Eurosurveillance: Waning Humoral Immunity Following Monkeypox Virus Infection and Vaccination, Canada, 2020 to 2023

  

#19,113

Just over two years ago, in ECCMID 2024 Study: Mpox (monkeypox) Antibodies Wane Within A Year of Vaccination, we looked at a study by researchers from Erasmus MC in Rotterdam that found:

. . . recipients of the 2-Dose JYNNEOS/ IMVANEX/ IMVAMUNE mpox vaccine who did not receive a childhood smallpox vaccination (discontinued in the 1970s) experienced substantial drops in their immune response after 12 months.

Another presentation, released at roughly the same time from Sweden (see Immune response to MPXV wanes rapidly after intradermal vaccination with MVA-BN (Jynneos)) found an even quicker loss (> 28 days) of detectable neutralizing antibodies after the second vaccination, writing:

Our findings corroborate previous data showing that intradermal MVA-BN vaccination results in neutralizing antibodies only in a proportion of vaccinees, and that a significant decline occurs already during the first months post-vaccination. Immunity after MPXV infection mounts a higher and more robust neutralizing response. In conclusion, the findings merits the study of booster doses.

Which was followed roughly 6 months later by an EID Journal Dispatch: Mpox Epidemiology and Vaccine Effectiveness, England, 2023, which found that nearly half of new community acquired mpox cases in 2023 were among vaccinated individuals. They note:

Nearly half of outbreak case-patients in 2023 were vaccinated, and there were more cases among those who had received 2 doses of MVA-BN vaccine than among those who had received 1 dose.

This unexpected result, they suspected, may have had more to do with the risk behavior of some who may feel `protected' by two-doses of the vaccine, than the vaccine itself.

To be fair, it was never expected that the JYNNEOS vaccine would be 100% effective against Mpox, or that it would convey life-long immunity. The authors also revealed  `. . . that no vaccinated persons had been hospitalized for mpox in 2023, indicating that the MVA-BN vaccine probably protects against severe disease requiring hospitalization.'

Since then we've revisited this story several times, including Preprint: The Two-dose MVA-BN Mpox Vaccine Induces a Nondurable and Low Avidity MPXV-specific Antibody Response  and  Preprint: A three-dose MVA-BN Mpox Vaccination Series Improves the Quality of Anti-monkeypox Virus Immunity. 

During this time we've also seen the emergence of new Mpox clades, including clade 1b and a new recombinant clade. While not currently deemed a PHEIC (Public Health Emergency of International Concern) by the WHO, these pox viruses continue to make inroads around the globe.

All of which brings us to a new Eurosurveillance research study, published yesterday, which finds additional evidence of declining protection over time from both Mpox Infection, and the MVA-BN (Jynneos) vaccine. 

This is quite a lengthy and detailed report, so I've just provided the link, summary, and concluding remarks below.  I'll have more after the break.

Waning humoral immunity following monkeypox virus infection and vaccination, Canada, 2020 to 2023
Jérémie Prévost1 , Sarah J Medina1 , Ana Citlali Márquez2,3 , Kristina Dimitrova1 , Tahereh Valadbeigy2 , Gabrielle Angelo P Cortez2 , Mruthula Narayan2 , William C Carson4 , Michael B Townsend4 , Agatha N Jassem2,3 , David Safronetz1,5

Key public health message

What did you want to address in this study and why?

Monkeypox virus (MPXV) is an emerging pathogen responsible for the mpox disease, which has spread to over 100 countries in 2022, causing more than 130,000 infections It has been suggested that MPXV (re)infections that occur after vaccination or previous MPXV infections have to do with immunity decreasing over time. We therefore wanted to investigate the durability of immune response to MPXV infection and vaccination.

What have we learnt from this study?

We developed specific and sensitive assays to track immunity to MPXV infection and vaccination. We showed that individuals infected with MPXV display a strong initial antibody response within the first 2 months after infection, but those antibodies decrease over the following 5 months. A similar decline occurred after mpox vaccination, where the antibodies reached low to undetectable levels after 30 months.

What are the implications of your findings for public health?

Decreasing immunity in both MPXV-infected and vaccinated populations suggests that vaccine booster doses may be necessary to maintain antibody levels and protection, in order to reduce the possibility of MPXV reinfections or vaccine breakthrough infections. Future studies need to assess immunity and long-term protection in individuals receiving booster doses of the MVA-BN vaccine compared with the standard two-dose regimen.

        (SNIP)

Conclusion

This study provides a characterisation of the magnitude and durability of MPXV-specific humoral immunity following natural infection and MVA-BN vaccination. Our findings show that both infection- and vaccine-induced antibodies decline over time.

