JAMA Open: Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic Testing

#18,931

Since we've already seen serological evidence suggesting asymptomatic (or exceedingly mild) HPAI H5N1 infection in humans (see MMWR: Serologic Evidence of Recent Infection with HPAI A(H5) Virus Among Dairy Workers), one might reasonably wonder why a particularly strict scoping review published this week in JAMA Open is getting so much press.

While important investigational tools, serological testing (hemagglutination inhibition (HI) assays & microneutralization (MN) assays) are not foolproof, and can sometimes yield false positives. 

Both are susceptible to potential cross-reactivity with seasonal influenza antibodies, have often used non-standardized antigens or varying cutoff titers, and may occasionally detect low, non-specific reactions.  

Even PCR tests - the `gold standard' - can be fooled by environmental contamination (e.g. poultry `dust' in nares) or lab contamination, and yield a false positive.  It appears to be rare, but it can happen (see CDC Report).

Which is why this report only considers a narrow, and highly restrictive, data set,

Inclusion Criteria

We included any study published through August 25, 2025, that reported a confirmed A(H5N1) virus infection that met primary or secondary outcome definitions and had a full-text report available in English. We excluded articles that reported results from A(H5N1) serologic testing in humans without molecular testing. We also excluded serosurveys and other immunologic studies,11 some of which have been interpreted as evidence of asymptomatic infection.

This sets the bar incredibly high, and likely ignores many other legitimate cases. But in its favor, their findings are far more difficult to dismiss. Even with these restrictions, they identified 10 reports which describe 18 asymptomatic human H5N1 infections over the past 20+ years.

Of those, 2 were confirmed via molecular and serologic confirmation (MSC) and 16 with molecular confirmation alone (MC).

First the link, and abstract, from the report (follow the link to read it in its entirety), after which I'll have a bit more.

Asymptomatic Human Infections With Avian Influenza A(H5N1) Virus Confirmed by Molecular and Serologic TestingA Scoping Review
Fatimah S. Dawood, MD1; Shikha Garg, MD, MPH1; Pragna Patel, MD, MPH1
et al
JAMA Netw Open
Published Online: October 29, 2025
2025;8;(10):e2540249. doi:10.1001/jamanetworkopen.2025.40249

Key Points

Question Have asymptomatic infections with highly pathogenic avian influenza A(H5N1) virus been reported in humans?

Findings This scoping review of published reports through August 25, 2025, identified 10 reports of 18 cases of asymptomatic infection with A(H5N1) virus, including 2 cases with molecular and serologic confirmation and 16 cases with molecular confirmation alone. Symptom ascertainment methods varied among reported cases.

Meaning Asymptomatic human avian influenza A(H5N1) virus infections have been infrequently reported, with most lacking serologic confirmation; prospective surveillance studies with serial respiratory and serum sampling and detailed symptom monitoring for persons with high-risk exposures could provide data to inform future public health responses.

Abstract

Importance Since 1997, more than 1000 infections with highly pathogenic avian influenza A(H5N1) virus among humans have been reported globally. Given ongoing A(H5N1) outbreaks in animals, understanding the frequency of A(H5N1) virus infections among asymptomatic persons can inform public health risk assessments and infection prevention guidance.

Objective To identify and characterize reported cases of asymptomatic A(H5N1) virus infection among humans with confirmation by both molecular testing of 1 or more respiratory specimens and 1 or more serum specimens meeting World Health Organization criteria (molecularly and serologically confirmed [MSC]) or molecular confirmation (MC) alone.

Evidence Review MEDLINE, Embase, Global Health, Cochrane, Scopus, Virtual Health Library, and Europe PubMed Central were searched for publication through August 25, 2025. Articles for full-text screening were evaluated by 2 investigators. Studies published through August 25, 2025, were included if they reported a confirmed A(H5N1) virus infection that met MSC or MC criteria and had a full-text report in English. Articles were excluded if they reported results from A(H5N1) serologic testing alone, serosurveys, or other immunologic studies.

