Front. Immunology: Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development

 

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While the world continues to treat COVID as if it is now a mild illness, over the past 6 years we've seen compelling evidence that repeated COVID infections can seriously affect one's health (see Nature: Acute and Postacute Sequelae Associated with SARS-CoV-2 Reinfection), along with a long litany of post-COVID sequelae. 

A few (of many) recent studies include:

Nature Comms: The Risk of Kidney Disease Increases Following SARS-CoV-2 Infection Compared to influenza

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

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

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

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

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

It may take years to fully parse out the long-term health impacts of COVID on society, but some researchers have expressed concerns over increased lung cancer risks due to SARS-CoV-2 infection (see 2022's SARS-CoV-2 and probable lung cancer risk). 

While it wasn't limited to COVID, last year in Nature: Respiratory Viral Infections Awaken Metastatic Breast Cancer Cells in Lungs, we saw a study in mice that demonstrate that common respiratory viruses may awaken dormant cancer cells.  The authors wrote:

Studies have shown that cancer metastasis can be triggered by inflammation. Infection by respiratory viruses, such as influenza and SARS-CoV-2, often causes inflammation. 

Last last year, Molecular Aspects of Medicine published The double-edged sword: How SARS-CoV-2 might fuel lung cancer, which suggested that Post-COVID-19 pulmonary fibrosis could be a precursor to lung cancer.

While we aren't at the point where we can say with any certainty that COVID infection causes cancer, researchers continue to find plausible reasons why it may create conditions that exacerbate the risks. 

Which brings us to a new study, which also suggests a potential link between COVID infection and an increased risk of lung cancer. First the Abstract, followed by some excerpts from a press release. 

Thymidine phosphorylase promotes SARS-CoV-2 spike protein-driven lung tumor development

Cayleigh Wallace 1†, Alex Gileles-Hillel 2†, Amelia Cox 1,,David Gozal 1,3, , Wei Li 1*, Hong Yue 1*

Abstract

Background:

COVID-19 survivors exhibit increased interstitial lung fibrosis, a known risk factor for lung cancer. We investigated whether SARS-CoV-2 spike protein (SP)-induced lung injury and elevated thymidine phosphorylase (TYMP) promote lung tumorigenesis.

Methods:

A TriNetX retrospective cohort analysis was combined with mechanistic studies in K18-hACE2TG and K18-hACE2TG/Tymp–/– mice. Mice received intratracheal SP or control lysate followed by a urethane-induced lung cancer protocol. Lung injury, inflammation, thrombosis, fibrosis, STAT3 activation, cytokine profiles, and tumor burden were assessed. In vitro assays evaluated SP- and RBD-induced ACE2 processing.

Results:

Propensity score-matched TriNetX cohorts demonstrated an increased lung cancer risk after COVID-19, particularly among current smokers (n = 166,807; RR 1.22; HR 1.50; P<.001). In mice, SP induced acute lung injury, neutrophil infiltration, and microthrombi, which were reduced in TYMP-deficient mice. SP markedly increased lung tumor incidence and aggressiveness, whereas TYMP deficiency reduced tumor formation from 50% to 18% of lung lobes. SP-induced STAT3 upregulation and collagen deposition were significantly attenuated in K18-hACE2TG/Tymp–/– mice. Cytokine profiling revealed a tumor-promoting, myeloid-dominant inflammatory milieu in K18-hACE2TG mice, in contrast to a T cell-inflamed, anti-tumor profile in K18-hACE2TG/Tymp–/– mice. SP and RBD altered ACE2 processing, generating lower-molecular-weight fragments consistent with enhanced turnover.

Conclusions:

SARS-CoV-2 SP drives lung injury, fibrosis, and tumorigenesis through a TYMP-dependent mechanism involving STAT3 signaling and inflammatory microenvironment remodeling. COVID-19 significantly increases lung cancer risk, especially in current smokers. TYMP represents a potential therapeutic target to mitigate long-term pulmonary consequences of COVID-19.

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Researchers explore potential link between COVID-19 and lung cancer risk 

Marshall University Joan C. Edwards School of Medicine

New findings from researchers at the Marshall University Joan C. Edwards School of Medicine and The Hebrew University of Jerusalem have identified a potential association between COVID-19 and increased lung cancer risk, driven by underlying biological mechanisms in the lung.

