UKHSA Announces 8th Clade Ib Mpox Case in the UK

 

Credit WHO

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For the second time this week (see here), and the third time in the last 10 days (see here), the UK has announced a new imported clade Ib Mpox case.  Between imported (n=5), and locally acquired cases  (n=3), today makes the 8th confirmed report from the UK since October. 

The clade Ib Mpox virus is reportedly more virulent, and potentially more transmissible, than the clade II mpox virus which began its world tour in the spring of 2022.

So far, we've seen 11 non-African nations report imported cases of this Mpox Ib clade; Sweden, Thailand, India, Germany, the United Kingdom of Great Britain and Northern Ireland, the United States of America, Canada, Pakistan, Belgium, China, and France.

Several countries, including China, Belgium, Germany, France and the UK have reported limited secondary transmission.

The report from the UK HSA follows:

Latest update

A new case of clade Ib mpox has been detected in England, the UK Health Security Agency (UKHSA) can confirm. 

The case was detected in London and the individual is now under specialist care at the Royal Free Hospital High Consequence Infectious Diseases unit. They had recently returned from Uganda, where there is currently community transmission of clade Ib mpox. The UKHSA and NHS will not be disclosing any further details about the individual.

The risk to the UK population remains low. In the context of the outbreak in parts of Africa, we expect to see the occasional imported case of clade Ib mpox in the UK.

This is the eighth case of clade Ib mpox confirmed in England since October 2024. This case has no links to the previous cases identified in England.

Close contacts of the case are being followed up by UKHSA and partner organisations. Contacts will be offered testing and vaccination where needed to prevent further infections and they will be advised on any necessary further care if they have symptoms or test positive.

Dr Merav Kliner, Incident Director at UKHSA, said:

The risk to the UK population remains low. Close contacts have been identified and offered appropriate advice in order to reduce the chance of further spread.

Clade Ib mpox has been circulating in several countries in Africa in recent months. Imported cases have been detected in a number of countries including Belgium, Canada, France, Germany, Sweden and the United States.

There has been extensive planning undertaken to ensure healthcare professionals are equipped and prepared to respond to confirmed cases.

Further updates on clade Ib mpox case numbers will be published on the following page: Confirmed cases of mpox clade Ib in United Kingdom.

Science: Pre-exposure Antibody Prophylaxis Protects Macaques From Severe Influenza

BSL-3 – Credit CDC PHIL

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Although a handful of countries have arranged to purchase a limited quantity of H5Nx vaccine (see here, here, here, and here) - existing vaccines may not be a good match against any emerging `pandemic strain' of H5 - and even a well-matched vaccine might only provide limited protection against severe disease. 

Given the difficulties of mass producing (and deploying) billions of doses of a pandemic flu shot  (see Manufacturing Pandemic Flu Vaccines: Easier Said Than Done), most people won't be offered a flu jab during the first year (see Referral: SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1).

While there are antivirals like Oseltamivir (aka Tamiflu), I.V. Peramavir, and the newer Baloxavir, all are in limited supply, must be administered early in the course of an illness, and - at best - can only reduce the severity and duration of symptoms (Clinical Inf. Dis.: Benefit of Early Oseltamivir Therapy for Adults Hospitalized with Influenza A: An Observational Study).

Add in the potential for (spontaneous or acquired) resistance, and the fact that we've had problems distributing these type of drugs during moderate-to-severe flu seasons, and it is easy to see why other approaches are needed. 

During the COVID pandemic a third option - monoclonal antibodies (mAbs) - were introduced late in 2020, and gained wider use in 2021.  For a time they were hailed as `game changers', but within a couple of years all had been rendered ineffective by changes to the virus (see FDA Withdraws EUA (Emergency Use Authorization) For Last COVID Monoclonal Antibody: Bebtelovimab).

Still, since mAbs can be used both as a treatment and a (short-term) prophylaxis, the could be quite handy during the opening months of any novel flu outbreak.  Front line personnel could potentially receive it as a preventative measure, and those critically ill might be treated with it (along with antivirals). 

One of the human mAbs that has been under investigation for years is MEDI8852, which binds to the HA gene of influenza A, allowing it to neutralize a broad spectrum of  subtypes (see 2017's  J.I.D. The Hemagglutinin A Stem Antibody MEDI8852 Prevents and Controls Disease and Limits Transmission of Pandemic Influenza Viruses).

Yesterday a research article was published in the Journal Science which detailed experiments performed at the University of Pittsburgh with MEDI8852 in preventing HPAI H5 infection in Macaques.  While most of this report is behind a pay wall, the University of Pittsburgh has published a summary press release.

First, the link to the report, followed by excerpts from the press release. I'll have a bit more after the break:

Pre-exposure antibody prophylaxis protects macaques from severe influenza
Masaru Kanekiyo , Rebecca A. Gillespie , Kristine Cooper, Vanessa Guerra Canedo , Priscila M. S. Castanha, Amarendra Pegu, Eun Sung Yang , Luke Treaster, Gabin Yun, [...], and Simon M. Barratt-Boyes +26 authorsAuthors Info & Affiliations
Science 30 Jan 2025 Vol 387, Issue 6733 pp. 534-541

Antibody Treatment Prevents Severe Bird Flu in Monkeys

Anastasia (Ana) Gorelova

1/30/2025

PITTSBURGH – A prophylactic antibody-based immune therapy protects monkeys against severe disease caused by H5N1 avian flu, University of Pittsburgh and NIH Vaccine Research Center researchers report today in Science.

