SSI: Large Danish Study Shows No Link Between Aluminum in Vaccines & Autism or Other Health Conditions

 

Credit ACIP/CDC

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Today the journal Annals of Internal Medicine has published a major study by researchers at Denmark's Statens Serum Institut (SSI) and the University of Copenhagen, which followed more than 1 million children (born between 1997 and 2018) who received childhood vaccines.

Significantly, they found no link between vaccine receipt and autism (and > 4 dozen other health conditions).

Due to their relatively small population (5.9 million) and a well-monitored universal healthcare system, Denmark's ability to conduct population based health studies is viewed as among the best in the world. 

The study may be accessed at:

Andersson NW, Bech Svalgaard I, Hoffmann SS, et al. Aluminum-adsorbed vaccines and chronic diseases in childhood. A nationwide cohort study. Ann Intern Med. 15 July 2025. doi:10.7326/ANNALS-25-00997

Those looking for a more easily digested synopsis will find it in the following (translated) media release from the SSI.  I'll have a postscript after the break.

Large Danish study: No link between vaccines and autism or 49 other health conditions

A new Danish study shows no link between aluminum in childhood vaccines and 50 health conditions such as autism, asthma and autoimmune disorders. The study thus confirms the safety of the Danish childhood vaccination program.

Last edited on July 15, 2025



A new, comprehensive Danish registry study, the largest of its kind to date, supports the safety of the Danish childhood vaccination program. The study, which includes data from over 1 million children, thus finds no increased incidence of, for example, autism, asthma or autoimmune disorders in vaccinated children.

"Our results are reassuring. By analyzing data from hundreds of thousands of Danish children, we have not found anything that indicates that the very small amount of aluminum used in the childhood vaccination program increases the risk of 50 different health conditions in childhood," says doctor Niklas Andersson from the Staten Serum Institut (SSI), who is the first author of the study.

The very small amounts of aluminum, which are included in certain vaccines as an adjuvant to enhance the effect, have been used since the 1930s.

The researchers from SSI have followed children born between 1997 and 2018 through the Danish health registries and analyzed the connection between vaccines containing aluminum and a total of 50 health conditions - including allergies, autoimmune disorders, neurological diseases and developmental disorders.

"It is the first study of this size and with such extensive analyses, and it confirms the high safety of the vaccines we have used for decades in Denmark," says Niklas Andersson.

The results are being published at a time when there is intense international debate about vaccine safety. Therefore, the Danish study comes at a particularly relevant time.

"In a time characterized by widespread misinformation about vaccines, it is crucial to be able to lean on solid scientific evidence. Large, population-based registry studies like this, which follow hundreds of thousands of children over many years, are part of the bulwark against the politicization of health knowledge, which can damage trust in vaccines. It is absolutely crucial that we clearly separate real science from politically motivated campaigns - otherwise we risk that it is Danish children who pay the price," says Department Head Anders Hviid from SSI, who led the large study.
Reference

Andersson NW, Bech Svalgaard I, Hoffmann SS, et al. Aluminum-adsorbed vaccines and chronic diseases in childhood. A nationwide cohort study. Ann Intern Med. 15 July 2025. doi:10.7326/ANNALS-25-00997

Facts about the study

• Researchers from the Statens Serum Institut (SSI) have analyzed data from more than 1 million Danish children born between 1997 and 2018 through Denmark's unique health registries to investigate whether there were long-term health effects of aluminum-containing vaccines.
• The study examined 50 different disorders and found no statistical correlation between the aluminum content in vaccines and an increased risk of developing autism, autoimmune disorders, asthma, or allergic diseases such as hay fever and food allergies.
• The study has just been published in the prestigious medical journal Annals of Internal Medicine.

Source: SSI

Fifteen years ago, in a blog called `The Monsters Are Due On Vaccine Street' I recalled a famous Twilight Zone episode, and noted that some of the same tactics were being used to undermine the public's faith in vaccines. 

`All it takes is for someone to instill a bit of doubt .  . .   a modicum of suspicion . . .  backed up by random, but seemingly connected events . . . and our insecurities, fears, and prejudices do the rest.'

Today, with overwhelming power of social media, what was once essentially a fringe movement has now become mainstream.  Propelled by `influencers' and glossy AI generated `clickbait' videos, quackery and misinformation abounds. 

• Childhood vaccine uptake is down, while measles and pertussis are rising (see Washington DOH Reports 25-fold Increase In Pertussis Cases in 2024 over 2023).  

• Flu vaccinations peaked in the last decade and have since declined, and only a small percentage of the population bothers with COVID shots anymore.  