The study, published in Frontiers in Immunology, integrates human clinical data with mechanistic research in animal and cellular models to better understand how SARS-CoV-2, the virus that causes COVID-19, may contribute to long-term lung disease.

“Our findings suggest that COVID-19 may do more than cause acute illness—it may also create biological conditions in the lung that could contribute to increased cancer risk over time,” said Wei Li, Ph.D., professor of biomedical sciences at the Joan C. Edwards School of Medicine and co-corresponding author on the study. “Understanding these pathways is critical as we continue to study the long-term health impacts of the virus.”

The study identified a key role for thymidine phosphorylase (TYMP), a protein that may interact with the SARS-CoV-2 spike protein to promote inflammation, fibrosis and tumor-related pathways in the lung. Researchers found that this interaction may activate processes associated with cancer growth and alter the lung’s immune environment in ways that could support tumor formation.

 
(Continue . . .)

While there is growing circumstantial evidence that COVID may promote tumor-promoting environments, we still lack causal proof. That may come in time, but even without it, we've pretty good evidence that repeated COVID infections are best avoided if at all possible. 

WHO Burundi: Investigation into a `Mystery' Disease in Mpanda

 

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Caveat : Reports of `mystery' diseases are fairly common around the globe, and while these reports usually turn out to be something already known, on rare occasions they can alert us to a new, or re-emerging threat.

Yesterday on FluTrackers, Pathfinder posted two reports on a `mystery' illness affecting several households in Burundi, in east Africa.  Since late March, at least 5 deaths, and roughly 3 dozen illnesses have been reported, `. . . primarily among members of the same household and close contacts.'

According to the WHO: `Symptoms include fever, vomiting, diarrhoea, blood in urine, fatigue and abdominal pain. Some severe cases have also presented with jaundice and anaemia.'

So far, tests have ruled out many of the `usual suspects'; Ebola virus disease, Marburg virus, yellow fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever.  Further testing is underway. 

While this could be something new, there are still a number of diagnoses that must be ruled out including infectious diseases like Severe Malaria, Leptospirosis, Enteric Fever, etc., environmental contaminants (heavy metals or pesticides), or food or alcohol poisoning. 

The CIA Factbook describes Burundi as:

Burundi is a landlocked, resource-poor country with an underdeveloped manufacturing sector. The economy is predominantly agricultural with roughly 90% of the population dependent on subsistence agriculture.

According to the WHO:

In Burundi, life expectancy at birth (years) has improved by ▲ 19.6 years from 44.4 [43.5 - 45.4] years in 2000 to 64 [63.3 - 65] years in 2021.

But this still puts it in the bottom 20% among african nations. The WHO AFRO statement follows:

Burundi investigates illness that has caused five deaths
11 April 2026

Bujumbura—The health authorities in Burundi, with support from the World Health Organization (WHO) and partners, are deepening investigations to determine the cause of an illness that has led to five deaths and sickened 35 people in Mpanda district in the north of the country.

Laboratory analysis has turned negative for Ebola and Marburg virus diseases, Rift Valley fever, yellow fever and Crimean-Congo haemorrhagic fever. An alert about the undiagnosed illness was received on 31 March 2026, primarily among members of the same household and close contacts. Symptoms include fever, vomiting, diarrhoea, blood in urine, fatigue and abdominal pain. Some severe cases have also presented with jaundice and anaemia.

“While it’s reassuring that preliminary analysis is negative for these serious infections, further investigations are ongoing to determine the cause of the disease,” said Dr Lydwine Badarahana, Burundi’s Minister of Health. “All the necessary measures are being taken to safeguard public health and prevent potential spread of infection.”

A joint team of experts from the country’s public health emergency operations centre and the national reference laboratory has been deployed to the field to support ongoing investigations.

WHO is supporting the Ministry of Health to strengthen disease surveillance, field investigation, clinical care, laboratory diagnosis and infection prevention and control, while also providing logistical support to sustain key operations. The Organization has also facilitated the shipment of samples to the National Institute of Biomedical Research in neighbouring Democratic Republic of the Congo for further analysis.

The Ministry of Health is leading the response, working with partner organizations to coordinate joint efforts. 

The old medical adage that; if you're in Central Park and hear hoofbeats, think `horses' not `zebras' still applies. But of course, Burundi is a long way from Central Park, so this is an outbreak worth keeping our eye on. 