This raises important considerations for long-term vaccine protection, the potential need for booster immunisations, and the risk of reinfection. Moreover, the development and validation of highly specific MPXV serological assays using discriminating antigens offer valuable tools for future serosurveillance studies.

        (Continue . . . .)


Complicating matters is the fact that the global supply of the JYNNEOS (MVA-BN) vaccine remains limited. Thus far, public health entities like the CDC, WHO, ECDC, etc. have not endorsed booster shots (with a few exceptions).

The following screenshot (4/10/26) from the CDC website illustrates the CDC's current position. 

While it would appear that there is some distance between the CDC's position, and these recent studies, the CDC states they are continuing to analyze the data. 

Since the eradication of smallpox in the 1970s, there has been a growing belief that poxviruses are a thing of the past; a near-forgotten relic of the 20th century.

But a 2020 report in the Bulletin of the World Health Organization warned that our waning immunity to smallpox puts society at increasing risk of seeing new poxvirus epidemics (see WHO: Modelling Human-to-Human Transmission of Monkeypox). 

The emergence and international spread of 2 new Mpox clades (Ib & IIb) since 2020 - and a new recombinant recently reported in Asia - serve to reinforce that warning. 

And while Mpox is currently at the top of our watch-list, some of the other emerging poxviruses we've looked at in recent years include:

Alaska Health Department Announces A Fatal Alaskapox Infection

A Newly Discovered Poxvirus Detected In Reindeer in Sweden & Norway

EID Journal: Novel Poxvirus in Proliferative Lesions of Wild Rodents in East-Central Texas, USA

A Novel Zoonotic Orthopoxvirus Resurfaces In Alaska

All of which makes it vital to understand just how protective, and long-lasting, our current vaccine options are against these types of viruses.  

Preprint: Using an Evolutionary Epidemiological Model of Pandemics to Estimate the Infection Fatality Ratio for Humans Infected with Avian Influenza Viruses

Credit CDC

#19,112

The assumption is - for practically every infectious disease - that official case counts are significant undercounts; aka `the tip of the pyramid'.  Many cases are mild, asymptomatic - or are misdiagnosed - or occur in medically underserved populations and are therefore never reported.

Over the years we've looked at a number of studies which have attempted to quantify these surveillance/reporting gaps, including:

• Last November's JAMA Open: Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic Testing and  2024's MMWR: Serologic Evidence of Recent Infection with HPAI A(H5) Virus Among Dairy Workers, 

• Both EID Journal: Estimation of Severe MERS Cases in the Middle East, 2012–2016 and Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study by Drosten & Memish et al., suggest that far more MERS-CoV cases have occurred than have been reported.

• CID Journal: Estimates Of Human Infection From H3N2v (Jul 2011-Apr 2012) which suggested that the number confirmed infections was 1 out of 200 community cases. 

• A 2014 seroprevalence study found antibodies against H9N2 ranged from 5.9% to 7.5% among poultry exposed individuals in Egypt, while a 2016 PLoS One study found a seroprevalence in Southern China ranging from 1.37% to 3.42%.

So it seems highly probable that novel avian flu virus spillovers into humans are far more common than official numbers would suggest.  How much higher?  Well, that probably varies considerably over time, and location. 

Today we've a preprint which endeavors to model the number of avian flu infections globally each year, its IFR (Infection Fatality Rate), and how pandemic risks might be lowered through spillover prevention. 

The late George E. P. Box (18 October 1919 – 28 March 2013) - Professor Emeritus of Statistics at the University of Wisconsin - is often credited with coining the familiar adage:

“All models are wrong, but some models are useful.”

With that caveat, the authors - using both recent and historical data - estimate that thousands of unreported avian flu infections occur each year, and that if 20% of those could be prevented, it might delay the next pandemic by nearly a decade.

The authors write:

We estimate that, on average, there are 6,441 annual human infections with AIV worldwide, which is much higher than the 986 human cases reported to date and suggests that many infections are undetected and could be because some humans infected with AIV are asymptomatic or symptomatic but not tested. 

Based on our estimate of  annual AIV infections and the assumption that all AIV deaths in humans are reported, the IFR of 32 deaths per 10,000 infections is much lower than the reported case fatality rate of 48%

It is obviously impossible to account for all of the variables in our chaotic environment, and so to make a model work, certain assumptions must be made.