Modern vaccines - including the COVID mRNA vaccines - have an enviable safety record. That said, there is no such thing as a 100% safe drug or medication for 100% of the population, and some adverse effects can occur. 

Even over-the-counter remedies, like NSAIDs or acetaminophen, can sometimes produce adverse - even fatal - reactions (see BMJ Research: NSAIDs & The Risk Of Heart Failure).

The decision to take any vaccine or medication should always be based on a risk-reward calculation.  Most of the time, those benefits far outweigh the risks.

But to analyze it properly, one needs to be able to distinguish pertinent facts from unsupported propaganda. 

A skillset that appears to be waning rapidly in today's society.

WHO: Influenza at the Human-Animal Interface Summary and Assessment, 1 July 2025

 

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Overnight the WHO published their June 2025 update on novel influenza (covers May 28th-July 1st), which adds 10 human H5N1 cases, 3 human H9N2 infections, and a 6th H10N3 case in China. 

Although the H9 and H10 cases were previously reported (see WHO WPRO Reports 6th H10N3 Case & 3 Additional H9N2 Cases In China), as were 8 H5N1 cases from Cambodia last month, there are 2 previously unannounced H5N1 cases in today's report (Bangladesh & India). 

Given the cutoff date of July 1st, Cambodia's latest case was not included. First, the summary, then we'll dig into some specifics on last month's cases.

Influenza at the human-animal interface

Summary and risk assessment, from 28 May to 1 July 20251

• New human cases : From 28 May to 1 July 2025, based on reporting date, the detection of influenza A(H5N1) in nine humans, influenza A(H9N2) in three humans and influenza A(H10N3) in one human were reported officially. Additionally, one human case of infection with an influenza A(H5N1) virus was detected.

• Circulation of influenza viruses with zoonotic potential in animals: High pathogenicity avian influenza (HPAI) events in poultry and non-poultry continue to be reported to the World Organisation for Animal Health (WOAH).3 The Food and Agriculture Organization of the United Nations (FAO) also provides a global update on avian influenza viruses with pandemic potential.4

• Risk assessment: Sustained human to human transmission has not been reported from these events. Based on information available at the time of the risk assessment, the overall public health risk from currently known influenza viruses circulating at the human-animal interface has not changed remains low. The occurrence of sustained human-to-human transmission of these viruses is currently considered unlikely. Although human infections with viruses of animal origin are infrequent, they are not unexpected at the human-animal interface.

• IHR compliance: All human infections caused by a new influenza subtype are required to be reported under the International Health Regulations (IHR, 2005).6 This includes any influenza A virus that has demonstrated the capacity to infect a human and its haemagglutinin (HA) gene (or protein) is not a mutated form of those, i.e. A(H1) or A(H3), circulating widely in the human population. Information from these notifications is critical to inform risk assessments for influenza at the human-animal interface.

A little over 5 weeks ago, in the May 2025 WHO Summary, we learned of 2 previously undisclosed H5 cases (clade 2.3.2.1a ) from Bangladesh; both collected from young children in Khulna Division last spring.  

Today's update provides a third case, this time from Chittagong division (> 250 Km to the east). 

A(H5N1), Bangladesh

On 31 May 2025, Bangladesh notified WHO of one confirmed human case of avian influenza A(H5) in a child in Chittagong division detected through hospital-based surveillance. The patient was admitted to hospital on 21 May with diarrhea, fever and mild respiratory symptoms and a respiratory sample was collected on admission.

On 28 May, the IEDCR confirmed infection with avian influenza A(H5) through RT-PCR. The N-type was later confirmed as N1. The patient has recovered, and exposure to backyard poultry was reported prior to symptom onset. No further cases were detected among the contacts of the case.

This is the 11th human infection with influenza A(H5N1) notified to WHO from Bangladesh since the first case was reported in the Dhaka division in 2008 and the third confirmed case in 2025.

The second new case (from India) remains somewhat of a mystery.  Not only is the report quite brief, the location provided (Khulna State) is a bit confusing, as Khulna is located in Bangladesh, not India. 

A(H5N1), India

A human infection with an H5 clade 2.3.2.1a A(H5N1) virus was detected in a sample collected from a man in Khulna state in May 2025, who subsequently died. Genetic sequence data are available in GISAID (EPI_ISL_19893416; submission date 4 June 2025; ICMR-National Institute of Virology; Influenza).