CHEST Review: Examining the Threat of H5N1 Highly Pathogenic Avian Influenza to Human Health

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This morning we've an open access review published in CHEST® - the monthly clinical research journal of the American College of Chest Physicians - which looks at the continued evolution of HPAI H5N1's threat to human health.

 

At a time when many government agencies appear to have reduced their coverage of HPAI (the CDC's last Avian Flu News & Spotlights update was Sept 8th, 2025), this review for clinicians is particularly timely. 

This article covers a lot of ground, starting with a a literature search and evidence review which documents HPAI's shift from being primarily a disease of birds to increased mammalian adaptation. 

While focusing primarily on H5N1 clade 2.3.4.4b, this review also briefly discusses the Cambodian 2.3.2.1e clade.  While H5N5 is mentioned, this article went to press prior to last year's announced human infection in Washington state.

Much of this review is focused on practical concerns for clinicians, including testing, treatment, and isolation of cases.  A few `pearls' from the narrative include:

• Exposure to cattle or commercial poultry operations thus may be indicative of potential clade 2.3.4.4b A(H5N1) infection; however, lack of exposure cannot rule out potential infection, as observed in 5 patients with unknown exposure or exposure to other animals.39,41

• Timely identification and isolation of infected patients is essential and is enabled by a low threshold of suspicion for patients with consistent clinical presentations and epidemiologic factors, including exposure to sick birds or cattle within 10 days of symptom onset.

• Patients with positive findings may go undetected if they do not seek diagnosis or treatment in the absence of access to health care or because they experience only mild symptoms.

 While this review acknowledges the `low' risk today, it warns that could change:

Future Directions

At this time, the risk posed to the general public from AIV is considered low.29 However, that reality could change at any time given the rapidly evolving situation involving infection in mammals and substantial knowledge gaps surrounding clade 2.3.4.4b A(H5N1) and human infections.

This is an excellent review for clinicians, and makes for a good Sunday morning read for anyone interested in the topic. 

Highly recommended. 

Open access

Examining the Threat of H5N1 Highly Pathogenic Avian Influenza to Human Health

Juliette Blais-Savoie, Emily Halajian, Kuganya Nirmalarajah, Andra Banete, Juan C. Corredor, Jonathon D. Kotwa,Yaejin Lee, Sugandha Raj, Shayan Sharif ,Nicole Mideo, Samira Mubareka

Publication: CHEST
Publisher: Elsevier
Date: April 2026

Abstract

Topic Importance

The clade 2.3.4.4b highly pathogenic avian influenza (HPAI) virus H5N1 is the etiologic agent for an ongoing panzootic with a rapidly increasing number of human infections. Although morbidity and mortality in humans with this clade seems to be limited to date, previous HPAI H5N1 viruses have been associated with mortality rates of approximately 50% in humans. Not all cases of clade 2.3.4.4b influenza A(H5N1) HPAI in humans have been associated with known exposure to infected animals. Therefore, clinicians must be aware of the changing viral ecology, human risk factors, and clinical presentations associated with H5N1 viruses to facilitate early case recognition and management of clade 2.3.4.4b A(H5N1) HPAI infection in humans.

Review Findings

Historic H5N1 presentations have involved multiorgan systemic disease, notably including severe neurological disease. Common symptoms associated with clade 2.3.4.4b A(H5N1) HPAI include conjunctivitis, fever, and upper respiratory tract infection. Exposure to infected dairy cattle is a novel risk factor.

Summary

The rapid global spread of clade 2.3.4.4b A(H5N1) viruses has been associated with severe disease and high mortality in many farmed animal species and wildlife. The composite picture of emerging risk to human health comprises an unprecedented number of mammalian infections, viral adaptations to mammalian hosts, severe neuroinvasive disease in naturally infected mammals, and spillover into novel species such as dairy cows with forward transmission to humans. Preparedness measures are crucial to mitigating significant human health impacts from this virus and must include a Canadian One Health Training Program in Emerging Zoonoses approach that promotes both animal and human health

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While HPAI H5Nx remains our biggest concern, recents human infections with other subtypes (see Taiwan CDC Update: Novel H7 Infection Identified as H7N7 and WHO DON: Avian Influenza A(H9N2) - Italy (Ex Senegal)) remind us that Nature's laboratory is open 24/7, and we could easily be blindsided by something unexpected coming out of left field.