The broadly neutralizing antibody, which recognizes a relatively stable region of the bird flu virus, is less prone to losing its efficacy than antibodies targeting influenza’s more mutation-prone structures. This feature ensures that the immune protection can withstand the possible emergence of virus variants, akin to the SARS-CoV-2 mutants that evolved during the COVID-19 pandemic, and provide lasting protection against a globally spreading airborne infection.

“This type of prevention can be very useful in controlling infection outbreaks and containing the bird flu pandemic,” said co-corresponding author Douglas Reed, Ph.D., associate professor of immunology at Pitt’s School of Medicine and the Center for Vaccine Research. “In our testing, the antibody performed beautifully. The antibody could be useful as a prophylactic of severe disease in vulnerable populations, and it also helped us establish the testing threshold for antibody levels in blood, which would be useful for judging the immune protection generated by a universal flu vaccine.”

(SNIP)

“This antibody is targeting a region that does not vary across different influenza viruses,” said co-corresponding author Simon Barratt-Boyes, Ph.D., professor of infectious diseases and microbiology at Pitt’s School of Public Health and immunology at Pitt’s School of Medicine. “Think about it as a tree – different species have different leaves and crowns, but tree trunks look very much the same. Similarly, the stalk region of the bird flu virus closely resembles the same structure of seasonal influenza, which makes it possible for stalk-targeting antibodies to provide universal protection.”

In a new study, monkeys pre-treated with a moderate dose of a broadly neutralizing MEDI8852 antibody were universally protected against severe disease and death. In addition to confirming the antibody’s efficacy in preventing serious adverse health outcomes, scientists were also able to establish its minimum serum concentration required for protection – a measurement useful for establishing the protective threshold of a potential universal flu vaccine.

The research sets the stage for the development of medical countermeasures against future influenza virus pandemics. Serum levels of MEDI8852 sufficient for protection remained stable for 8 to 12 weeks, suggesting that, if given early, it could protect first responders and others caring for patients at the beginning of an outbreak of H5N1. 

Masaru Kanekiyo, Ph.D., of the NIH Vaccine Research Center, also contributed to the study. Other authors of this research are affiliated with the NIH Vaccine Research Center, Pitt, UPMC, University of Georgia and AstraZeneca.

This research was supported by the Vaccine Research Center, an intramural division of the National Institute of Allergy and Infectious Diseases; and the National Institute of Allergy and Infectious Diseases (grants, R01AI154894 and UC7AI180311, and contracts 75N93021C00014 and HHSN261201500003)

Although animal studies have been promising, MEDI8852 remains an investigational drug, and has not been approved for clinical use. It could be employed during a pandemic under an EUA (Emergency Use Authorization), as were the COVID mAbs.

While we have some existing pharmacological options for treating and preventing novel flu, none are particularly robust. 

• Vaccines and mAbs may reduce the severity of illness, but many breakthrough infections are still expected.

• Antivirals - if given early enough - may reduce the severity and duration of symptoms, and may improve survival rates of some people. But are far from being a `cure'. 

• All of these drugs may have (usually mild or moderate) adverse effects (AEs), that may discourage their use.

• And timely access to these drugs - even in high resource regions - is likely to be a problem.  For the rest of the world, highly unlikely. 

Our first line of defense will - once again - rely heavily on NPIs (non-pharmaceutical interventions), like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.  

All reasons why there is still value in trying to prevent - or at least delay - the next pandemic.

Preprint: Detection of Low Pre-existing Humoral Immunity Against Influenza Virus H5N1 clade 2.3.4.4b in Unexposed Individuals

 

Credit CDC Antigenic Characterization

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While an H5 pandemic is in no way certain, one of the burning unanswered questions in the world of virology is: `If HPAI H5 were to spark a pandemic, how much pre-existing immunity is there in the general population?'

Since we've not seen an H5 influenza pandemic before (at least in living memory), the assumption has been `little or none'.  

Last summer the CDC released a report (CDC A(H5N1) Bird Flu Response Update: Population Immunity to A(H5N1) clade 2.3.3.4b Viruses)  which - based on an analysis of sera (blood) collected from people of all ages in all 10 HHS regions - found:

Data from this study suggest that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States.  Antibody levels remained low regardless of whether or not the participants had gotten a seasonal flu vaccination, meaning that seasonal flu vaccination did not produce antibodies to A(H5N1) viruses.

This means that there is little to no pre-existing immunity to this virus and most of the population would be susceptible to infection from this virus if it were to start infecting people easily and spreading from person-to-person. This finding is not unexpected because A(H5N1) viruses have not spread widely in people and are very different from current and recently circulating human seasonal influenza A viruses.

But at the same time we've seen evidence which suggests that H5 viruses have a preference for infecting, and often killing, young people (see A Predilection For The Young).  Curiously, in China's 5 year battle against H7N9 - the opposite was true - with those under 40 far less affected (see comparison chart below). 

In 2016's Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at research which suggested the influenza HA Group type you are first exposed to makes a significant, and lasting, impression on your immune system. 

• Those born prior to the mid-1960s were almost certainly first exposed to Group 1 flu viruses (H1N1 or H2N2)

• Those born after 1968 and before 1977 would have been exposed to Group 2 (H3N2) 

• After 1977, both Group 1 and 2 viruses co-circulated, meaning the first exposure could have been to either one. 

We've also seen some research that suggests exposure to H1N1 (or the seasonal flu shot) may provide  some limited protection, since the the NA gene segment in seasonal H1N1 virus is antigenically similar to the NA in the clade 2.3.4.4b H5N1 virus (see EID Journal: A(H5N1) NA Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09).