Today's report provides a more extensive review of the 8 cases reported by Cambodia last month:

Brief updates on the H9 and H10 cases are also included:

A(H9N2), China

Since the last risk assessment of 27 May 2025, three human cases of infection with A(H9N2) influenza viruses were notified to WHO from China on 9 June 2025. The cases were detected in Henan, Hunan and Sichuan provinces. Two infections were detected in adults who were also hospitalized. The cases had symptom onset in May 2025 and have recovered. All cases had a known history of exposure to poultry prior to the onset of symptoms. No further cases were detected among contacts of these cases and there was no epidemiological link between the cases. 

 

A(H10N3), China

On 9 June 2025, China notified the WHO of one confirmed case of human infection with avian influenza A(H10N3) virus in an adult from Shaanxi Province, with a history of asthma. Symptom onset occurred on 21 April, and the patient was admitted to hospital with pneumonia on 25 April. At the time of reporting, that patient was under treatment and improving. 

According to the epidemiological investigation, a history of exposure to backyard poultry in Inner Mongolia was reported. The patient is a farmer and raises chickens and sheep. Environmental samples did not test positive for influenza A(H10) viruses. All close contacts tested negative for influenza A and remained asymptomatic during the monitoring period.

Since 2021, China has notified WHO of a total of six confirmed human cases of avian influenza A(H10N3) virus infection.

In addition to these case updates, the WHO once again implores member nations to abide by the 2005 IHR regulations which require prompt notification of the WHO of all human infections caused by novel flu subtypes.

According to a report 2 years ago (see Lancet Preprint: National Surveillance for Novel Diseases - A Systematic Analysis of 195 Countries) many member nations still lack the capability to fully investigate cases, while others simply choose not to for economic, societal, or political reasons.

For a multitude of reasons, the cases that do get reported are almost certainly just the tip of a much larger iceberg.  And as this report illustrates, there is more than just H5N1 percolating in the wild. 

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

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History has shown that influenza pandemics can vary widely, both in severity and in demographic impact. The 1918 H1N1 pandemic was not only high-severity, it was reportedly far deadlier to healthy young adults than to the elderly (see epi curve above). 

In 2010, (see Study: Years Of Life Lost Due To 2009 Pandemic), researchers estimated the median age of death due to seasonal influenza-related illness in the United States to be 76. 

But in the 1957 H2N2 pandemic, and again in 1968's H3N2 pandemic, we saw a pronounced age shift to a younger cohort (see Pandemic versus epidemic influenza mortality: a pattern of changing age distribution).

`Half of influenza-related deaths during the 1968-1969 influenza A (H3N2) pandemic and large proportions of influenza-related deaths during the 1957-1958 influenza A (H2N2) and the 1918-1919 influenza A (H1N1) pandemics occurred among persons <65 years old.'

While the 2009 H1N1 pandemic was milder, we saw an even greater age shift. The CDC’s estimate of average and median age of death due to the 2009 Pandemic virus reads:

Based on two CDC investigations of confirmed 2009 H1N1-related deaths that occurred during the spring and fall of 2009, the average age of people in the U.S. who died from 2009 H1N1 from April to July of 2009 was 40. The median age of death for this time period was 43. From September to October of 2009, the average age of people in the U.S. who died from 2009 H1N1 was 41, and the median age was 45.

Bucking these trends, the 5-year epidemic of H7N9 in China had its greatest impact on older adults and the elderly (see "Avian influenza A (H7N9) virus infections in humans across five epidemics in mainland China, 2013–2017). The authors wrote: 

A linear increase in fatality risk was observed from the younger age groups to older age groups (Figure 4B). Case-patients aged over 60 years consistently had higher risks for death, death/mechanical ventilation, death/mechanical ventilation/ICU admission than case-patients aged below 60 years.

Yet H5N1, which is currently high on our watch list, has consistently skewed towards a younger demographic. Eighteen years ago, in A Predilection For The Young, I wrote about the disturbing skewing of H5N1 cases (and deaths) among younger individuals (see WHO Chart below).

More recently (see here, and here) we've looked at the skewing of fatal H5N1 cases in Cambodia towards a younger cohort.

Over the past decade it as become increasingly apparent that the first influenza virus you are exposed to shapes your immune response to other subtypes later in life (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).

While the subtype (H1, H2, H3, etc.) is often assumed to have the biggest impact, the HA Group type (see chart below) can also drive future immune responses (see Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting).

Obviously, knowing what cohorts or risk groups would be most vulnerable in a future influenza pandemic would greatly aid in preparedness, and in the allocation of vaccines and antivirals. 

