such as controlling the entry of people and vehicles and disinfecting inside and outside the farm with the mindset of protecting their own farm, ” and requested , “ In particular , as there have been many cases in laying hen farms this season , to prevent further outbreaks , disinfection and access control for vehicles transporting eggs and feed, which are major risk factors for transmission , should be doubled or tripled . ”

Aside from ramping up their agency response to 11, there is another glaring change in this latest announcement. Previous statements have focused heavily on farm biosecurity lapses, and repeatedly warned of increased fines and other penalties for future violations. 

Curiously, today's announcement has zero mention of fines or penalties. 

While I'm sure that blatant disregard for biosecurity is still punishable, it is possible (and yes, I'm speculating) that this may be a tacit admission from MAFRA that even high-compliance farms are vulnerable to this year's crop of highly infectious avian flu viruses. 

If that should prove to be the case, then South Korea - and potentially many other countries - could be facing a particularly difficult second half to this year's avian flu season. 

 Stay tuned. 

Referral: JAMA - COVID-19 in Pregnancy Linked With Risk of Neurodevelopmental Disorders in Early Childhood

 

Photo Credit – CDC

#19,008

While we are still in our year-end science `news drought', we do have a release from JAMA, and a link to a new study Obstetrics & Gynecology, which shed new light on the impact of maternal COVID infection on the health of the unborn child. 

This is a topic we've looked at previously, including in 2022's Nature: Deleterious Effects of Nervous System in the Offspring Following Maternal SARS-CoV-2 Infection.  

We've also looked at the impact of maternal influenza (and other viral)  infections on the unborn child, where we've seen similar patterns emerge. A few examples include:

Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring

JAMA Psych: Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero

Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring

JAMA Psych: Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero

Many researchers believe this is more likely due to Maternal Immune Activation (MIA) - which includes cytokine releases and fever - than to fetal exposure to a specific pathogen. 

In today's report, researchers report that in a study of  > 18 000 live births in the Mass General Brigham health system between March 2020 and May 2021, 861 were exposed to maternal SARS-CoV-2 infection.

When compared to the unexposed cohort, those exposed to COVID-19 in utero had a 29% higher risk of neurodevelopmental delays (e.g. speech or motor issues) by age 3.

Researchers found that males were at higher risk than females, and the risk appeared greatest in those exposed during the third trimester of pregnancy.  

While the results are compelling, this was a single retrospective study; which may have been subject to screening bias and other confounders. Meaning it falls short of proving a `causal connection'.  

That said, its findings do fall in line with other studies we've seen on COVID and other maternal viral infections, and it deserves serious consideration. 

Since neither of these articles appear to be open-access, for copyright reasons I'll just provide the links below for you to follow.  

First up is a plain-language summary published by JAMA at:

COVID-19 in Pregnancy Linked With Risk of Neurodevelopmental Disorders in Early Childhood
Samantha Anderer1

The full research paper can be accessed at:

Neurodevelopmental Outcomes of 3-Year-Old Children Exposed to Maternal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Utero

Shook, Lydia L. MD; Castro, Victor MS; Ibanez-Pintor, Laura MD; Perlis, Roy H. MD, MSc; Edlow, Andrea G. MD, MScAuthor Information
Obstetrics & Gynecology 147(1):p 11-20, January 2026. | DOI: 10.1097/AOG.0000000000006112

 

Preprint: Inoculation with HPAI H5N1 Genotype D1.1 in Naïve Dairy Cows and Dairy Cows Previously Exposed to Genotype B3.13

 

#19,007

HPAI H5N1, which has infected more than 1,000 U.S. dairy herds, continues to surprise. Until earlier this year, cattle spillovers were exclusively due to genotype B3.13, but we've now seen genotype D1.1 in dairy cows in at least 3 states.  

Earlier studies had suggested that dairy cows build a robust immunity to H5N1 after initial infection, but that study was conducted at a time when only B3.13 was thought to infect cattle.

Since the USDA doesn't report on reinfected herds (or on individual cows), we don't have a lot of data on how often reinfections might occur.  We also don't know how a past infection with genotype B3.13 might impact a cow exposed to genotype D1.1. 