Findings Of 1567 unique reports that underwent title or abstract screening, 42 were selected for full-text screening, of which 10 met inclusion criteria (3 reports about 2 MSC cases and 7 reports about 16 MC cases). The 2 MSC cases occurred among adults in Pakistan and Vietnam who were identified by investigations of household contacts of index A(H5N1) case patients; 1 case patient also had exposure to A(H5N1) virus–infected chickens as the possible infection source and 1 is thought to have been infected through human-to-human transmission. Neither MSC case patient used personal protective equipment. Of 16 reported MC cases (14 adults, 2 children), 11 were identified by enhanced surveillance of persons exposed to A(H5N1) virus–infected poultry (8 in Bangladesh, 2 in Spain, and 1 in the UK) and the remaining 5 MC cases (3 in Vietnam, 2 in Cambodia) were identified by investigations of household contacts of index A(H5N1) case patients.

Conclusions and Relevance Asymptomatic human infections with A(H5N1) virus have been infrequently reported, with most cases identified through enhanced surveillance or household contact investigations of persons with known exposure. Robust data collection is needed from persons with possible asymptomatic A(H5N1) virus infection to inform future public health responses.

(SNIP) 

Conclusions

Prospective surveillance studies with serial respiratory and serum sampling and detailed symptom monitoring in persons with high-risk exposures to infected animals or close contact with humans with confirmed A(H5N1) virus infection could elucidate the true fractions of human A(H5N1) virus infections that are asymptomatic with and without seroconversion and the duration of viral shedding with asymptomatic infection. Careful attention to the timing of initiation of influenza antiviral postexposure prophylaxis and antiviral treatment would be needed when interpreting results.

Such studies could provide information to guide risk assessment, infection control guidance, and population immunity projections but are resource intensive and may be unacceptable in some populations. Whether persons with asymptomatic A(H5N1) virus infections are a transmission risk to their close contacts is an additional critical knowledge gap.

This review highlights the need for robust data collection from persons with possible asymptomatic A(H5N1) virus infection to inform future public health responses.

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Although this study finds only a reassuringly small handful of cases that meet their criteria, it provides compelling evidence they do exist. 

The reality is, asymptomatic cases have only rarely been tested for H5N1, and even mildly or moderately symptomatic individuals are unlikely to be identified, unless they are sick enough to be hospitalized.  

Once again, their primary recommendation, and the one thing that nearly every study calls for (see here, here, here, here, and here); enhanced surveillance and testing for HPAI H5N1, seems to be the last thing that governments want to do. 

As long as confirmed cases are low and there is `no evidence of sustained or efficient human transmission of H5N1', they don't have to make the hard political and economic decisions on how to contain it. 

But as Dr. Carl Sagan pointed out years ago, `Absence of evidence is not evidence of absence'.  While our current reluctance to aggressively test for this virus may provide short-term bliss, it risks our sleepwalking into the next pandemic. 

China CDC Weekly: Epidemiological and Genetic Characterization of Three H9N2 Viruses Causing Human Infections — Changsha City, Hunan Province, China, April 2025

 

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While we are understandably focused on the continued evolution and spread of HPAI H5N1 around the globe, in China - over the past 24 months - we've seen roughly 50 human infections with LPAI H9N2 reported, mostly in children. 

Given the relatively mild presentation of H9N2 in humans - and the infrequency of testing outside of big city hospitals - the actual number of cases in China is assumed to be much higher. 

LPAI H9N2 is a Low Path (LPAI) virus (in poultry), and is therefore not a `reportable' disease to WOAH. It can, however, cause significant morbidity and mortality in poultry, and so poultry vaccination against H9N2 in China - which began in the late 1990s - is nearly universal.

But, as we've discussed previously - while existing H9 vaccines can greatly reduce poultry morbidity and mortality - they don't prevent the spread and continue evolution of the virus (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China).

Over the past couple of years we've seen increasing reports that some isolates now  preferentially bind to human-type (α2,6-linked) receptor cells (see Characterization of H9N2 Avian Influenza Virus Isolated from Chickens and Waterfowl in Parts of Southern China from 2018 to April 2024).

The information we get out of China on human infections is generally cryptic - and follow ups are rare - but today we have an unusually detailed report (published this week in China's CDC Weekly), on 3 pediatric cases which were reported last April from Changsha City, Hunan Province, China.

The gist of the report (which we'll get to) is found in the discussion section:

Three children infected with H9N2 AIV were identified in Changsha in April 2025, and no epidemiological links were found between these mild and sporadic cases. Genetic analysis showed that the H9N2 viruses had enhanced binding ability to upper respiratory tract receptors, particularly the α2,6-sialic acid receptors.