But, as today's preprint by Danuta M. Skowronski et al. reports that immune imprinting may depend on more than just the first HA exposure, as the first NA (neuraminidase) may play a significant role as well.

This is a fascinating report, which adds both H5N6 and H9N2 to the equation. Despite sharing a near-identical HA with H5N1, H5N6 consistently skews towards an older demographic.

H9N2, on the other hand, skews to an even younger cohort than H5N1.

This paper posits that the lower attack rate and CFR from H5N1 over the past 15 years may be due to the `original pediatric priming' of children from the NA of the 2009 H1N1 pandemic, and a `massive boost opportunity' for older cohorts who were first exposed to H1N1 (born prior to 1957).

The authors also suggest that while this anti-NA immunity may help moderate the severity of both H5N1 and H9N2, it may also represent a double-edge sword. They write:

Homosubtypic anti-NA in particular may have attenuating effects on H5N1 and H9N2 zoonotic risk, notably severity, with implications for targeted messaging and mitigation measures.

Alternatively, while beneficial to those directly exposed, anti-NA may also paradoxically contribute to unrecognized infections, potentially facilitating surreptitious shedding, spreading and viral adaptation, with implications for case detection, containment and enhanced surveillance.

There is a lot to unpack here, and you'll want to download and read the full report.  I'll have a bit more after the break.

Neuraminidase imprinting and the age-related risk of zoonotic influenza

Danuta M. Skowronski, Samantha E. Kaweski, Lea Separovic, Suzana Sabaiduc, Gabriel Canizares, Ayisha Khalid, Charlene Ranadheera, Nathalie Bastien, Gaston De Serres

doi: https://doi.org/10.1101/2025.07.03.25330844

Highly pathogenic avian influenza of the H5N1 subtype has shown recent unprecedented expansion in its geographic and host range, increasing the pandemic threat. The younger age of H5N1 versus H7N9 avian influenza in humans has previously been attributed to imprinted pre-immunity to hemagglutinin stalk (HA2) epitopes shared with group 1 (H1N1, H2N2) versus group 2 (H3N2) influenza A subtypes predominating in the human population before versus after 1968, respectively.

Here we review the complex immuno-epidemiological interactions underpinning influenza risk assessment and extend the imprinting hypothesis to include a potential role for cross-protective neuraminidase (NA) imprinting. We compare H5N1 distributions and case fatality ratios by age and birth cohort (as proxy for HA2 and/or NA imprinting epoch) not only to H7N9 but also H5N6 and H9N2 avian influenza, representing more varied conditions of zoonotic influenza relatedness to human subtypes of the past century.

We show homosubtypic NA imprinting likely further modulates the age-related risk of zoonotic H5N1 and H9N2, with implications for pandemic risk assessment and response.

       (Continue . . . )

While it is conceivable that some degree of community immunity to the NA of H5N1 might help blunt any future impact, it is far from guaranteed. Influenza A is a notoriously mutable virus, and H5 has swapped out its NA gene repeatedly over the years.

H5N8 dominated between 2014-2020, we continue to see spillovers of H5N6 viruses to humans in China, and over the past two years we've seen an increasing number of detections of H5N5 in mammalian wildlife in Canada and Northern Europe.

Emerg. Microbes & Inf: Unique Phenomenon of H5 HPAI Virus in China: Co-circulation of Clade 2.3.4.4b H5N1 and H5N6 results in diversity of H5 Virus

Cell Reports: Multiple Transatlantic Incursions of HPAI clade 2.3.4.4b A(H5N5) Virus into North America and Spillover to Mammals

Although it also carries an N1 neuraminidase gene, the older H5N1 clade circulating in Cambodia continues to produce an impressive 30%-40% case fatality rate. Granted, its N1 is structurally different from clade 2.3.4.4b, but we've already seen them reassort.

An H5N1 pandemic is far from assured, and we could easily be blindsided by something else. Predicting the next pandemic is a mug's game.  

But the more we learn about how past exposures to flu viruses affect our immune responses, the better equipped we'll be to deal with whatever comes next. 

Where Have All The Planners Gone?

 
Credit WHO

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While we are thankfully now in an interpandemic period there are plenty of obvious (and not so obvious) zoonotic threats in the wild that could - with little or no warning - kick off the next pandemic. 

For decades the assumption had been that only influenza A viruses were capable of sparking a modern pandemic. But three brushes with coronaviruses (SARS, MERS-CoV, and COVID) over the past 2 decades have proved that pandemics can come in many flavors. 

Twenty years ago - with the rise of H5N1 in Asia and then Europe - there was a huge push for every nation, every state, and most federal and state agencies to create (and test) their pandemic plan. 