As an example, the authors used an average of 38 years between pandemics, based on the last 7 zoonotic pandemics going back 245 years (1781–2026). But the gap between the last 2 pandemics was 11 years, and many studies suggest that the frequency and severity of pandemics is rising. 

Since my grasp of statistics is roughly equivalent to the guy who drowned trying to cross a stream that was - on average - 3 feet deep, I'll forego any further comments on the methods or assumptions used,  and simply invite you to read the report in its entirety.

I'll have a bit more after you return.  

Using an evolutionary epidemiological model of pandemics to estimate the infection fatality ratio for humans infected with avian influenza viruses
Joshua Mack,  Michael Li,  Amy Hurford
doi: https://doi.org/10.64898/2026.01.21.26344526

        PDF 

Abstract

The risk of highly pathogenic avian influenza virus infection to humans is challenging to estimate as many human avian influenza virus (AIV) infections are undetected because infections may be asymptomatic, symptomatic but not tested, and difficult to identify through contact tracing, as human-to-human transmission is rare.

We derive equations that consider the evolutionary mechanisms that give rise to pandemics and are parameterized to be consistent with records of past pandemics. We estimate that thousands of human AIV infections occur worldwide in an average year and estimate the infection fatality ratio as 32 deaths per 10,000 infections (95% confidence interval: [9.6, 75]). This estimate is comparable to SARS-CoV-2 during the recent pandemic and higher than seasonal human influenza.

We estimate that preventing animal-to-human influenza spillovers would delay pandemic emergence by several years. Preventing human infections with AIV is necessary given the high risk of severe outcomes to individuals and to reduce the risk of pandemics occurring in the future.

        (SNIP) 

Efforts to prevent human infections with non-pandemic capable genotypes of HPAI virus are necessary given the high individual risk of severe outcomes (as measured by the IFR), but also to lower the risk of a pandemic emerging in any given year.

We estimate that preventing 20% of animal-to-human AIV spillovers annually would delay pandemic emergence by an average of 9.4 years and preventing 50% of spillovers would delay pandemic emergence by 37.5 years.

 Measures that prevent the spillover of HPAI virus to humans include not touching, feeding or handling potentially infected birds or other animals, when contact cannot be avoided wearing gloves and a well-fitted respirator or medical mask, reporting infected animals to the appropriate animal health authority [7], the humane destruction of infected and exposed animals, and strict quarantine and animal movement controls to prevent disease spread [10]. 

       (Continue . . . )

Regardless of the actual numbers, this study suggests that thousands of undetected bird flu infections happen every year, with a significant risk of death. With each infection also comes a small chance for the virus to mutate into a human-adapted pathogen, capable of sparking a pandemic. 

Farm workers, vets, hunters, poultry and other livestock handlers, and animal rescue personnel are at particularly high risk of exposure, and their use of proper PPEs (gloves, masks, etc.) and following other biosecurity measures could help lower those risks. 

 

Protect Yourself From H5N1 When

Working With Farm Animals [2 MB, 1 page]

Whether we can get those at highest risk to actually take those preventative steps remains to be seen. 

Taiwan CDC: Letter To Doctors on Locally Acquired H7N7 Case

 

#19,111 

Six days ago, in Taiwan CDC: Human Infection with a Novel H7 Avian Virus, we saw the first locally acquired human H7 influenza infection in Taiwan. The following day, that virus was further identified as H7N7.

While this appears to be an isolated incident, cases like this may happen more often than we are aware simply because the index of suspicion is generally low, infections can be mild or moderate, and most testing outside of the hospital doesn't identify the subtype. 

It often requires a bit of luck for these cases to be identified. Two years ago the ECDC issued guidance for member nations on Enhanced Influenza Surveillance to Detect Avian Influenza Virus Infections in the EU/EEA During the Inter-Seasonal Period.

In that summary, the ECDC pointed out:

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

While there's no quick fix for this problem, a reminder to doctors to be vigilant and to raise their index of suspicion when examining patients with acute respiratory symptoms, can increase the odds of detection. 

Today, in their first update on this case since last Friday, Taiwan's CDC has released the following (translated) letter to local doctors.  

I'll have a bit more after the break.

The Centers for Disease Control (CDC) has confirmed its first locally acquired case of H7N7 influenza A 

Doctors are urged to be vigilant and immediately report and test any suspected cases (CDC Circular No. 605 to the Medical Profession).
Release Date: 2026-04-08

Dear medical professionals nationwide,

the Centers for Disease Control (CDC) announced its first locally acquired case of H7N7 influenza A on April 3rd of this year (2023). The case involves a man in his 70s who works in poultry farming and has a history of chronic illness. He developed symptoms of runny nose, cough, and body aches on March 20th and sought medical attention at a hospital on March 22nd due to fever, where he was admitted to the hospital on the same day. Imaging examination revealed pneumonia.