The report goes on describe some of the notable HA mutations suggesting enhanced mammalian adaptation:

Analysis of receptor-binding sites showed that the HA proteins had mutations at amino acid positions H191N, A198V, Q226L, and Q234L, which potentially enhanced the binding ability of the virus to the receptor (5-6).

While there is still no evidence of sustained or efficient human-to-human transmission of H9N2, the virus continues on a path towards greater mammalian adaptation.  

A few excerpts from the full report (but you'll want to read it in its entirety), after which I'll return with a postscript.

Outbreak Reports: Epidemiological and Genetic Characterization of Three H9N2 Viruses Causing Human Infections — Changsha City, Hunan Province, China, April 2025

Chaoyang Huang1,2,&; Yi Liu1,&; Zheng Huang3; Shuilian Chen3; Zhifei Zhan1,2; Qianlai Sun1; Ruchun Liu3; Liang Cai1,2, , ;Kaiwei Luo1 

Summary

What is already known about this topic?

A total of 117 H9N2 cases of human infection of Chinese origin had been reported to the World Health Organization (WHO) by May 9, 2025, with 22 of them originating in Hunan Province.

What is added by this report?

This article reported on the investigation of three new H9N2 avian influenza virus (AIV) infections detected in Changsha, Hunan Province, in April 2025. No epidemiological link was found among them. Exposure to live poultry was identified as the primary risk factor for infection. Sequence analysis of the three H9N2 AIVs showed a similarity of 99.71%–99.82% between hemagglutinin (HA), and the homology of the neuraminidase (NA) genes was 98.41%–99.83%. Although the tests showed that the HA had enhanced binding ability to upper respiratory tract cells’ receptors, no evidence of sustained human-to-human transmission has been found so far.

What are the implications for public health practice?

This study indicated that H9N2 AIV remains a public health issue in China. We need to strengthen publicity and education efforts to inform people of the potential risk of avian influenza virus, especially to keep children away from poultry and poultry-related facilities, to effectively prevent the occurrence of avian influenza A(H9N2) infection.

ABSTRACT

Introduction: In April 2025, three suspected human cases of avian influenza were identified in Changsha, China. Laboratory testing confirmed three cases of H9N2 AIV infection. This report summarizes the epidemiological findings from cases and contact investigations, along with genetic characterization of the isolated H9N2 strains.

Methods: Comprehensive epidemiological assessments were conducted for each confirmed case. Virus isolation and culture were performed using throat swab specimens obtained from the cases. Isolated H9N2 strains were sequenced using next-generation sequencing (NGS). HA and NA gene sequences were analyzed for homology; evolutionary trees were constructed; and key antigenic sites were examined to identify genetic features.

Results: All three cases were sporadic. No influenza-like illness was observed among close contacts or live poultry store employees during the 10-day medical monitoring period. Phylogenetic analysis indicated that the HA gene of all three H9N2 strains belonged to the A/Duck/Hong Kong/Y280/97 (Y280-like) clade within the Eurasian lineage. HA gene sequence homology was 99.7%–99.8%, and NA gene homology was 98.4%–99.8%. The HA protein cleavage site was identified as PSRSSR↓GLF. Several HA protein site mutations were detected — H191N, A198T/V, Q226L, and Q234L — that had been previously associated with increased binding to receptors. HA-232H, 234L, and 236G support a binding preference for the human-type sialic acid-α-2,6-galactose receptors.

Conclusion: All three H9N2 avian influenza cases were mild and involved reported exposure to poultry or related environments. Genetic analysis revealed high homology of HA and NA among the isolated viruses. No epidemiological links were identified between cases, and no evidence was found of sustained human-to-human transmission. Continued avian influenza surveillance and public health education are warranted.

The H9N2 avian influenza virus (AIV) is the most prevalent avian influenza virus circulating among poultry in China (1). While it primarily leads to economic losses in the poultry industry, it has also repeatedly crossed the species barrier to infect humans, raising public health concerns. Since 2015, China has consistently reported human H9N2 infections to the WHO, with 117 cumulative cases by May 9, 2025 (2). Among these, 19 cases were reported in Hunan Province by the end of 2024 (3), followed by three additional cases in April 2025.

Therefore, it is crucial to closely monitor variations in H9N2 infectivity — particularly its potential for cross-species transmission to humans. This study presents the epidemiological profiles of three human H9N2 cases detected through influenza-like illness (ILI) surveillance from Changsha, China, along with the molecular characteristics of the corresponding H9N2 viruses.