In an attempt to answer some of those questions we have a preprint from researchers at the USDA and Iowa State University that looks at both naïve and previously exposed (B3.13) dairy cows that are inoculated with the newer D1.1 genotype. 

What they found was previously infected dairy cows were still susceptible to the D1.1 virus, albeit producing milder symptoms and shedding less virus. Something that could also make it more difficult to detect new spillovers. 

First the link and abstract to the preprint, after which I'll have a brief postscript. 

Inoculation with highly pathogenic avian influenza H5N1 genotype D1.1 in naïve dairy cows and dairy cows previously exposed to genotype B3.13

Kaitlyn Sarlo Davila1,,Meghan Wymore Brand1,,Ellie Putz1,,Paola Boggiatto1, Hannah Seger1, Amy Baker2, Tavis Anderson3, Carl Hutter1, Alexandra Buckley1,  Allison Vander Plaats, Rachel Friedrich4, Patrick Gordon4,  Bailey Arruda1, Carine Souza1, Brittney Davidson1, Mitchell Palmer1

This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-8339573/v1
This work is licensed under a CC BY 4.0 License

Abstract

USDA confirmed by whole genome sequence the first detection of HPAI H5N1 clade 2.3.4.4b genotype D1.1 in dairy cattle. While genotype D1.1 has been the dominant strain circulating in migratory birds in North America, the Nevada cases represent the first detection of a genotype other than B3.13 in cattle and the second known spillover event from wild birds into lactating dairy cattle. D1.1 clinical presentation in dairy herds in both Nevada and Arizona was mild compared to HPAI B3.13. However, this is based on a small number of affected herds and may not be the case for the broader population.

Here we sought to experimentally reproduce infection of dairy cattle with HPAI H5N1 genotype D1.1. and also sought determine if cattle with serum antibodies following natural infection with HPAI B3.13 were protected against reinfection with HPAI D1.1. Four adult Holstein lactating cows were moved into ABSL-3-Ag containment, two cows free of influenza A virus and two cows free of influenza A virus, but with serum antibodies from a natural H5N1 infection (genotype B3.13 ).

All cows were inoculated via the intramammary route with 1 ml of 1 x 105.4 TCID50/ml A/dairy cattle/Nevada/24-002644-003/2025 into two contralateral quarters. The drop in milk production and rumination observed in this study were similar to those reported in experimental intramammary challenge of lactating cows with HPAI B3.13, as well as natural infections, indicating that clinical presentation of HPAI D1.1 was similar in severity to experimental challenge with HPAI B3.13. 

Unlike the HPAI B3.13 intramammary challenges, HPAI D1.1 migrated and infected a non-inoculated quarter. The two B3.13 convalescent cows were susceptible to reinfection with D1.1, demonstrating clinical signs including a drop in milk production and rumination, pyrexia, and mastitis.

However, milk production and rumen motility recovered more quickly in the two convalescent cows than in the two naïve cows and pyrexia was not as severe. Viral RNA was also not detected in the milk of the convalescent cows after 10 DPI while it was detected in the milk of the naïve cows for the durations of the study.

Furthermore, while viral RNA was detected in the milk of both convalescent cows, no viable virus was isolated. While convalescent cows with serum but not milk antibodies to B3.13 are susceptible to reinfection with D1.1 and clinical disease antibodies can transudate into the milk and bind virus, likely preventing further spread throughout the herd.

The single-nucleotide variant analyses of whole genome sequences virus recovered from the milk of previously naïve cows also uncovered some potentially important patterns. Genes HA and MP were found to have strong evidence for natural selection and analysis indicates a fitness advantage is conferred through some key mutations that could lead to antigenic drift and immune escape.

        (Continue . . . )

The takeaway from all of this is that while reinfection with the same genotype might be limited, previously infected herds cannot be assumed to be immune to newer/different H5N1 genotypes.

Another reminder, as if we needed it, that early assumptions about emerging pathogens often require frequent reexamination. 