A major caveat is, most of the studies we've seen over the past year have focused on the `bovine' B3.13 genotype of H5N1, which is just one of scores of H5 (subtypes/genotypes) circulating around the globe. It has been uncharacteristically mild in humans (compared to historical H5 strains), and their results may not apply across the board. 

But even if they do apply, the levels of immunity being reported in these studies have been quite limited.  All of which brings us to a new preprint, published this week in the BioRxiv, published by researchers at the University of Cologne, Germany. 

They describe finding `low but detectable' levels of pre-existing immunity to the H5N1 B3.13 genotype, but are unable to predict how much protection (if any) they might afford.

The full report runs 31 pages, so I've only posted the abstract and a few excerpts. Follow the link to read it in its entirety.  I'll have a brief postscript after the break. 

Detection of low pre-existing humoral immunity against influenza virus H5N1 clade 2.3.4.4b in unexposed individuals

Katharina Daniel, Leon Ullrich, Denis Ruchnewitz,  Matthijs Meijers,  Nico Joel Halwe,  Ursula Wild,  Jan Eberhardt, Ricarda Stumpf, Maike Schlotz,  Marie Wunsch,  Luana Girao Lessa, Christopher Dietrich, Andreas Pinger, Anna-Lena Schumacher,Maximilian Germer, Malena Rohde, Christian Kukat,  Lutz Gieselmann,  Henning Gruell,  Donata Hoffmann, Martin Beer, Thomas Erren, Michael Lässig, Christoph Kreer, Florian Klein

doi: https://doi.org/10.1101/2025.01.22.634277

This article is a preprint and has not been certified by peer review [what does this mean?].

Preview PDF

Abstract

The repeated spill-over of Influenza A virus H5N1 clade 2.3.4.4b from cattle to humans highlights the risk of a human H5N1 pandemic. Given the impact of pre-existing immunity on the course and severity of viral infections, we assessed in detail the humoral immunity against the H5N1 A/Texas/37/2024 isolate in H5N1-naïve individuals. 

To this end, we performed complementary binding and neutralization assays on 66 subjects and ranked activities among a panel of 76 influenza A virus isolates. We detected low but distinct cross-neutralizing titers against A/Texas/37/2024 with a 3.9 to 15.6-fold reduction compared to selected H1N1 or H3N2 strains.

Moreover, by cloning and evaluating 136 monoclonal antibodies from single memory B cells, we identified potent A/Texas/37/2024-neutralizing monoclonal antibodies in five out of six investigated individuals. These antibodies predominantly utilize VH1-69 gene segments, cross-neutralize H1, and compete with antibodies targeting the HA stem. Our findings demonstrate partial pre-existing humoral immunity to A/Texas/37/2024 in H5N1-naïve individuals.

(SNIP)

In summary, we demonstrate detectable but low levels of A/Texas/37/2024 humoral immunity in H5N1-naïve individuals with the presence of memory B cells that encode for potent H5-neutralizing antibodies. This is in contrast to the lack of cross-neutralizing antibodies for SARS-CoV-2 before the emergence of the Covid-19 pandemic (50, 51). However, in our study, we neither infer risks for H5N1 transmission from cattle to humans nor within the human population. Moreover, as we have learned from influenza and other viral pathogens, single mutations can be sufficient to mediate viral escape from humoral immunity as well as from antibody therapeutics (52–55). Therefore, further studies are needed to determine reliable correlates of protection for newly emerging influenza virus variants. 

Limitations 

This study is subject to the following limitations. First, the cohort is restricted to 66 individuals from the local area of Cologne, Germany and exhibits an above-average vaccination rate of 70%. Second, only a limited number of 6 individuals from this cohort were subjected to single B cell analysis. Third, direct comparison of neutralizing activity between human and avian HA subtypes might be affected by different preferences for α2- 6- over α2-3-linked glycans: Human and avian influenza A virus subtypes differ in their specificity for α2-3-linked or α2-6-linked sialic acids, with H5N1 (including A/Texas/37/2024) favoring α2-3-linked sialic acid, and human influenza A viruses favoring α2-6- over α2-3-linked sialic acid (56–59).

To determine pseudovirus infectivity, we used MDCK-SIAT1 cells, which overexpress α2-6 linked sialic acid (32) and are thus more readily infected by human subtype HA-pseudotyped viruses (i.e., H1, H2, H3). Finally, our analyses do not include clinical parameters and therefore we cannot draw conclusions on how pre-existing levels of H5-reactive antibodies reduce disease severity and clinical outcomes. 

(Continue . . . )

As we've discussed before (see here and here), the oft-quoted 50% CFR (Case Fatality Rate) of H5N1 is probably greatly exaggerated, as it is based only on cases sick enough to be hospitalized, and countries with better medical facilities (like Egypt) saw far fewer fatalities.

But even a more reasonable 2%-5% CFR would represent a public health crisis unlike anything we've seen in the modern era. 

So any advantage - even a small one - provided by childhood HA imprinting, pre-existing memory B cells, prior influenza infection, or seasonal flu vaccination, could end up having a huge impact. 

ECDC: Avian Flu - Virus mutations and Response Strategies

 


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Today the ECDC has released two major documents pertaining to the growing threat posed by avian influenza.  Due to their lengths (109 & 34 pages), I've only had time to briefly skim the contents, but I've posted the ECDC news release, and links (with summaries) from both reports. 

Avian influenza: EU agencies track virus mutations and analyse response strategies

News story

29 Jan 2025Avian influenza viruses pose an increasing threat, with the potential to adapt to humans and trigger future pandemics. Employing a One Health approach, the European Centre for Disease Prevention and Control (ECDC) and the European Food Safety Authority (EFSA) have issued scientific advice that assesses avian influenza virus mutations and the potential of these viruses to spread to humans, along with recommendations for the animal and public health sectors.