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As we've discussed previously, Live Poultry Markets (LPMs)  are an important venue for spillovers to humans, and testing of local markets where these children were exposed showed high levels of H9N2 virus in poultry.

The Changsha CDC conducted emergency monitoring of the sources of chickens and ducks in the live poultry stores of Case 1 and Case 2, as well as the Shuiduhe Market and Huangxing Town Market, on April 27, 2025. 

A total of 62 environmental samples were collected, and the nucleic acid test results showed that 33 samples were positive for H9N2 AIV, and 2 samples were positive for H5 AIV.

While H9N2 currently presents as a relatively mild virus in humans, it is also extremely promiscuous; willing and able to reassort with a wide variety of other influenza A viruses.  

In nearly every novel avian flu virus of concern, you'll find internal gene contributions from H9N2 (see last January's Transboundary & Emerging Dis.: The H5N6 Virus Containing Internal Genes From H9N2 Exhibits Enhanced Pathogenicity and Transmissibility).

H9N2 is such a versatile virus, it has even been detected in Egyptian Fruit bats (see Preprint: The Bat-borne Influenza A Virus H9N2 Exhibits a Set of Unexpected Pre-pandemic Features).

All of which suggests that, unless and until H9N2 can be better controlled, our avian flu woes may extend far beyond just H5Nx in the years ahead. 

JAHA: Viral Infections and Risk of Cardiovascular Disease: Systematic Review and Meta‐Analysis

#18,929

While many people regard influenza and COVID as fairly minor respiratory illnesses, over the past few years we've seen a lot of research showing an apparent link between current (or recent) viral infection and cardiovascular complications, including heart attacks and strokes. 

A few of many examples include:

• In 2023, an NIH study found SARS-CoV-2 Infects Coronary Arteries, Increases Plaque Inflammation, and likely leads to increased cardiac events.
• In 2022, in PloS One: Early Risk of Acute Myocardial Infarction Following Hospitalization for Severe Influenza found the absolute risk of having an AMI within 12 months of a severe influenza hospitalization was low (0.92%), but the relative risk (compared to non-hospitalized controls) was nearly doubled.
• In 2018's NEJM: Acute Myocardial Infarction After Laboratory-Confirmed Influenza Infection, we saw a study that found a `significant association ' between recent (lab confirmed) influenza infection and Myocardial Infarction.

• And in May 2017, in Int. Med. J.: Triggering Of Acute M.I. By Respiratory Infection we looked at research from the University of Sydney that found the risk of a heart attack is increased 17-fold in the week following a respiratory infection such as influenza or pneumonia.

While the influenza/COVID -cardiovascular link grows stronger with each year, update of vaccines that may prevent, or lessen the impact, of these infections continue to fall. 

Today the Journal of the American Heart Association has published what appears to be the most comprehensive review to date of how viral infections contribute to cardiovascular disease (CVD).  

Instead of looking at just one pathogen, or one outcome, this review covers 10 major (acute & chronic) viral infections, and multiple CVD outcomes (CHD, stroke, heart failure, and CVD death).  

First a link and excerpt from the press release, after which I'll have the link and abstract from the open access review. 

Some acute and chronic viral infections may increase the risk of cardiovascular disease

Prevention measures, including vaccination, may play important role in cutting the risk of serious cardiovascular events, according to a new study in Journal of the American Heart Association

Research Highlights:

• A review of 155 scientific studies found influenza and COVID infections raised the risk of heart attack or stroke as much as three-to five-fold in the weeks following the initial infection.

• Viruses that linger in the body, such as HIV, hepatitis C and varicella zoster virus (the virus that causes shingles), can lead to long-term elevations in the risk of cardiovascular events.

• The study researchers say preventive measures, including vaccination, may play an important role in reducing the risk of heart attacks and strokes, especially in people who already have heart disease or heart disease risk factors.

DALLAS, Oct. 29, 2025 — In the weeks following a bout of influenza or COVID, the risk of heart attack or stroke may rise dramatically, and chronic infections such as HIV may increase the long-term risk of serious cardiovascular disease events, according to new, independent research published today in the Journal of the American Heart Association, an open access, peer-reviewed journal of the American Heart Association.