Based on the clinical symptoms and the patient's contact history, the doctor reported the case as a novel influenza A virus and administered antiviral medication. Further testing by the CDC confirmed the patient's sample as H7N7 influenza A virus, a low pathogenic avian influenza virus (LPAI), which remained sensitive to antiviral drugs. The patient's condition improved, and two subsequent tests were negative. He was released from isolation on April 3rd of this year.

To prevent the spread of novel influenza A, physicians are urged to remain vigilant and conduct thorough "TOCC" inquiries during consultations (including travel history, occupation, contact history, and whether there has been any clustering).

If a case simultaneously presents with both "acute respiratory infection, with clinical symptoms possibly including fever (≥38℃), cough, etc." and "clinical, radiological, or pathological findings showing parenchymal lung disease," and has had close contact with a highly probable or confirmed case with symptoms within 10 days prior to symptom onset, has a travel or residence history in areas with novel influenza A outbreaks, or has had exposure to birds or pigs or visited bird or pig-related locations, then the case meets the reporting criteria for novel influenza A.

Reporting and specimen collection should be conducted as soon as possible according to the "Novel Influenza A Reporting Definition and Specimen Collection and Submission Procedures." Guidelines regarding the definition of novel influenza A cases and prevention measures are available on the Centers for Disease Control and Prevention website (http://www.cdc.gov.tw).

Thank you for joining us in protecting the health and safety of the public.

While perfectly reasonable given the current threat level - and the practical limitations of subtype testing in an outpatient clinical setting - this level of surveillance has a fairly low probability of picking up sporadic mild (or even moderate) novel flu cases in the community. 

Three years ago, in UK Novel Flu Surveillance: Quantifying TTD, we looked at the UKHSA's Technical Briefing #3, which found that it might take weeks - and hundreds of cases - before community spread of a novel flu could be confirmed using standard surveillance.

This is their `best case' R₀ 1.2 scenario

In response to the recent rise in spillovers of novel influenza A to humans, we've seen documents issued by the CDC (see CDC HAN: Accelerated Subtyping of Influenza A in Hospitalized Patients) and the ECDC (see ECDC: Updated Reporting Protocol for Zoonotic Influenza Virus) urging more aggressive testing; although these represent advisory - not regulatory - guidance.

Again last fall, in NAS : Diagnostic Tools, Gaps, and Collaborative Pathways in Human H5N1 Detection (Rapid Expert Consultation), we looked at many of the challenges inherent in detecting community cases of novel influenza. 

While it is certainly worth looking for, the reality is we'll have to get very lucky if we hope to detect the early spread of a novel flu virus in the community. 

Preprint: Bovine H5N1 Influenza Viruses Have Adapted to More Efficiently Use Receptors Abundant in Cattle

 

Positively selected mutations in the cattle H5N1 head domain
are reaching fixation as the virus continues to circulate.

#19,110

We've a fascinating, albeit somewhat technical preprint this morning, which identifies two HA mutations (D104G & V147M) that have become `fixed' and dominant in B3.13 H5N1 isolates (see graphic above) in the two years since the first spillover into Texas cattle. 

While these mutations (and others) have been previously elucidated (see Emergence of Antigenic Variants in Bovine H5N1 Influenza Viruses), today's paper links these changes to the virus's successful use of a different type of receptor cell (NeuGc); one that is not found in humans or birds, but is present in cattle and some other mammals. 

The authors write: 

Whilst humans and birds contain only a single type of sialic acid, N-acetylneuraminic acid (NeuAc), that is usable by influenza viruses 8-10, many mammalian species contain a second type of sialic acid, N-glycolylneuraminic acid (NeuGc). 

       (Snip) 

In several other influenza host species, such as pigs 14,15 and horses 16, high expression of CMAH in tissues results in the display of NeuGc on glycans.   

Most influenza viruses preferentially bind to sialylated glycans terminating in NeuAc, and, at best poorly use NeuGc-containing glycans as a receptor 17. However, a now extinct equine H7N7 virus showed a strong preference towards NeuGc 17,18.79 

While the B3.13 genotype still retains its strong affinity for NeuAc‑type (avian‑like α2,3‑linked sialic acid) receptors, it has found an alternative sialic acid in cattle it can bind to (NeuGc). 

Interestingly, these changes have not been observed in the D1.1 genotypes detected in cattle (see USDA APHIS Reports Wisconsin Dairy Herd Infected With Genotype D1.1). 