The work of the two Agencies draws on extensive data, including genetic analyses, human case studies, and antibody presence to outline current risks and mitigation strategies.

Pamela Rendi-Wagner, ECDC Director, said “Global developments demand that we stay alert and make sure Europe is prepared to respond to the threat of avian influenza. ECDC is supporting EU/EEA Member States in preparing, preventing and containing potential future outbreaks in animals and humans. Having strong preparedness plans in place is paramount to protect public health in Europe.”

“In 2024, avian influenza viruses expanded their reach, infecting previously unaffected species. Our work identifies key mutations linked to a potential spread to humans, requiring rapid detection and response. Collaboration and data sharing along the chain of actors involved remain essential in tackling emerging situations,” said Bernhard Url, EFSA Acting Executive Director.   

Experts generated a comprehensive list of mutations, from which they identified 34 genetic mutations that might increase the potential of avian influenza viruses to spread to humans. Using molecular analysis and genomic surveillance, animal and public health laboratories can refer to the list of mutations, which should be continuously updated, to monitor the emergence of strains that could potentially transmit to humans.

The scientific opinion also identifies how the adaptation of avian influenza viruses to mammals can be driven by factors such as genetic mutations, the mixing of genetic material between viruses, and the interaction with host immune response, alongside extrinsic factors that can increase the chance of transmission to humans, like human activities and environmental changes that increase contact between wildlife, poultry, livestock, and humans. High-density farming, low biosecurity practices, deforestation, urbanisation, and global trade amplify the risk of spillovers from animals to humans.

Key recommendations:

Genetic analysis: Use genetic sequencing to detect mutations or virus adaptations to mammals early. Invest in systems to quickly identify emerging viruses and mutations that enable animal-to-human spread.  

Animal surveillance: Monitor sick or dead mammals linked to infected wild birds, poultry or mammals. Track unexplained illness during high-risk periods and areas with avian influenza.  

Public health surveillance: Test exposed individuals and routinely send samples to further identify the flu sub-type. During outbreaks in animals, hospitals should enhance surveillance and vigilance, especially during flu season peaks when the risk of mixing of genetic material between viruses rises.  

Prevention measures: Implement robust farm biosecurity measures, train staff, vaccinate poultry, and prepare outbreak response plans. Ensure humans at risk follow influenza vaccination and antiviral treatment guidelines.

Public health preparedness measures: Raise awareness among high-risk groups, the general public and train healthcare workers to recognise and manage avian influenza. Ensure coordinated response plans for human cases. Develop guidelines and standard operating procedures for testing of exposed individuals and contacts of patients, including preventive protocols. Ensure coordinated response plans for human cases as part of national prevention, preparedness and response plans.

Alongside the scientific opinion, the Agencies also developed a guidance on how to investigate and control outbreaks of avian influenza affecting both humans and animals, using a coordinated One Health approach. Experts developed flowcharts outlining response actions for five outbreak scenarios at the human-animal-environment interface, emphasising the importance of an interdisciplinary response among all stakeholders. This work will support Member States in creating tailored national guidelines.  

The first, and largest report presents a risk assessment framework for dealing with zoonotic avian influenza, and includes a list of mutations related to mammalian adaptation.

Preparedness, prevention and control related to zoonotic avian influenza
Assessment
29 Jan 2025

A risk assessment framework was developed to evaluate the zoonotic potential of avian influenza (AI), focusing on virus mutations linked to phenotypic traits related to mammalian adaptation identified in the literature.

Virus sequences were screened for the presence of these mutations and their geographical, temporal and subtype-specific trends. Spillover events to mammals (including humans) and human seroprevalence studies were also reviewed. Thirty-four mutations associated with five phenotypic traits (increased receptor specificity, haemagglutinin stability, neuraminidase specificity, enhanced polymerase activity and evasion of innate immunity) were shortlisted.

AI viruses (AIVs) carrying multiple adaptive mutations and traits belonged to both low and highly pathogenic subtypes, mainly to A(H9N2), A(H7N9), A(H5N6) and A(H3N8), were sporadic and primarily detected in Asia. In the EU/EEA, H5Nx viruses of clade 2.3.4.4b, which have increased opportunities for evolution due to widespread circulation in birds and occasional cases/outbreaks in mammals, have acquired the highest number of zoonotic traits. Adaptive traits, such as enhanced polymerase activity and immune evasion, were frequently acquired, while receptor-specific mutations remained rare.

Globally, human cases remain rare, with the majority overall due to A(H5N1), A(H5N6), A(H7N9) and A(H9N2) that are among the subtypes that tend to have a higher number of adaptive traits. The main drivers of mammalian adaptation include virus and host characteristics, and external factors increasing AIV exposure of mammals and humans to wild and domestic birds (e.g. human activities and ecological factors). Comprehensive surveillance of AIVs targeting adaptive mutations with whole genome sequencing in animals and humans is essential for early detection of zoonotic AIVs and efficient implementation of control measures. All preparedness, preventive and control measures must be implemented under a One Health framework and tailored to the setting and the epidemiological situation; in particular, enhanced monitoring, biosecurity, genomic surveillance and global collaboration are critical for mitigating the zoonotic risks of AIV.

Download


Preparedness, prevention and control related to zoonotic avian influenza - EN - [PDF-12.76 MB]

The second report provides public health guidance for One Health investigations into outbreaks of zoonotic influenza in humans and in animals. 