While most of these plans optimistically envisioned a repeat of the relatively mild 1968 or 1957 influenza pandemics, they at least got leaders thinking about the threat, and inspired many drills. 

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

In February of 2007, the CDC & HHS unveiled their Community Strategy for Pandemic Influenza Mitigation plan. This 108-page document covered a variety of topics, including the creation of a pandemic severity scale, and the expected role of NPI's (Non Pharmaceutical Interventions) in combating any pandemic outbreak (see The CDC Does NPI).

In 2009 an influenza pandemic finally arrived, but instead of H5N1 it turned out to be a less virulent swine-origin H1N1 virus. Deaths were far less than expected (although younger people were hit hardest), and in its aftermath many countries scaled back their pandemic planning.

The CDC/HHS updated their pandemic plans in 2017 (see CDC/HHS Community Pandemic Mitigation Plan - 2017), but around the country (and around the world), actual pandemic preparedness was largely put on a back burner.

As a result, the world was caught flat-footed and unprepared for the COVID pandemic of 2020. More than five years later, however,  we are starting to see a wave of new pandemic plans (and pandemic vaccine purchases) unveiled around the globe:

• Earlier this month Switzerland Unveils New Pandemic Plan
• Last summer both South Korea and Japan issued revised pandemic plans
• Last November Hong Kong held a Coordinated Avian Flu Drill `Amazonite'.
• Last April the ECDC published ECDC Guidance: Recommendations for Preparedness Planning for Public Health Threats,
• Over the past year, PAHO (Pan American Health Organization) has repeatedly urged its member nations to proactively prepare to deal with a potential influenza pandemic
• and recently the WHO ratified a 2025 Pandemic Agreement.

But these updated response plans remain rare, and many countries, states, and agencies are still using badly outdated plans from 2006-2007; most of which envision a mild-to-moderate influenza pandemic - and are gathering dust in some  file cabinet.

I've tried, but have failed, to find a comprehensive list of current state pandemic plans (if anyone knows of one, please let me know).  ASPR/TRACIE published a short list of plans in 2020 (n=10), many of which dated back to 2007/2008, and many of those links are now broken. 

They reported an updated Pandemic Plan from Kansas in 2020, but the link is broken, and a search (earlier today) of the Kansas DOH returns the following error:

ASPR/TRACIE included an updated 2019 Pandemic Plan for the state of Arizona, but once again the link is broken. While a search returned a relatively new (2023) Infectious Diseases of High Consequence Plan, the most recent pandemic plan I could find was dated 2011. . 

If there is a newer pandemic plan on the DOH site, it is well hidden

Illinois has a pandemic flu webpage and plan, but it hasn't been updated in more than a decade (2014).  To give you an idea of what this 125-page document is planning for, I've reproduced their assumptions below:

COVID killed nearly 5 times their maximum estimate for pandemic flu, and that is almost certainly an undercount. 

Missouri is a bit of an outlier, coming in with a newly minted (52-page) Pandemic Influenza Response Plan (2024), but it is 100% influenza-centric; COVID is never mentioned, and the word `coronavirus' only appears twice (in a list of acronyms). 

To their credit, they do suggest a CFR of `up to 2%' is possible, and warn that a vaccine will likely be unavailable in the opening months.  

I've run into multiple dead ends looking for (old or updated) state pandemic response plans, with many seemingly no longer accessible by the public. 

The CDC did post a list of National Pandemic Strategy documents in May of 2024.

Of the 8 links provide, half (n=4) are dated 2006, 1 is from 2009, while 3 others are from 2015-2020. All predate both the emergence of the new H5Nx threat and the worst of the COVID pandemic.  

Although my brief survey of state plans is far from comprehensive, and there may be plans `in the pipeline' that have yet to be released, we appear to be falling further behind in our preparedness for the next pandemic. 

Prior to 2020 table-top exercises and pandemic drills were relatively commonplace, but if they occur at all today, they do so with little or no publicity. 

Many of the CDC's pandemic guidance documents now have broken links, have been `retired', and can only be found in the https://stacks.cdc.gov/ archive. 

Ready.gov provides a rudimentary pandemic preparedness section, but the robust guidance that was once available to the public is now very hard to find, including the following 16-page Household Pandemic Planning guide, which emphasized the use of NPIs - or Non-Pharmaceutical Interventions - during a pandemic.

There is an old adage that no pandemic plan ever survives contact with the virus, and as we saw in the opening months of COVID, many countries quickly abandoned nearly all of their existing protocols. 