WHO DON: Avian Influenza A(H9N2) - Italy (Ex Senegal)

 
Senegal - Base Map Credit Wikipedia

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In late March we learned of the first (imported) human infection with H9N2 in Europe when Italy's MOH announced a hospitalized case (see Italy: MOH Statement on First LPAI H9N2 Human Case in Europe (imported)). 

At that time, few details were made available, including the country of origin. 

Yesterday the WHO released a detailed DON (Disease Outbreak News) report, where we learn that the infected individual was a man who had traveled to Italy after staying in Senegal for more than 6 months - who presented at a local hospital with fever and persistent cough - and who tested positive for both Mycobacterium tuberculosis and LPAI H9N2. 

Unlike most H9N2 infections we've seen in Asia and (less often) in Africa, this patient denied having contact with poultry, birds, wildlife, or a rural environment. The source of his infection remains unknown.

This is the second human case to be reported from Senegal. 

The first occurred during the opening wave of COVID (January 2020); no WHO DON was generated, and most of what we know about it comes from a report (Genetic characterization of the first detected human case of low pathogenic avian influenza A/H9N2 in sub-Saharan Africa, Senegal) published several months later.

The first case - involving a 16 month-old child - occurred before H9N2 had been identified in Senegal's poultry. While details on this 2020 case are scant, I can find no indication of a likely exposure. 

In 2023's Influenza A Virus in Pigs in Senegal & Risk Assessment of AIV Emergence and Transmission to Humans, we saw a study that found evidence of A/H9N2, A/H5N1, A/H7N7 and A/H5N2 in local pigs, with H9N2 and H7N7 antibodies detected in > 50% of samples tested. 

The authors wrote:

Serological analyses revealed that 83.5% (95%CI = 81.6–85.3) of the 1636 sera tested were positive for the presence of antibodies against either H9N2, H5N1, H7N7 or H5N2. Influenza H7N7 (54.3%) and H9N2 (53.6%) were the dominant avian subtypes detected in Senegalese pigs.

Given the co-circulation of multiple subtypes of influenza viruses among Senegalese pigs, the potential exists for the emergence of new hybrid viruses of unpredictable zoonotic and pandemic potential in the future.

In 2024, Ghana (also in West Africa) reported a human case; that of a 5 y.o. (see WHO DON: Avian Influenza A(H9N2) - Ghana), who once again, reportedly had `. . . no known history of exposure to poultry or any sick person with similar symptoms prior to onset of symptoms.'

Yesterday's WHO DON report follows, after which I'll have a bit more.

Avian Influenza A(H9N2) - Italy
10 April 2026

Situation at a glance

On 21 March 2026, the National International Health Regulations (IHR) Focal Point for Italy notified the World Health Organization (WHO) of the identification of a human case of avian influenza A(H9) in an adult male returning from Senegal. Next generation sequencing confirmed Influenza A(H9N2). According to epidemiological investigations, the patient had no known history of exposure to poultry or any person with similar symptoms prior to the onset of symptoms.

Authorities in Italy have implemented a series of measures aimed at monitoring, preventing and controlling the situation. According to the IHR (2005), a human infection caused by a novel influenza A virus subtype is an event that has the potential for high public health impact and must be notified to the WHO. This is the first imported human case of avian Influenza A(H9N2) reported in the European Region. Based on currently available information, WHO assesses the current risk to the general population posed by A(H9N2) viruses as low but continues to monitor these viruses and the situation globally.

Description of the situation

On 21 March 2026, the National IHR Focal Point for Italy notified WHO of the identification of a human case of avian influenza A(H9) in an adult male.

The patient had been in Senegal for more than six months and traveled to Italy in mid-March. Upon arrival, he visited the emergency department with a fever and a persistent cough.

On 16 March, a bronchoalveolar lavage specimen was collected, which showed a positive Mycobacterium tuberculosis result, as well as detection of un-subtypeable influenza A virus. The patient was placed in a negative-pressure isolation room with airborne precautions. He was treated with antitubercular medication and antiviral oseltamivir. By 9 April, his condition was stable and improving.