Coordinated One Health investigation and management of outbreaks in humans and animals caused by zoonotic avian influenza viruses

Public health guidance
29 Jan 2025

The report should assist in developing guidance documents to facilitate coordinated One Health investigations and the management of outbreaks in humans and animals caused by zoonotic avian influenza viruses.

Executive summary


When investigating and controlling outbreaks caused by zoonotic avian influenza viruses (AIV), a One Health approach is key. However, knowledge-sharing on AIV-specific One Health strategies, tools and action plans remains limited across the EU/EEA. It is crucial to establish responsibilities, capacity requirements, and collaboration mechanisms during 'peace time' to enable timely and effective outbreak investigations and management.

This report focuses on five scenarios for outbreak investigation and management of zoonotic AIV at the human animal-environment interface, emphasising key actions for the stakeholders involved. The document primarily highlights the collaborative framework necessary for interdisciplinary coordinated responses, referring to more detailed guidance and technical reports published elsewhere when applicable. Three scenarios are triggered by suspected outbreaks in animals, including kept animals of listed species, non-listed species, companion animals and wild birds/mammals. The other two scenarios are initiated by a probable human case or detection of the virus in wastewater or environmental samples (e.g. surface water or other sources).

All scenarios require cross-sectoral coordination and a One Health approach. While the specific sequence of actions and communication needs may differ across scenarios, the overarching response mechanisms for outbreak investigations and management remain consistent. By presenting each scenario alongside the integrated actions of stakeholders, the report identifies critical development needs, such as tools (e.g. communication and data sharing platforms); key points for information exchange across sectors, triggers for joint risk assessments, and gaps in existing knowledge.

The document should assist in developing guidance documents to facilitate coordinated One Health investigations and the management of outbreaks in humans and animals caused by zoonotic avian influenza viruses.

Download


Coordinated One Health investigation and management of outbreaks in humans and animals caused by zoonotic avian influenza viruses - EN - [PDF-4.99 MB]

Emerg. Microbes & Infections: Emergence of a Novel Reassortant HPAI Clade 2.3.4.4b A(H5N2) Virus, 2024

 

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The superpower of influenza A viruses is their ability for different subtypes to co-infect a host, swap genetic material, and generate a new `hybrid' virus; a reassortant.  This reassortment can generate new genotypes, or - if the HA and NA are involved - a new subtype. 

Reassortment - or Antigenic`Shift' - can produce abrupt changes in the behavior of the generated hybrid.  Most are evolutionary failures, unable to compete with its parental strains. But every once in awhile, a new, `improved', virus emerge.  

As any virologist will tell you; `Shift Happens'. 

Reassortment is the process that enabled an avian H5N1 virus (B3.13) to infect cattle, and has recently produced a more virulent D1.1 genotype, which is spreading rapidly across the nation.  It produced a new H5N9 subtype in California poultry, and it could potentially lead to a hybrid of seasonal and avian flu sometime in the future (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses).

Today we have a report, published this week in Emerging Microbes & Infections, of the discovery of an HPAI H5N2 clade 2.3.4.4b virus in Egypt, one that came about through the merger of the H5N1 virus and the ubiquitous, and highly mutable, LPAI H9N2 virus. 

We've often discussed the role that H9N2 has played in the creation of some of the most dangerous HPAI viruses, including H5N1, H5N6, H10N3, and H7N9 (see Transboundary & Emerging Dis.: The H5N6 Virus Containing Internal Genes From H9N2 Exhibits Enhanced Pathogenicity and Transmissibility).

While much as been made over the fact that humans may have some limited cross-immunity to the N1 component of H5N1, a new subtype - sporting an N2 or an N9 surface gene - might prove far more problematic. 

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

Emergence of a novel reassortant highly pathogenic avian influenza clade 2.3.4.4b A(H5N2) Virus, 2024

Rabeh El-Shesheny,Mokhtar Gomaa,Mohamed El Sayes,Mina Nabil Kamel,Ahmed El Taweel,Omnia Kutkat, show all

Article: 2455601 | Accepted author version posted online: 27 Jan 2025

Cite this article https://doi.org/10.1080/22221751.2025.2455601 

Abstract

Reassortant highly pathogenic avian influenza A(H5N2) clade 2.3.4.4.b viruses were detected from ducks and environmental samples in Egypt, June 2024. Genomic and phylogenetic analyses revealed a novel genotype produced by reassortment of an A(H5N1) clade 2.3.3.4b virus with an A(H9N2) G1-like virus. Monitoring the spread of this virus is important.

Egypt has experienced repeated outbreaks of highly pathogenic avian influenza (HPAI) viruses of the H5 goose/Guangdong lineage since 2006, causing devastating losses to the poultry industry and directly affecting food security. During the past and current decades, several clades of HPAI viruses were detected. Most recently, clade 2.3.4.4b A(H5N1) was introduced into Egypt during the winter of 2021 and replaced the previous HPAI A(H5N8) clade 2.3.4.4b strains [1]. Phylogenetic analyses showed that these viruses retained genomic characteristics similar to Eurasian strains, suggesting continuous evolution and adaptation of the virus in the region. These introductions have resulted in serious economic repercussions on the poultry sector in this country. Furthermore, a total of 359 confirmed cases of human infection with HPAI (H5N1) were reported from Egypt to the World Health Organization (WHO).

In addition to the HPAI (H5Nx) viruses, low pathogenic avian influenza (LPAI) H9N2 subtype is widely circulating in poultry in Egypt since the beginning of 2010 [2,3]. The co-circulation of both subtypes, A(H5N1) and A(H9N2) viruses, was observed in our active surveillance [4]. Furthermore, we detected H5N1/H9N2 co-infection in the same domestic poultry host [4]. Two studies reported natural reassortment events in Egypt between H5N1 and H9N2 viruses [5,6]. Furthermore, four cases of human infection with H9N2 AIV were reported in Egypt in 2014-2015 [7].