• China quickly went `off-book' in fighting their novel coronavirus epidemic; quarantining  hundreds of millions of people, shutting down cities, blocking roads, and essentially implementing martial law.

• While less dramatic, the responses by governments, airlines, and public health agencies outside of China have greatly exceeded what was envisioned in the WHO's NPI guidance plan. Particularly in regards to travel restrictions.

While plans may need to be adjusted to fit the next global health threat, having a practical response framework - and testing and debugging that plan - is invaluable.  It's why  firefighters. paramedics, and the military all invest so heavily in training. 

To quote President Dwight D. Eisenhower on D-Day; `Plans are worthless, but planning is everything.'

But if we don't up our game, the only thing we'll be planning for is failure. 

UK APHA: Detection of Avian H7N1 In Grey Seal

 
Credit UK APHA

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We've known for decades that marine mammals (seals, whales, sea lions, otters, etc.) are susceptible avian, and other types, of influenza viruses. The emergence and spread of HPAI H5Nx clade 2.3.4.4b around the globe has killed tens - perhaps hundreds - of thousands of pinnipeds over the past 2 years.

Preprint: Pathology of Influenza A (H5N1) Infection in Pinnipeds Reveals Novel Tissue Tropism and Vertical Transmission.

Nature Reviews: The Threat of Avian Influenza H5N1 Looms Over Global Biodiversity

But other avian viruses have been documented in marine mammals for decades. A few (of many) reports include: 

• During the winter of 1979-1980 seals were found suffering from pneumonia on the Cape Cod. In that instance, the culprit turned out to be an H7N7 influenza. (see Isolation of an influenza A virus from seals G. Lang, A. Gagnon and J. R. Geraci)
• In November of 2011 a die off of seals in New England that was eventually tied to an H3N8 avian Flu Virus. 2012's mBio: A Mammalian Adapted H3N8 In Seals, presented  evidence that this virus had recently adapted to better bind to alpha 2,6 receptor cells, the type found in the human upper respiratory tract. 

• A large outbreak was reported from northern Europe (mostly Denmark and Germany & Sweden) in 2014, when as many as 3,000 harbor seals reportedly died from avian H10N7 (see Avian H10N7 Linked To Dead European Seals), prompting warnings to the public not to touch seals.
• In 2017, during the HPAI H5N8 epizootic in Europe, that emerging subtype (clade 2.3.4.4.B) was found in Grey seals in the Baltic Sea (see EID Journal: Highly Pathogenic Avian Influenza A(H5N8) Virus in Gray Seals, Baltic Sea). 

Earlier this year the UK reported (two) outbreaks of clade 2.3.4.4b HPAI H5N5 in Grey seals (see here, and here). They reported finding the mammalian adaptive mutation PB2-E627K mutation in some of these isolates.

This amino acid substitution has been seen in other mammalian spillovers (see Cell Reports: Multiple Transatlantic Incursions of HPAI clade 2.3.4.4b A(H5N5) Virus into North America and Spillover to Mammals).

This week the UK's APHA/Defra is reporting the detection of a low-path avian H7N1 virus in a grey seal pup, which was found dead near Cornwall.  While H7 viruses have been (rarely) reported in pinnipeds, this (AFAIK) appears to be the first confirmed H7N1 virus. 

First the brief report, after which I'll have a bit more on H7 viruses. 

Note 2: findings in a grey seal in Cornwall

Sampling of a dead 8-month-old grey seal reported in Cornwall confirmed the presence of influenza A of subtype H7N1. The potential source of infection is wild birds, although very few seal sequences are available and the diversity of influenza A viruses in seals is poorly understood as is the dynamic of virus exchange between seals and birds. The cleavage site sequence indicated a motif consistent with a low pathogenicity virus if this virus had been found in poultry. However, the relevance of that cleavage site for seals is less clear.

The sequence generated from this positive seal sample included a mammalian adaptive mutation (E627K) in one gene (PB2) but this mutation has been observed in numerous positive samples from mammals detected previously both in Great Britain and globally, and in isolation isn’t considered to represent an increase in zoonotic risk. We cannot determine with certainty whether influenza A was the sole cause of death, and it is possible other factors may have contributed.

While H5 avian viruses have captured most of our attention over the past 25 years, for 5 years during the last decade China's H7N9 epidemic showed us that H7 viruses has genuine pandemic potential, producing > 1600 infections in China.

H7N9 Epidemic Waves - June 14th 2017 - Credit FAO

Other human spillovers include:

• In December of 2016, at least two veterinarians caring for sick cats at a NYC shelter were mildly infected with H7N2 (see J Infect Dis: Serological Evidence Of H7N2 Infection Among Animal Shelter Workers, NYC 2016).