Today's study has an impressive pedigree, featuring such familiar names as Thomas Peacock, Wendy Barclay, and Ian H Brown.  I've only reproduced the abstract and a brief excerpt, so follow the link to read it in its entirety.

I'll have a bit more after the break.

Bovine H5N1 influenza viruses have adapted to more efficiently use receptors abundant in cattle
Jack A. Hassard,Jiayun Yang,Bernadeta Dadonaite, Jonathan E. Pekar, Jin Yu, Samuel A. S. Richardson, Rute M. Pinto, Kristel Ramirez Valdez, Philippe Lemey, Jessica L Quantrill, Jinghan Xue, Tereza Masonou, Katie-Marie Case, Jila Ajeian, Maximillian N.J. Woodall, Rebecca A. Ross, Nicolas Hudson, Kan Zhong, Hongzhi Cao, Samuel Jones, Hannah J. Klim, Brian R. Wasik, Desi N Dermawan, Jean-Remy Sadeyen, Dirk Werling,Dylan Yaffy, Joe James, Alessandro Nunez, Paul Digard, Ian H Brown, Daniel H. Goldhill, Pablo R. Murcia,Claire M. Smith, Yan Liu, Jesse D. Bloom, Munir Iqbal,Wendy S. Barclay, Stuart M. Haslam, Thomas P. Peacock

doi: https://doi.org/10.64898/2026.04.02.715584
This article is a preprint and has not been certified by peer review [what does this mean?].

Preview PDF

Abstract

Sustained mammal-to-mammal transmission of high pathogenicity H5N1avian influenza viruses is reshaping the host range of these pathogens. One of the longest-running mammalian transmission chains involves the B3.13 genotype circulating in U.S. dairy cattle which was detected early in 2024. Genomic analysis revealed selection and rapid fixation of haemagglutinin mutations D104G and V147M. 

We demonstrate, via glycomic profiling, that bovine tissues, including the mammary gland, are enriched in N- and O-linked glycans capped with N-glycolylneuraminic acid (NeuGc), a sialic acid absent in humans and birds, which instead express only N-acetylneuraminic acid (NeuAc). 

Early cattle H5 viruses poorly recognized NeuGc, but D104G and V147M enabled efficient engagement of both NeuAc- and NeuGc-containing receptors. 

These mutations enhanced replication in bovine mammary tissue without major attenuation of replication in human lung and primary nasal epithelial cells. NeuGc-driven receptor adaptation therefore promotes viral fitness in cattle while potentially limiting immediate zoonotic risk. Deep mutational scanning further identifies alternative haemagglutinin substitutions that confer NeuGc usage and represent surveillance markers for emerging cattle H5 lineages.

       (SNIP) 

Together, these findings suggest that host-specific modifications of sialic acids can act as powerful evolutionary filters shaping influenza receptor usage during mammalian emergence. Incorporating this broader glycan diversity into surveillance frameworks may therefore improve our ability to anticipate host shifts and assess zoonotic risk as influenza viruses continue to expand into new mammalian reservoirs. 

       (Continue . . . )

While the long-term impact all of this is difficult to predict, the glass-half-full interpretation is; the B3.13 lineage is currently adapting more towards bovine than human hosts.

So far, however, these mutations have only widened the ways that cattle can be infected, and haven't substantially reduced binding to NeuAc-containing receptors.  

The most remarkable thing is how quickly B3.13 has developed NeuGc compatible mutations and has turned them into a fitness advantage. We are witnessing active and robust viral adaptation in cattle, not just passive spillover from birds.

Yet surveillance and testing of livestock remains suboptimal, and in some regions, non-existent. 

While ignorance may be bliss in the short run, it can prove costly over time (see WPRO Table-Top Exercise Crystal: A `Bovine' Novel Flu Outbreak Scenario). 

The Lancet: Long COVID and Risk of Incident Cardiovascular Disease

Atrial Fibrillation 

#19,109

During the opening salvo of the COVID pandemic we saw an abrupt increase in out-of-hospital cardiac arrests; in early April 2020, the New York Fire Department reported a 400% increase in sudden cardiac arrest deaths (see NBC affiliate Massive Spike in NYC ‘Cardiac Arrest’ Deaths Seen as Sign of COVID-19 Under counting).

While most of these cases were never tested for COVID-19, this trend became so pronounced that the city ordered new Standards Of Care During A Pandemic: CPR & Cardiac Arrest, limiting the use of CPR in the field. 