These co-circulation and co-infection events provide appropriate conditions for the emergence of novel reassortant viruses with unknown biological characteristics and zoonotic potential. Here, we characterized the complete genome of five HPAI (H5N2) novel virus strains from Egypt and report the identification and characterization of a novel natural reassortant HPAI (H5N1) virus that obtained the NA and NS genes from an H9N2 virus.

The Study

Through active surveillance of influenza viruses in poultry and wild birds in Egypt, we detected five HPAI A(H5N2) viruses from live bird markets (LBMs) in June 2024.

Three viruses, A/MuscovyDuck/Egypt/BA21820OP/2024(H5N2), A/MuscovyDuck/Egypt/BA21821C/2024(H5N2), and A/MuscovyDuck/Egypt/BA21822OP/2024(H5N2) originated from duck swabs, while two viruses, A/environment/Egypt/BA21829W/2024(H5N2) and A/Environment/Egypt/BA21832W /2024(H5N2) were detected from water samples from poultry waterers.

(SNIP)

To identify mutations that may be associated with virulence, pathogenicity, and transmission in mammals, we analyzed the amino acid sequences of the novel viruses. The E627 K or D701N substitutions in PB2 that increase virulence in mammals were not detected. However, all five isolates had amino acid substitutions that included L89 V, G309D, T339 K, and I504 V in PB2, known to increase virulence in mice [9], and A515 T in PA, known to increase polymerase activity [10]. All the strains expressed PB1-F2 of 90 amino acids and had an N66S mutation (Table S3). S31N amantadine resistance marker in M2 protein [11] was detected in our strains. Our analyses showed that NS1 protein contains amino acid substitutions P42S and V149A which might increase replication efficiency as well as virulence in mammals (Table S3).

Discussion

H9N2 avian influenza viruses (AIVs) play a critical role in the evolution of influenza viruses as they are donors of genetic material to emerging zoonotic viruses such as H5Nx, H7N9, and H10N8 AIVs. The H5 HPAI of different clades reassorted with N2 genes in various countries but the clade 2.3.4.4c showed the highest number of reassortment events (n = 536 strains) (Table S4). The reassortments of H5Nx clade 2.3.4.4b HPAI and LPAI viruses were reported in various countries. Novel reassortments of clade 2.3.4.4 HPAI and LPAI from North America were responsible for outbreaks in domestic cattle and spillover into poultry as well as mammals [12,13]. In a previous study, the insertion of the N2 gene from an H9N2 virus into an H5 vaccine strain on a PR8 backbone increased its replication as compared to a strain that had the N1 [14]. Hence, those novel viruses have the potential to display biological features that may enhance their virulence, pathogenicity, replication, and transmission in avian and mammalian hosts.

Our study represents the first report of detection and genomic characterization of HPAI H5N2 clade 2.3.4.4b in Egypt. The genomic characteristics of those viruses revealed mutations that could have important implications on animal and human health. Further surveillance and biological studies are urgently required to assess the potential of spread of this virus and evaluate its biological characteristic to investigate its zoonotic potential and understand its associated risks.

Six years ago, in  J. Virology: Genetic Compatibility of Reassortants Between Avian H5N1 & H9N2 Influenza Viruses, we looked at the results of an Egyptian lab experiment which found that reassortments between H5N1 and H9N2 could produce multiple viable, and potentially dangerous, progeny. 

The authors wrote:

To evaluate the potential public health risk of reassortants of these viruses, we used reverse genetics to generate the 63 possible reassortants derived from contemporary Egyptian H5N1 and H9N2 viruses, containing the H5N1 surface gene segments and combinations of the H5N1 and H9N2 internal gene segments, and analyzed their genetic compatibility, replication ability, and virulence in mice. Genes in the reassortants showed remarkably high compatibility.

The replication of most reassortants was higher than the parental H5N1 virus in human cells. Six reassortants were thought to emerge in birds under neutral or positive selective pressure, and four of them had higher pathogenicity in vivo than the parental H5N1 and H9N2 viruses.

Our results indicated that H5N1-H9N2 reassortants could be transmitted efficiently to mammals with significant public health risk if they emerge in Egypt, although the viruses might not emerge frequently in birds.

Less than a year later, in EID Journal: Novel Reassortant HPAI A(H5N2) Virus in Broiler Chickens, Egypt, we saw a new proof of concept in the field, after an HPAI H5N8 virus reassorted with an LPAI H9N2 virus, and produced a new HPAI H5N2 virus in Egyptian poultry.

While the world seems to be focused on HPAI in North America, this should remind us that H5Nx viruses are occurring all around the globe, and that a new threat could emerge anytime, and from just about anywhere. 

Stay tuned. 

WHO: 46th Update On Multi-country Outbreak of Mpox & Risk Assessment on Clade Ia

 
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Less than 3 years ago Mpox was confined almost exclusively to central and west Africa - with only a handful of exported cases - and consisted of two clade (I & II).  Clade II, which was found primarily in the DRC, was the more severe of the two. 

But for years researchers have warned that the Monkeypox virus was becoming more transmissible, and it had the ability to mutate into a more dangerous variant.

A 2016 study (see EID Journal: Extended H-2-H Transmission during a Monkeypox Outbreak) looked at a large 2013 outbreak of Monkeypox in the DRC and suggested that the virus's epidemiological characteristics may be changing (possibly due to the waning smallpox vaccine derived immunity in the community).