“It is well recognized that human papillomavirus (HPV), hepatitis B virus and other viruses can cause cancer; however, the link between viral infections and other non-communicable diseases, such as cardiovascular disease, is less well understood,” said Kosuke Kawai, Sc.D., lead author of the study and adjunct associate professor in the division of general internal medicine and health services research at the David Geffen School of Medicine at the University of California, Los Angeles. “Our study found acute and chronic viral infections are linked to both short- and long-term risks of cardiovascular disease, including strokes and heart attacks.”

The researchers set out to systematically review all published studies that investigated the association between any viral infection and the risk of stroke and heart attack, initially screening more than 52,000 publications and identifying 155 as appropriately designed and of high quality allowing for meta-analysis of the combined data.

In studies that compared people’s cardiovascular risks in the weeks following documented respiratory infection vs. the same people’s risk when they did not have the infection, researchers found:

• People are 4 times as likely to have a heart attack and 5 times more likely to have a stroke in the month after laboratory-confirmed influenza.

• People are 3 times more likely to have a heart attack and 3 times as likely to have a stroke in the 14 weeks following COVID infection, with the risk remaining elevated for a year.

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Viral Infections and Risk of Cardiovascular Disease: Systematic Review and Meta‐Analysis
Kosuke Kawai, ScD kkawai@mednet.ucla.edu, Cresencia Felician Muhere, MD, Elkin V. Lemos, MD, PhD , and Joel M. Francis, MD, PhD Author Info & Affiliations
Journal of the American Heart Association
https://doi.org/10.1161/JAHA.125.042670

Abstract

Background

We conducted a systematic review and meta‐analysis of studies examining the association of viral infections with the risk of cardiovascular disease, including coronary heart disease (CHD) and stroke.

Methods

MEDLINE, Embase, Web of Science, African‐Wide Information, and the Cochrane Library database were searched from inception to July 2024.

Results

We included 155 studies. HIV infection was consistently associated with an elevated risk of CHD (pooled adjusted risk ratio [RR], 1.60 [95% CI, 1.38–1.85]) and stroke (RR, 1.45 [95% CI, 1.26–1.67]). SARS‐CoV‐2 infection was associated with an increased risk of CHD (RR, 1.74 [95% CI, 1.44–2.11]) and stroke (RR, 1.69 [95% CI, 1.23–2.31]). In self‐controlled case series studies, laboratory‐confirmed influenza infection was associated with an elevated risk of acute myocardial infarction (pooled incidence rate ratio, 4.01 [95% CI, 2.66–6.05]) and stroke during the first 1 month (incidence rate ratio, 5.01 [95% CI, 3.41–7.37]). In cohort studies, hepatitis C virus infection was associated with a higher risk of CHD (RR, 1.27 [95% CI, 1.13–1.42]) and stroke (RR, 1.23 [95% CI, 1.04–1.46]). Herpes zoster was also associated with an elevated risk of CHD (RR, 1.12 [95% CI, 1.08–1.15]) and stroke (RR, 1.18 [95% CI, 1.09–1.27]). There is insufficient evidence to determine the effect of cytomegalovirus on cardiovascular disease. Although on a limited basis, hepatitis A virus, herpes simplex virus type 1, respiratory syncytial virus, human papillomavirus, dengue, and chikungunya have been linked to an increased risk of cardiovascular disease.

Conclusions

Influenza, SARS‐CoV‐2, HIV, hepatitis C virus, and herpes zoster were associated with an increased risk of major cardiovascular events. Vaccines may play an important role in preventing the risk of cardiovascular disease.

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While there's a popular belief that `What doesn't kill you, makes you stronger', the reality is, what doesn't kill you can sometimes set you up for something that will. 

We've seen growing, and consistent, evidence that repeated viral infections exact a hidden toll on one's health, which may show up weeks, months, or sometimes even years post-infection (see Nature: Viral Infections and the Risk of Neurodegenerative Diseases (Meta-Analysis & Systemic Review)

Which is why, for the past 20+ years, I've gotten the flu shot each fall, I've stayed current with COVID shots/boosters since early 2021, and I've recently taken my first (of two) Shingles vaccines. 

None are guaranteed to protect me, of course. But the evidence suggests they improve my odds. 

And at my age, that's all I can reasonably expect. 