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

By mid-summer of that year, it was apparent that COVID was more than just a respiratory virus (see Nature Med. Review: Extrapulmonary manifestations of COVID-19), and can cause blot clots, along with severe cardiovascular damage. 

That first summer 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:

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

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

While `Long COVID' and PASC (Postacute Sequelae of COVID) are now officially recognized conditions, researchers are still unravelling their impact.

Today we've a study from Sweden's Karolinska Institutet  which links `Long COVID' to new or emerging (incident) cardiovascular disease.

First the study, then a link and some excerpts from a press release, after which I'll return with a postscript.

Long COVID and risk of incident cardiovascular disease: a prospective cohort study using the Multimorbidity Integrated Registry Across Care Levels in Stockholm (MIRACLE-S) cohort

Pia Lindberga,b Pia.lindberg@ki.se ∙ Samuel Wiqvistg ∙ Maria Juszczykc,h ∙ Seika Leed ∙ Marta A. Kisield ∙ Caroline Wachtlere,f ∙ et al.  

Summary

Background

Long COVID has emerged as a global health challenge, with increasing evidence of cardiovascular sequelae. Most previous studies have focused on hospitalised cohorts, whereas cardiovascular risk in community-managed long COVID cases remains less explored. We aimed to investigate the incidence of major cardiovascular events in individuals with long COVID compared to those without long COVID in a large population-based setting.

Methods

Multimorbidity Integrated Registry Across Care Levels in Stockholm (MIRACLE-S) is a population-based cohort that covers all providers of healthcare for around 2.5 million residents in Stockholm County. Individuals aged 18–65 years with a physician-assigned long COVID diagnosis (ICD-10: U09.9) between October 2020 and January 2025 were identified. Exclusion criteria were hospitalisation for acute COVID-19 or pre-existing cardiovascular disease. Cox proportional hazards models estimated the effect of long COVID on a composite cardiovascular outcome (myocardial infarction, heart failure, cardiac arrhythmias, stroke, peripheral arterial disease), adjusting for demographic, lifestyle, and mental health factors.

Findings

Among 1,217,693 individuals, 8999 (0.7%) had long COVID diagnosis (66% women). Cumulative incidence of any cardiovascular event was higher in long COVID group (women 18.2%, men 20.6%) compared with control group (women 8.4%, men 11.1%). In a fully adjusted model, long COVID was associated with the composite cardiovascular outcome (women HR 2.06, 95% CI 1.92–2.22; men HR 1.33, 1.20–1.48), cardiac arrhythmia (women HR 3.11, 2.85–3.39; men HR 1.61, 1.41–1.85), and coronary artery disease (women HR 1.25, 1.04–1.52; men HR 1.26, 1.05–1.51). Heart failure incidence was elevated in women only (HR 1.25, 1.00–1.55), as also was peripheral artery disease (HR 1.25, 1.05–1.50). Long COVID was not associated with stroke in either sex.

Interpretation

Long COVID is associated with increased risk of incident cardiovascular disease, particularly cardiac arrhythmias, heart failure, and coronary artery disease. These findings underscore the need for systematic follow-up and integration of long COVID into cardiovascular risk assessment.

        (SNIP)

Discussion

This population-based cohort study demonstrates that individuals who developed long COVID after mild-to-moderate infection have an elevated risk of future cardiovascular disease analysed as a composite outcome. In particular, cardiac arrhythmias demonstrated markedly increased incidence in women with long COVID, although both sexes were affected. Risk of coronary artery disease was also elevated and in women and men, while heart failure and periphery artery disease were significant in woman patients with long COVID only. 

These findings are consistent with previous studies showing increased risk of cardiovascular sequelae in long COVID-19, including studies in non-hospitalised populations.2,4,17 The magnitude of excess risk for arrhythmias (HR ∼3.1 in women; HR ∼1.6 in men) is in agreement with earlier epidemiological and clinical research.3,7,18

These findings suggest an elevated burden of cardiovascular morbidity in individuals with long COVID, even in the absence of acute infection requiring hospitalisation.

        (Continue . . . )

 

Long COVID associated with increased risk of cardiovascular disease

People with long COVID are at increased risk of developing cardiovascular disease, according to a new study from Karolinska Institutet published in eClinicalMedicine. The results show that the risk of conditions such as cardiac arrhythmias and coronary artery disease is higher even among those who were not hospitalised during the acute infection.

(SNIP)

 During the follow-up period of around four years, people with long COVID were more likely to suffer from cardiovascular disease: 18.2 per cent of women and 20.6 per cent of men experienced some form of cardiovascular event, compared with 8.4 per cent of women and 11.1 per cent of men in the group without long COVID.