When Seasonal Flu Exceeds Expectations

Flu Virus binding to Receptor Cells – Credit CDC

#19,006

It is summer down under, and typically the nadir of the Australian flu season, but this year - as Virologist and blogger Dr. Ian McKay reports - seasonal flu is still going strong more than 3 months after their calendar-based flu season should have ended. 

A few days ago Ian wrote: 

Instead of the annual epidemic returning to baseline levels, cases stopped declining in October and have started to rise again in November, December, and perhaps also in January (still a few days left). Just to note, there is always some flu around, just usually at very low levels outside the epidemic peak period.

I would invite you to read Ian's entire analysis, because the same subclade K of seasonal H3N2 which emerged there last July, is now running roughshod over the United States, Canada, Europe, Asia, and the rest of the Northern Hemisphere. 

Due to the holidays, surveillance and reporting over the past few weeks have  likely under-represented its current impact here in the United States. We'll get another belated FluView on Monday, but it often takes until mid-January before reporting returns to normal. 

Meanwhile, early reports (see WHO EURO Statement: More than half of WHO European Region experiencing intense, early influenza season driven by new strain) and the latest FluView data (which is at least 2 weeks old at this point), attest to its impact. 

Whether we'll experience the same protracted flu season as has Australia remains to be seen - but it is certainly possible - making it still very much worth getting this year's flu vaccine if you haven't already. 

Despite concerns that this year's vaccine may not be as effective against this drifted subclade; it is still expected to provide valuable protection against severe disease (see UKHSA Preprint: Early Influenza Virus Characterisation and Vaccine Effectiveness in England in Autumn 2025, A Period Dominated by Influenza A(H3N2) Subclade K)

How much protection?  Well, we probably won't have good data until later this month, and the full story won't be known until next summer.  But anything that reduces your chances of being hospitalized with severe influenza has value. 

Which is why I also wear a mask in public, use copious amounts of hand sanitizer, and try to avoid crowded indoor spaces.  A strategy which has helped keep me respiratory illness free for nearly 5 years.  

Last year was pegged as being the worst flu season in nearly a decade (see MMWR: Influenza-Associated Hospitalizations During a High Severity Season (United States, 2024–25)), but this year could end up being even more challenging.

 

Already New York state is reporting a faster start to this year's flu season (see dashboard below) and last week their DOH reported (New York State Department of Health Confirms Most Flu Cases Ever Recorded in One Week).

While many people trivialize the flu, numerous studies suggest strong links between influenza infection and cardiovascular events like heart attacks and strokes (see also Eur. Resp.J.: Influenza & Pneumonia Infections Increase Risk Of Heart Attack and Stroke).

In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we also looked at a study published in Cell Neuron which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.

And every once in a while seasonal flu will serve us up a curveball, sometimes even in the middle of the season.  A few examples:

• In 2008, H1N1 abruptly developed nearly 100% resistance to oseltamivir;
• In 2014, we saw a late summer mutation appear in the H3N2 virus (see HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus) which greatly reduced the effectiveness of that year's flu vaccine.
• in 2016, we saw warnings over mutated (D225G) H1N1 viruses in Russia and in Europe (see ECDC Risk Assessment : Reports Of Severe A(H1N1)pdm09 In Europe);
• And while it has had only limited impact so far, we are now watching another slow rise in antiviral resistance in H1N1

But the biggest seasonal flu aberration may well have been the Liverpool Flu of 1951, which - for about six weeks - caused a virulent flu virus to spread across the UK and into Canada was as deadly as the 1918 pandemic.

This graphic comes from the March 16th, 1951 Proceedings of The Royal Society of Medicine – page 19 – and shows in detail the tremendous spike in influenza deaths in early 1951 over the (admittedly, unusually mild) 1948 flu season.  

In 2006 the CDC's EID Journal published a stellar account of this event, and it is very much worth reading. 

Viboud C, Tam T, Fleming D, Miller MA, Simonsen L. 1951 influenza epidemic, England and Wales, Canada, and the United States. Emerg Infect Dis [serial on the Internet]. 2006 Apr [date cited].

A sobering reminder that even seasonal flu deserves our respect.