Preprint: A Divergent Betacoronavirus with a Functional Furin Cleavage Site in South American Bats

 

#18,928

Over the past 24-hours the tabloids and mainstream media have been filled with reports of a `new' coronavirus discovered in a Brazilian bat; one that shares an uncomfortably close genetic profile with both SARS-COV-2 and MERS-CoV. 

While all of that makes for great clickable headlines, it is worth noting this `new' virus was actually detected in samples that were collected between May and August 2019 (months before COVID emerged), but have only recently been analyzed. 

That doesn't mean this isn't a potential zoonotic threat, only that it has been around for some time without actually spilling over to humans; as have likely other similar coronaviruses, many yet to be discovered. 

And indeed, since the original SARS-CoV outbreak in 2002-2003, we've seen similar viruses reported around the globe, including:

Health Sci Rpts (Narrative Review): Pathogenicity and Potential Role of MERS-CoV in the Emergence of “Disease X”

V. Sinica: Pangolin HKU4-related Coronaviruses Found in Greater Bamboo Bat From Southern China

Emerg. Microbes & Infect.: Novel Coronaviruses In Least Horseshoe Bats In Southwestern China

PNAS: SARS-like WIV1-CoV Poised For Human Emergence

While once only influenza A was thought likely to spark a global pandemic, COVID proved that coronaviruses can have the `right stuff' as well.  

Which is why we continue to follow MERS-CoV reports closely, and we've seen calls for the development of `Pan-Coronavirus' vaccines, that could conceivably protect against a wider range of threats. 

What has caught the eye of many with this preprint is that this virus - dubbed BRZ batCoV - contains a furin cleavage site that is nearly identical to the one found in SARS-CoV-2; a motif that is credited with increasing COVID's host cell tropism and viral spread.  

I've posted the link and abstract below, and the full PDF is available at this link.  

I'll have a brief postscript after the break. 

A divergent betacoronavirus with a functional furin cleavage site in South American bats

Kosuke Takada, Nicholas Yamahoki, Jonathon C. O. Mifsud, Itsuki Anzai, Tadashi Maemura, Francisco Borges Costa, Eric Takashi Kamakura de Carvalho Mesquita, Mateus de Souza Ribeiro Mioni, Tiago JS Lopes, Yoshihiro Kawaoka, Jane Megid, Edward C. Holmes, Tokiko Watanabe
doi: https://doi.org/10.1101/2025.10.24.684489

Abstract

Bats are natural reservoirs for a wide range of RNA viruses. Members of the genus Betacoronavirus, including Severe Acute Respiratory Syndrome virus 2 (SARS-CoV-2) and Middle East Respiratory Syndrome virus (MERS-CoV), have attracted particular attention due to their recent zoonotic emergence. However, much of the known diversity of betacoronaviruses is based on data from Asia, Africa, and the Middle East, with limited genomic information available from the Americas.

Herein, we report the complete genome of a novel bat betacoronavirus identified from a Pteronotus parnellii bat sampled in Brazil. Phylogenetic analysis revealed that this virus is sufficiently distinct from the five recognized Betacoronavirus subgenera to represent a new subgenus.

Of note, the spike protein of this novel bat coronavirus possesses a functional furin cleavage site at the S1/S2 junction with a unique amino acid sequence motif (RDAR) that differs from that found in SARS-CoV-2 (RRAR) by only one amino acid.

Comparative structural analysis identified other betacoronaviruses in bats with furin cleavage sites at the S1/S2 junction, suggesting that this region is a structurally permissive “hotspot” for cleavage site incorporation. Our study provides a broader understanding of the phylogenetic and functional diversity of bat coronaviruses as well as their zoonotic potential.

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Severe pandemics were once thought to come along every few decades, but recent studies suggest that the frequency, and impact, of pandemics are only expected to increase in the years ahead.

BMJ Global: Historical Trends Demonstrate a Pattern of Increasingly Frequent & Severe Zoonotic Spillover Events

PNAS Research: Intensity and Frequency of Extreme Novel Epidemics

While I can't tell you what emerging disease will spark the next pandemic - or when that may happen - history tells us it is just a matter of time.

And when that day comes, we'll regret every day we squandered not aggressively preparing for its arrival.