When the researchers then adjusted the results for factors such as age, socio-economic status and other known risk factors, the differences remained. Women with long COVID had just over twice the risk of receiving a cardiovascular diagnosis compared with women without long COVID. Men had approximately a third higher risk.

“We found that cardiac arrhythmias and coronary artery disease were more common among both women and men with long COVID. In women, there was also an increased risk of heart failure and peripheral vascular disease.

(Continue . . . )

Despite the preponderance of evidence enumerating the long-term negative health consequences of SARS-CoV-2 infection, much of the world now considers COVID be no worse than the catching `common cold', and that the real health risk lies in taking the vaccine.

As a result, uptake of the vaccine has plummeted, and few bother to take any precautions against infection. 

A recent study (see PLoS Med.: Association Between COVID-19 Vaccination and Sudden Death in Apparently Healthy Younger Individuals) found no evidence that COVID-19 vaccines increase the risk of sudden cardiac death in young healthy adults, but they did find a strong link between recent COVID infection and an increased risk of sudden cardiac death.  

But since they don't reflect popular opinion, these types of studies tend to be ignored by the media, and by the general public.

Emerg Microbes & Inf: Antiviral Activities of Multiple Antivirals Against HPAI H5N1 in Vitro and in Mice

CDC Influenza Antiviral Medications: Summary for Clinicians - Jan 2026

#19,108

For Americans (and indeed, for much of the world), our first line antiviral against severe influenza is oseltamivir (aka `Tamiflu'), an antiviral which was developed in the late 1990s.

There are other options (e.g. inhaled zanamivir, or 1-dose oral baloxavir, etc.), but they are not only more expensive, they are in far shorter supply. While the U.S. government doesn't release exact numbers, oseltamivir reportedly makes up well over 90% of all (SNS) stockpiled influenza antivirals.

None of these drugs are a panacea against influenza infection, but they are expected to reduce the severity and duration of infection; assuming they can be delivered to the patient in the first 24-48 hrs of infection.

How well they might work against a pandemic avian flu strain, like H5N1, isn't really known, particularly the standard 5-day (B.I.D) treatment course of oseltamivir or the 1-dose treatment with Baloxavir.  

We've seen concerns raised over the effectiveness of oseltamivir, including a year ago in St. Jude Researchers: Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk; excerpt below:

Our evidence suggests that it is likely going to be hard to treat people severely infected with this bovine H5N1 bird flu strain,” said corresponding author Richard Webby, PhD, St. Jude Department of Host-Microbe Interactions. “Instead, reducing infection risk by not drinking raw milk and reducing dairy farm workers’ exposures, for example, may be the most effective interventions.”

“In general, baloxavir [Xofluza] caused a greater reduction in viral levels than oseltamivir [Tamiflu], but neither was always effective,” said first author Jeremy Jones, PhD, St. Jude Department of Host-Microbe Interactions.

Last January, in Nature Comms: Oseltamivir and Baloxavir Monotherapy and Combination Therapy Efficacy Against Clade 2.3.4.4b A(H5N1) Influenza Virus Infection in Ferrets, we saw a CDC study which looked at both mono and combination therapy with oseltamivir and baloxavir in ferrets infected with H5N1 (genotype D1.1).

In short, they found:

• Ferrets infected with H5N1 D1.1 and treated with oseltamivir saw little or no clinical or virologic benefit compared to no treatment, with persistent high fevers, weight loss, and systemic viral replication.
• Ferrets treated with Baloxavir saw significantly less fever, weight loss, and viral replication. Some ferrets, however, saw a late rise in fever (after 4 days) and viral shedding, suggesting a viral rebound. 
• Ferrets treated with both drugs saw similar clinical protection to baloxavir alone, but did not show signs of rebound. 

Note: Ferrets are a good, but not perfect, proxy for humans in influenza research, so these results may not be 100% applicable to humans.  

A month later, we looked at a study (Nature Comms: Baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating lethal influenza A(H5N1) HA clade 2.3.4.4b infection in mice) by Webby & Jones et al. which suggests that baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating clade 2.3.4.4b (circa 2022) H5N1 avian viruses (in mice).

 

All of which brings us to a new study which raises additional doubts on the effectiveness of oseltamivir monotherapy against HPAI H5.

This is a lengthy, and technically dense, study. While many will want to read it in its entirety, the bottom line is that the existing 5-day course of oseltamivir appears inadequate to treat severe HPAI H5N1 infection (at least, in mice). 