On 20 March, a regional reference laboratory identified the A(H9) subtype, and on 21 March, next-generation sequencing confirmed influenza A(H9N2). Initial genetic findings suggest the infection was likely acquired from an avian source linked to Senegal. Additional samples have been sent to Italy’s National Influenza Center, where further characterization confirmed virus subtype Influenza A(H9N2), with close genetic similarity to strains previously identified in poultry in Senegal.

No direct exposure to animals, wildlife or rural environments was identified. There was also no reported contact with symptomatic or confirmed human cases. Further epidemiological investigations on the source of exposure are ongoing.

Contacts identified in Senegal were asymptomatic. All identified and traced contacts in Italy have tested negative for influenza and completed the period of active monitoring for the onset of symptoms and the quarantine required by national guidelines. They also received oseltamivir as a preventive measure.

Epidemiology

Animal influenza viruses normally circulate in animals but can also infect people. Infections in humans have primarily been acquired through direct contact with infected animals or through indirect contact with contaminated environments. Depending on the original host, influenza A viruses can be classified as avian influenza, swine influenza, or other types of animal influenza viruses.

Avian influenza virus infections in humans may cause diseases ranging from mild upper respiratory tract infection to more severe diseases and can be fatal. Conjunctivitis, gastrointestinal symptoms, encephalitis and encephalopathy have also been reported.

Laboratory tests are required to diagnose human infection with influenza. WHO periodically updates technical guidance protocols for the detection of zoonotic influenza using molecular methods.

Human infections with influenza A(H9) viruses have been reported from countries in Africa and Asia, where these viruses are also detected in poultry. The majority of cases of human avian influenza A(H9N2) infection have been reported from China. This is the first imported human case of avian Influenza A(H9N2) virus infection reported in the European Region.

Public health response

Contact tracing procedures have been initiated, and relevant authorities in Italy, as well as internationally (National IHR Focal Point for Senegal, WHO, and European Centre for Disease Prevention and Control (ECDC)) have been informed through IHR channels. Once avian influenza was suspected, the response moved quickly from hospital-level management to regional laboratory confirmation and national coordination. Additionally, the regional surveillance system was notified, integrated within the One Health avian influenza reporting framework.

WHO risk assessment

Most reported human cases of A(H9N2) virus infection have been linked to exposure to infected poultry or contaminated environments, with the majority of cases experiencing mild clinical illness. Sporadic human cases following exposure to infected birds or contaminated environments can be expected since the virus remains enzootic in poultry populations. 

Avian influenza A(H9N2) viruses have been detected in poultry and environmental samples collected at live bird markets in Senegal and authorities in the country reported a human case of infection with an A(H9N2) virus in 2020.

Current epidemiological and virological evidence indicates that none of the characterized influenza A(H9N2) viruses thus far have acquired the ability for sustained transmission among humans. Thus, the likelihood of sustained human-to-human spread is low at this time. Infected individuals traveling internationally from affected areas may be identified in another country during or after arrival. However, if this were to occur, further community-level spread is considered unlikely. The risk assessment would be revisited if and when further epidemiological and virological information becomes available.

WHO advice

This case does not change the current WHO recommendations on public health measures and surveillance of influenza.

The public should avoid contact with high-risk environments such as live animal markets/farms or surfaces that might be contaminated by poultry feces. Respiratory protection is highly recommended for those handling live or dead (including slaughtering) poultry in occupational or backyard-farming settings. Good hand hygiene, i.e. frequent washing of hands or the use of alcohol-based hand sanitizer is recommended. WHO does not recommend any specific additional measures for travelers.

Under Article 6 of the IHR, all human infections caused by a new subtype of influenza virus are notifiable. The case definition for notification of human influenza infection caused by a new subtype under the IHR is provided here. State Parties to the IHR are required to immediately notify WHO of any laboratory-confirmed case of a human infection caused by such an influenza A virus.

WHO advises against the application of any travel or trade restrictions based on the current information available on this event.

As we've discussed often, our ability to detect novel flu in the community is limited, and is often heavily dependent on luck. Most people with mild or moderate flu never consult a doctor - and even of those that do - few will be tested for a novel subtype. 

In 2024 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., which cautioned:

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.

It is fair to assume that novel flu detection is even less likely in medically underserved communities. Which means there could easily be more community cases in West Africa than have been reported.  

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

  

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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

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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

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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.