Emerg. Microbes & Inf.: Tiger deaths in Vietnam due to infection with HPAI H5N1 Virus Bearing Mutations Associated with Mammalian Host Adaptation

 

#18,927

In October of last year we saw multiple reports of captive tigers in Vietnam dying from HPAI H5N1 (see Vietnam: Govt. Confirmation Of `Dozens' Of Tiger Deaths (H5N1 Suspected), a pattern we've seen repeated a number of times, including 2016's Fatal H5N1 Infection In Tigers By Different Reassortant Viruses - China.

Typically, tigers (and other captive carnivores) are infected via consumption of raw poultry, which is often a mainstay of their diet.

Yesterday the journal Emerging Microbes and Infections published a Research Letter on this event, which reveals the H5N1 clade involved to be 2.3.2.1e - the same as has been linked to recent human infections in Cambodia. 

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

The authors describe finding several mutations of note, including the PB2-E627K  mammalian adaptation, as well as HA-N158D and HA-T160A which can enhance transmissibility.

This is an early release of an accepted manuscript, and the finalized (and edited) version of the PDF will be published at a later date. 

I've posted the link, abstract, and a brief excerpt below. Follow the link to read the report in its entirety.  I'll have a brief postscript after the break. 

Research Letter

Tiger deaths in Vietnam due to infection with H5N1 highly pathogenic avian influenza virus bearing mutations associated with mammalian host adaptation

Murasaki Amano,Nguyen Thi Nga,Nguyen Le Khanh Hang,Nguyen Dang Tho,Nguyen Thi Diep,Dam Thi Vui, show all

Article: 2582252 | Accepted author version posted online: 28 Oct 2025

Cite this article https://doi.org/10.1080/22221751.2025.2582252 

Abstract

Recently, infections with the H5N1 subtype of highly pathogenic avian influenza virus (H5N1-HPAIV) in mammals have been reported worldwide, including in cows in the United States and successive human cases in Cambodia. In Vietnam, 47 tigers and three leopards died from H5N1-HPAIV infection between August and October 2024. This study aimed to determine the origin of the H5N1 strains that infect tigers in Vietnam and to identify specific mutations associated with mammalian infection.

Specimens were collected from tigers that died of suspected H5N1-HPAIV infection in southern Vietnam in September–October 2024. RNA was extracted and subjected to whole-genome sequencing. Time-stamped phylogenetic analysis was performed using H5N1 sequences recently detected in Vietnam and neighbouring countries. Phylogenetic results revealed that the strain found in tigers (Tiger H5N1 strain) belonged to clade 2.3.2.1e and was genetically close to the H5N1-HPAIV lineage responsible for ongoing human infections in Cambodia since 2023.

Tiger H5N1 strains harboured several amino acid substitutions associated with mammalian host adaptation or transmissibility, such as E627 K in polymerase basic protein 2, similar to the Cambodian human H5N1 strains. This mammalian-adapted H5N1 lineage should be continuously monitored in poultry and mammals, including humans, in Vietnam to prevent further transmission.

        (SNIP)

The most recent report investigating the lineage and distribution of the H5N1 influenza virus in Vietnam was published in 2019 [14]. This report indicated that clade 2.3.2.1 was distributed in central and southern Vietnam, while clade 2.3.4.4 was predominantly found in northern Vietnam [14].

However, since 2020, clade 2.3.4.4b has rapidly spread worldwide, resulting in avian influenza outbreaks reported in 84 countries between 2022 and 2023 [15]. In Vietnam, clade 2.3.4.4b has also expanded nationwide since 2020, and as of 2025, clade 2.3.4.4b has become the majority within the country (Supplementary Figure S2).

At present, clades 2.3.2.1e and 2.3.4.4b are found in the same geographical area in southern Vietnam.

Notably, the identification of clade 2.3.2.1e viruses with mammalian adaptation potential in this study has given rise to concerns regarding the acquisition of mammalian adaptation capacity through genetic reassortment. Acquisition of mammalian adaptation capacity by a highly infectious lineage such as clade 2.3.4.4b could potentially trigger the next pandemic. Consequently, it should be essential to carefully monitor the emergence of reassortants in Vietnam over the forthcoming decade.  

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Influenza viruses evolve primarily through abrupt reassortment and much slower antigenic drift. Eighteen months ago we learned that this older 2.3.2.1 c clade had reassorted with the newer clade 2.3.4.4b virus in late 2023.

This new reassortment was recently reclassified as clade 2.3.2.1e (see WHO: Influenza at the Human-Animal Interface Report - Identifies New H5 Clade 2.3.2.1e Infections in Cambodia & Vietnam).