The DRC had reported a 600% increase in cases over both 2011, and 2012.  The authors also cite a higher attack rate, longer chains of infection, and more pronounced community spread than have earlier reports.

Like all viruses, Monkeypox continues to evolve and diversify, as discussed in the 2014 EID Journal article Genomic Variability of Monkeypox Virus among Humans, Democratic Republic of the Congo, where the authors cautioned:

Small genetic changes could favor adaptation to a human host, and this potential is greatest for pathogens with moderate transmission rates (such as MPXV) (40). The ability to spread rapidly and efficiently from human to human could enhance spread by travelers to new regions.

And in the spring of 2022, a new clade IIb began spreading internationally, forcing the WHO to declare a PHEIC (Public Health Emergency of International Concern).  While that outbreak slowed over time, at least 100,000 cases were reported outside of Africa. 

In late 2023 another - more formidable - clade Ib clade emerged (see Preprint: Sustained Human Outbreak of a New MPXV Clade I Lineage in Eastern Democratic Republic of the Congo), that was reported to be more transmissible, and potentially more severe.

In mid-August of 2024 the WHO declared the Mpox outbreak in Central Africa to constitute a PHEIC  after reports that clade (Ib) of the virus had begun to spread outside of the DRC (see More African Nations Reporting Mpox - Africa CDC Mpox Update (Jul 30th)). 

Today, there are 4 officially recognized clades of the Mpox virus (Ia, Ib, II, IIb), and more could emerge over time. A reminder of what can happen when an emerging virus is allowed to simmer for years without serious interventions.

Last month the WHO published a new, updated risk assessment, which puts the risk of national and international spread of clade Ib as HIGH and Ia, II, and IIb as MODERATE.  

So far, at least 11 non-African nations have reported imported clade IIb cases over the past 6 months. 

Yesterday the WHO released their latest update (#46) on the multi-country spread of Mpox (see excerpts below).  Follow the link to read the report in its entirety. 

Highlights

• The outbreak of mpox due to clade Ib monkeypox virus (MPXV) continues predominantly in the Democratic Republic of the Congo, Burundi and Uganda, with new travel-related cases identified in previously unaffected countries. 

• The Democratic Republic of the Congo remains the most affected country, experiencing circulation of both clade I MPXV subclades. Despite many of the provinces reporting stable trends in cases, the situation in the country remains concerning, with continued sustained circulation of virus strains. The escalating violence in the eastern part of the country poses additional challenges for the mpox response.

• Burundi and Uganda continue to report the most cases outside of the Democratic Republic of the Congo. 

• New travel-related cases of mpox due to clade Ib MPXV have been detected in countries that had already detected travel-related cases before, including China, Germany, Thailand, the United Kingdom of Great Britain and Northern Ireland and the United States of America. 

• Azerbaijan has reported its first case of mpox. Information on the MPXV clade is not yet available. 

In a separate document issued earlier this week, the WHO released a Risk Assessment on the clade Ia Mpox virus (which has not spread internationally). While confidence is limited (low to moderate), right now it doesn't appear to pose as big of risk to the international community as clade Ib.

As our collective immunity from the smallpox vaccine - which was discontinued in the late 1970s - wanes, there will be increased opportunities for emerging pox viruses to make a comeback.  We ignore them at considerable risk to global public health. 

Some other 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

More Reports On HPAI H5N5 In Iceland

 

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While our biggest avian flu concern remains HPAI H5N1, over the years we've seen closely related H5N2, H5N3, H5N4, H5N5, H5N6, H5N8, and H5N9 viruses - the product of H5N1 reassorting with other LPAI viruses - infecting both birds and mammals around the globe.

While most have struggled to compete with H5N1, between 2014-2020, HPAI H5N8 became the dominant subtype globally, and HPAI H5N6 viruses have shown persistence in China and East Asia for more than a decade. 

Since regaining its mantle in 2021, H5N1 has had little competition. But over the past few years we've seen reports of an H5N5 variant - first in Europe and Asia, then in Canada - which has not only managed to survive, it appears to be thriving. 

WOAH WAHIS Listing of Countries Reporting H5N5

Last July, in Cell Reports: Multiple Transatlantic Incursions of HPAI clade 2.3.4.4b A(H5N5) Virus into North America and Spillover to Mammals, researchers reported finding the mammalian adaptive E627K mutation in a number of samples.

They wrote:

Thus, while A(H5N5) viruses are comparably uncommon, their high virulence and mortality potential demand global surveillance and further studies to untangle the molecular markers influencing virulence, transmission, adaptability, and host susceptibility.

Not quite 3 weeks ago, the Icelandic Food and Veterinary Authority (MAST) reported an H5N5 Infection In Domestic Cat.  Several days later, MAST reported another cat infected (see translation below).

Another cat with bird flu

News - 10.01.2025

As stated in the Food Agency's report earlier this week, bird flu H5N5 was diagnosed for the first time in cats killed before Christmas. Today, the UI Experimental Plant analyzed pathology that Keldum had bird flu H5N5 in other cats. That cat was from a home in Seltjarnarnes. He had been ill with similar symptoms to the previous cat; fever, weakness and nervousness (seizures and stiffness), before being killed. He is most likely to have been infected with bird seed. Other cats are in the home and they are healthy. There is no connection between the cats that have been diagnosed with bird flu. There is no indication that the bird flu is infected between cats.

Numerous reports have been received by the Food Agency on the death of wild birds recently, especially on gray geese in the capital. Bird flu H5N5 was diagnosed this week in elves and gray geese.

The Food and Drug Administration recommends that people try to prevent their cats from coming into contact with birds.