The author report Baloxavir as being more potent, but even a 5-day B.I.D course (10 times the current dose) only saved 16.7% of treated mice.  Extending treatment to 7 days (14 doses), raised survival to 50%. 

While a 7-day course of Baloxavir (BMX) was strongest single-drug therapy, extended courses of MNP+BXM and OSP+BXM provided the most effective treatments.

Before everyone freaks out, due to their higher metabolic rate, the half-life of baloxavir is much shorter in mice than in humans. While it remains to be determined, an equivalent dose in humans might be more like 2 or 3 doses spread out over a week's time. 

First the link, abstract, and a brief excerpt. I'll have a bit more after the break.

Antiviral activities of multiple antivirals against highly pathogenic avian influenza A H5N1 in vitro and in mice

Danlei Liu ,Yujing Fan,Ka-Yi Leung,Ruiqi Zhang,Hoi-Yan Lam,Xiaochun Xie,Honglin ChenORCID Icon,Kwok-Hung Chan &Ivan Fan-Ngai Hung 

Article: 2645843 | Received 28 Jul 2025, Accepted 12 Mar 2026, Published online: 31 Mar 2026

https://doi.org/10.1080/22221751.2026.2645843 

ABSTRACT

In 2024, a bovine H5N1 strain was first isolated from dairy cows in Texas and confirmed to transmit cross-species to humans. Therefore, research on treatments for human infection should be accelerated.

In our study, the antiviral effects of baloxavir acid (BXA), oseltamivir carboxylate (OSC), EIDD-1931 (NHC), and ribavirin (RBV) against five H5N1 strains were evaluated in vitro. 

Cell viability and viral replication were measured to assess the antiviral effects. The results showed that the EC50 of BXA treatment was the lowest. The BXA/NHC and BXA/OSC combination treatments showed more potent inhibitory effects than each monotherapy. The 15 mg/kg baloxavir marboxil (BXM) / 125 mg/kg molnupiravir (MNP) and the 15 mg/kg BXM / 10 mg/kg oseltamivir phosphate (OSP) were tested in BALB/c mice. 

The mice were inoculated with 10 times the 50% mouse lethal dose (10 MLD50) of bovine H5N1 virus. Treatments began 1-day post-infection (1 dpi) and were administered orally twice daily for 5 or 7 days. Changes in body weight, clinical signs, and survival were monitored; lung and brain tissues were collected for virological, immunological, and histological analyses. Most mice died from severe neurological symptoms. 

Compared with the 5-day treatment, the 7-day treatment effectively inhibited viral replication and increased survival rates to 50% in BXM, BXM/MNP, and BXM/OSP treatments. Mice treated with BXM/MNP or BXM/OSP combination therapy showed lower viral yields in the lungs than those treated with BXM alone. The results provide a reference for human treatment, and extending the 7-day combination treatment should be considered.

        (SNIP)

In summary, BXA, NHC, OSC, and RBV can significantly inhibit the replication of various H5N1 viruses in vitro. The combination treatments of NHC/BXA and OSC/BXA showed stronger antiviral effects. In mice, the 7-day BXM, MNP/BXM, and OSP/BXM treatments significantly increased survival rates.

Combination treatments significantly suppressed the viral replication in both the lungs and brains of mice. Therefore, extended BXM-based combination therapies could be considered as a first-line treatment for humans. The results provided a reference for clinical treatment.

        (Continue . . . )

 

Over the past couple of years we've seen increased calls for a shift in pandemic antiviral strategy towards Baloxavir (or combination therapy), but most countries have invested heavily in oseltamivir, making any change likely slow in coming.

Baloxavir is made only by Roche/Shionogi plants, while oseltamivir is now a generic drug manufactured around the world. The global supply of oseltamivir is probably 50 times greater than baloxavir, while the cost is roughly 1/10th.

The reality is, even oseltamivir will be hard to get - at least during the first critical first 24-48 hrs of infection - during a severe global influenza pandemic. It seems likely that `extended'  baloxavir or combination therapy will be limited to hospitalized patients with severe disease. 

Given our limited supply of antivirals and an expected wait of least 6 months before having any large quantities of vaccine, we will once again have to rely heavily on preventing infection; wearing face masks, hand washing, improved indoor ventilation, staying home while sick, and avoiding crowds.

Which is why I've already got my supply of masks, hand sanitizer, and OTC meds in the hall closet, and have stayed current with all of my vaccines.

If you aren't similarly prepared, you may want to revisit:

#Natlprep 2025: Personal Pandemic Preparedness