While a clade 2.3.4.4b virus could eventually pick up these mutations on its own, another reassortment event could provide it with a convenient shortcut, boosting its pandemic potential.  

Conversely, clade 2.3.2.1e could continue to expand its geographic range - as have other H5 clades - and present an enhanced threat of its own. 

As much as we'd like to think of HPAI H5 as a single threat, the reality is there are hundreds of genotypes, numerous subtypes (H5N1, H5N2, H5N5, H5N6, etc.), and a handful of active clades in circulation around the globe.  

While the odds are long that any one will become a pandemic strain, each is embarked on its own evolutionary path. 

And it only takes one to get `lucky' in order to plunge the world back into another  global health crisis. 

UKHSA: Updated Risk Assessment On Mpox Clade Ib

 

Credit UK HSA

#18,926

Over the past 10 days we've seen signs of community transmission of the emerging Mpox Clade Ib virus reported both in the United States (see Los Angeles County Reported 3 (locally acquired) Clade I Mpox Cases) and in Europe (see ECDC Statement & Threat Assessment Brief Following Recent Reports of Local Transmission of Mpox Clade Ib in Europe). 

While local (usually household) transmission outside of Africa has been previouslyl reported by a few countries, it has been rare, and has nearly always been traced to known contact with a recent traveler from Africa.

In response to these recent reports of community transmission,  yesterday the UK's Health Security Agency (UKHSA) published an updated risk assessment, their first since December of 2024.  

While this 20-page document provides a number of plausible scenarios, it starts off with the following. 

Summary

Since the last technical assessment on 19 December 2024:

• the epidemiology of clade I mpox may have changed with person-to-person transmission now occurring outside the African Region including amongst specific gay, bisexual and other men-who-have-sex-with-men (GBMSM) networks in at least 2 other WHO regions (EURO and PAHO)

• the probability of importation into the UK has increased from medium to high

• the risk of onwards transmission in the UK is likely to be controlled to some degree by the existing GBMSM vaccination programme and remains low to medium at present; however there are significant uncertainties in this assessment relating to the circulating virus properties, the groups at risk and the level and duration of immunity from natural infection or vaccine. 

A year ago the UK released their Updated Mpox Technical Briefing #9 which presented 3 possible scenarios for the spread of Mpox in the UK ranging from the least to most impactful.

A) incursions and small clusters of cases,

B) a controllable epidemic, and

C) community transmission

At that time, the UKHSA stated that `. . . Currently indicators are most compatible with scenario A . . .'.  

But less than 4 months later (Dec 2024), this had shifted to " . . . The indicators are currently most compatible with scenario B – a virus with moderate transmissibility (similar to or slightly exceeding the transmissibility of the clade II outbreak).'

Today's update, while acknowledging the possibility of seeing a wider epidemic (Scenario C), keeps the previous assessment, stating:

Since the last technical briefing published on 19 December 2024, indicators continue to be assessed as being most compatible with Scenario B based on the transmissibility of the virus.

While our assessment is that globally we are in Scenario B (a controlled epidemic), in Africa initial transmission is among adults driven by close contact, including sexual contact, with a shift to younger age groups where initial clusters are not controlled. It is uncertain whether community transmission is self-sustaining without sexual transmission seeding outbreaks.  

You'll want to follow the link to read the full report, which discusses uncertainties regarding both transmission of the virus and the effectiveness and duration of protection from the current JYNNEOS vaccine.

(For more background see Preprint: The Two-dose MVA-BN Mpox Vaccine Induces a Nondurable and Low Avidity MPXV-specific Antibody Response).

The report concludes with the following:

4.2 Future assessment

It is highly likely that the number of imported cases outside of Africa will increase in the next 6 months (moderate confidence). There has been a deterioration in the epidemiology of the outbreak in Africa in the last 12 months. The number of countries with community transmission of clade I mpox has increased from 1 to 9 countries, some of which have greater connectivity to Europe (For example, Uganda and Kenya).

It is likely there will be an increase in secondary transmission and larger outbreaks are likely to occur in at risk populations outside of Africa in the next 6 months (low confidence). 

There are signals that there may be increasing transmission outside of Africa, including possible undetected transmission in countries. Additionally, there is evidence of community transmission of clade I mpox within the GBMSM community.