• 3 mild cases were reported in Italy in 2013 (see ECDC Update & Assessment: Human Infection By Avian H7N7 In Italy).

• Mexico reported a couple of mild human H7N3 infections back in 2012 (see MMWR: Mild H7N3 Infections In Two Poultry Workers - Jalisco, Mexico), resulting in conjunctivitis without fever or respiratory symptoms.

• Twenty-two years ago (2003) world's attentions were focused on a different avian flu virus - HPAI H7N7 - which spread rapidly across hundreds of poultry farms in the Netherlands, infecting scores of farmers, and which killed a local veterinarian (see Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003).

A follow up investigation of the 2003 outbreak by the RIVM found the spread of the virus to be far greater than originally reported, suggesting as many as 1,000 human infections occurred. 

So, while H7 viruses are generally thought of as being less dangerous than H5 viruses - and primarily an agricultural concern - that reputation is not entirely warranted.

That said, the detection of H7N1 in a single seal pup in the UK is mostly likely a one-off, or incidental finding. Obviously, if more turn up, it will warrant additional scrutiny. 

But this is another reminder that much of what happens with viral evolution goes on outside of our view.  While we focus on our current  HPAI H5 threat, we could easily be blindsided by something brewing unseen out in left field. 

Which is why we need to treat pandemic preparedness as integral to our national security, not as something we hastily ramp up whenever a new threat appears. 

eBioMedicine: Susceptibility and Shedding in Mx1+ and Mx1− Female Mice Experimentally Infected with Dairy Cattle A(H5N1) Influenza Viruses

 

Balb/cj Mice - Credit Wikipedia

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In June of last year we saw - for the very first time - mice (Mus musculus aka the common house mouse) added to the USDA's list of wild mammals detected with H5N1 in the United States (see USDA Adds House Mouse To Mammals Affected by H5N1).

This was somewhat unexpected, as wild mice naturally express Mx1 - a resistance factor that significantly reduces (but doesn't entirely eliminate) their susceptibility to influenza A viruses  - which is why genetically altered Mx1- (deficient) mice are often used in influenza research.

Since then, more than 1/3rd of all H5 infected wildlife reported to the USDA (132 out of 384) have come from mice (n=124) or rats (n=8), many of which were recovered in or near infected dairy farms.  

Last September we looked at two studies which challenged previously held assumptions (see 2007's Mx1 gene protects mice against the highly lethal human H5N1 influenza virus): 

• First, in Emer. Microbe & Inf.: HPAI Virus H5N1 clade 2.3.4.4b in Wild Rats in Egypt during 2023, we a surprisingly high percentage of wild rats testing positive for H5 antibodies in Egypt.

• A second, a study in Pathogens (Susceptibility of Synanthropic Rodents to H5N1 Subtype HPAI Viruses), where researchers challenged several rodent species (house mice, brown rat, black rat) with two (older 2010, 2007) HPAI H5N1 viruses, and found they are both susceptible to the virus and could potentially play a role it its evolution and spread.

Evidence now suggests the susceptibility of Mx1+ mice to H5N1 varies depending upon the strain - and as the HPAI virus continues to adapt and evolve -  older research must be revisited. 

Today we've a new study, specifically focused on the susceptibility and shedding of Bovine (genotype B3.13) H5N1 in both Mx1+ and Mx1- laboratory mice, that finds both are susceptible to the virus, and both excrete the virus in their urine.  

It is worth noting that exposure to mouse/rat urine and/or dropping is often associated with transmission of many zoonoses, including hantaviruses, leptospirosis, Tularemia, and Lassa fever (see Viruses Review - The Hidden Threat: Rodent Borne Diseases).

While many will want to read the full open access report, I've posted the link and some excerpts below.  I'll have a bit more after the break.

Susceptibility and shedding in Mx1+ and Mx1− female mice experimentally infected with dairy cattle A(H5N1) influenza viruses

Asim Biswasa,f ∙ Amie J. Eisfelda,f ∙ Lizheng Guana ∙ Chunyang Gua ∙ Tong Wanga ∙ Hassanein H. Abozeida,e ∙ et al. Show more

Summary

Background

Clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) (HPAI H5N1) viruses have spread prolifically in dairy cattle in the US, resulting in dozens of human infections, some without well-established links to animal contacts. Many wild mammals have also been affected, including peridomestic house mice.

Methods

Here, we evaluated susceptibility, tissue tropism, and shedding in female PWK/PhJ and BALB/cJ mice, two laboratory strains derived from house mice that differ in expression of the antiviral restriction factor Mx1. PWK/PhJ mice, which were selected for their natural expression of Mx1, better reflect the antiviral capacity of most wild house mice, whereas BALB/cJ mice lack functional Mx1.

Findings

We found that, regardless of Mx1 expression status, mice are susceptible to infection by dairy cattle HPAI H5N1 viruses, that infection leads to systemic spread to non-respiratory sites, and that infected animals shed virus into the environment via urine. Shed virus remained infectious in urine for at least 24 h at room temperature.

Interpretation

These findings suggest that wild house mice could contribute to HPAI H5N1 environmental contamination and may play a role in transmission to other hosts.

Funding

This work was supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Response (contract 75N93021C00014) and by grants from the Japan Agency for Medical Research and Development (JP25wm0125002, JP253fa627001, and JP24fk0108626, to Y.K.).

Research in context

Evidence before this study

The recent outbreak of highly pathogenic avian influenza A(H5N1) (HPAI H5N1) viruses in dairy cattle has led to multiple human infections and the first reported HPAI H5N1-related death in the United States, according to the CDC. Surveillance data reported by the USDA has also identified infections in several wild mammal species, including wild house mice, which frequently live near humans and livestock. Previous studies have shown that laboratory mice lacking the influenza restriction gene Mx1 are susceptible to infection with HPAI H5N1 from dairy cattle. However, it remains unclear whether mice with a functional Mx1 gene—such as those found in wild populations—can support viral replication and shed virus in ways that might contribute to transmission risk.

Added value of this study

We demonstrate that mice naturally expressing a functional Mx1 gene are susceptible to infection with dairy cattle-derived HPAI H5N1. The virus disseminated systemically, was shed in urine, and remained infectious in urine for at least 24 h at room temperature. These findings suggest that wild mice may contribute to environmental contamination and could potentially play a role in interspecies transmission.

Implications of all the available evidence

Although the role of rodents in the spread of HPAI H5N1 is not yet fully understood, our findings provide experimental evidence that wild-derived mice expressing Mx1 can become infected, develop severe disease, and shed infectious virus. These results support the need for further investigation into the contribution of wild rodents to HPAI H5N1 transmission on farms and suggest that rodent control may be an important component of biosecurity strategies.

        (Continue . . . )

 

Surveillance for HPAI in wildlife in the United States - and the rest of the world - is mostly passive, and relies both on a combination of luck and a willingness of local authorities to report and/or test dead animals. 

The USDA map of HPAI H5 detections since early 2022 (below) suggests that some states may be looking harder than others.  Indeed, some states have yet to report a single finding. 

Admittedly, many animals die unseen in remote swamps, forests, or deserts while others may recover, escaping detection (see Emerg. Microb. & Inf.: High Number of HPAI H5 Virus Infections & Antibodies in Wild Carnivores in the Netherlands , 2020–2022). 

Even the most aggressive jurisdictions are apt to miss the vast majority of infections in the wild. We are undoubtedly only seeing the tip of the iceberg. 

We have seen a few studies where researchers have proactively sampled rodents, shrews, and voles in the wild for novel, or zoonotic, viruses. 

• In 2015's Taking HPAI To The Bank (Vole) found this European mammal was susceptible to two types of avian flu viruses (H5N1 & H7N1), most were able to carry the virus asymptomatically, shed the virus in copious amounts, and were able to pass on the virus to naïve co-housed sentinel voles.

• A 2019 study out of Boston found RT-PCR evidence of IAV (Influenza A Virus) in 11% of 163 Norway rats (Rattus norvegicus) trapped and swabbed (note: half came from paw swabs, which may indicate contamination rather than infection). 

• And just last year, in Nature: Decoding the RNA Viromes in Shrew Lungs Along the Eastern Coast of China - we looked at a study that found a wide range of zoonotic viruses - including HPAI H5N6 - in shrews.

Sadly, nearly 4 years into this North American HPAI epizootic we know surprisingly little about the ecology of H5Nx in mammalian wildlife, and whether they are capable of spreading these viruses to livestock, pets, and even humans. 

The unseen impacts of long chains of infection over time; in cattle, poultry, wild birds, and in peridomestic animals (mice, rats, cats, voles, skunks, etc.) should give us pause.

 

While most will end up evolutionary failures - like in the classic serial passage experiment shown above - something new and improved may emerge over time. 

And if we aren't actively looking, we'll never see it coming.