         (Continue . . . ) 

On January 22nd, MAST announced the detection of H5N1 in a captive wild mink, along with more die offs in wild birds.

Bird fluemia is still to be detected

News - 22.01.2025

Bird flu H5N5 is still detected in wild birds and the UI Experimental Pathology that Keldum has now also confirmed the analysis of the virus in a mink found dead in the Reykjavik Aquarius on January 17. No new cases have been detected in cats or other mammals.

The Food Agency is received every day numerous reports of wild bird death. Samples are taken for research in the case of birds of regions or of species not previously identified by the virus.

After studies of samples from a number of gray goose confirmed bird flu, it is assumed that there is an overwhelming likelihood that gray geese found dead in the metropolitan area have been killed due to avian influenza and therefore no longer sampled. The Food Agency, in collaboration with the Reykjavik Animal Service, estimates that approx. 150 carcasses of gray goose have been found since the beginning of the year in Reykjavik, and since last week also elsewhere in the metropolitan area.

When bird flu H5N5 was introduced on a turkey farm in December, various measures were ordered. These included the killing of all birds in the house in question, strict transport restrictions in a specific area of the environment, increased quarantine, surveillance, cleaning and disinfection. The measures managed to prevent further spread of the virus among poultry.

         (Continue . . . ) 

Based on the machine translation of these, it appears that Iceland's MAST are only reporting two cats infected with the H5N5 virus.  But, in the first case, two other cats from the same litter died, and were not tested, which is apparently why WOAH is reporting 4 cats infected. 

In addition to Iceland, H5N5 reports have been filed with WOAH from the UK, Norway, Germany, and Greenland. 

Canada's most recent report was December 23rd. So far, the United States has yet to report this subtype.

While I'm not expecting a shifting away from H5N1 anytime soon, it isn't beyond the realm of possibility that a new subtype - H5N5, H5N2, H5N6 or some other n-type - could emerge and give it a run for its money. 

As a segmented virus with 8 largely interchangeable parts, the flu virus is like a viral LEGO (TM) set which allows for the creation of new subtypes or genotypes. Each gene segment can host multiple unique amino acid changes (e.g. HA-Q226L, PB2-E627K, etc) that can alter the behavior - and host range - of the virus.

All reasons why we shouldn't be surprised when the flu does the unexpected. 

UKHSA: 7th Confirmed Mpox Clade Ib In UK

 

Credit WHO

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Less than a week ago the UK HSA announced the 6th clade Ib Mpox case in the UK (3 imported, 3 locally acquired).  Today they are announcing their 7th case; detected  in an individual who recently travelled from Uganda. 

The clade Ib Mpox virus is reportedly more virulent, and potentially more transmissible, than the clade II mpox virus which began its world tour in the spring of 2022.

So far, we've seen 11 non-African nations report imported cases of this Mpox Ib clade; Sweden, Thailand, India, Germany, the United Kingdom of Great Britain and Northern Ireland, the United States of America, Canada, Pakistan, Belgium, China, and France.

Several countries, including China, Belgium, Germany, France and the UK have reported limited secondary transmission.

The latest update from the UKHSA is unusually brief.

Latest update

Another case of clade Ib mpox has been detected, bringing the total number of confirmed cases since October 2024 to 7, the UK Health Security Agency (UKHSA) can confirm.

The individual had recently travelled to Uganda. The risk to the UK population remains low.

The UKHSA and NHS will not be disclosing any further details about the individual.

Professor Susan Hopkins, Chief Medical Adviser at UKHSA, said:

The risk to the UK population remains low. Close contacts have been identified and offered appropriate advice in order to reduce the chance of further spread.

Last month the WHO published a new, updated risk assessment, which puts the risk of national and international spread as HIGH.

UKHSA Statement On H5 Positive Case In the UK

 

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Today the UK HSA announced a human case of H5N1 in a person with poultry exposure in the West Midlands.  Like so many other statements we see from public health agencies on H5 cases, this announcement is long on reassurance and short on details.  

Human case of avian flu detected in England

UKHSA confirms rare case of bird flu (H5N1) in the West Midlands region.

From: UK Health Security Agency Published27 January 2025

UKHSA has confirmed a case of influenza A(H5N1) in a person in the West Midlands region. Bird-to-human transmission of avian influenza is rare and has previously occurred a small number of times in the UK.

The person acquired the infection on a farm, where they had close and prolonged contact with a large number of infected birds. The risk to the wider public continues to be very low.

The individual is currently well and was admitted to a High Consequence Infectious Disease (HCID) unit.

The birds were infected with the DI.2 genotype, one of the viruses known to be circulating in birds in the UK this season. This is different to strains circulating among mammals and birds in the US.

Although there has been no demonstrated human-to-human transmission despite extensive recent surveillance of influenza A(H5N1), UKHSA has been tracing all individuals who have been in contact with the confirmed case of avian influenza. Those at highest risk of exposure have been offered antiviral treatment. This is done to reduce the chance that any virus they have been exposed to will be able to cause infection.

The case was detected after the Animal and Plant Health Agency (APHA) identified an outbreak of avian influenza(H5N1) in a flock of birds. UKHSA carried out routine monitoring on people who had been in close contact with the infected birds.

Professor Susan Hopkins, Chief Medical Adviser at UKHSA, said:

The risk of avian flu to the general public remains very low despite this confirmed case. We have robust systems in place to detect cases early and take necessary action, as we know that spillover infections from birds to humans may occur.

Currently there is no evidence of onwards transmission from this case.

People are reminded not to touch sick or dead birds and it’s important that they follow Defra advice about reporting any suspected avian influenza cases.

UK Chief Veterinary Officer Christine Middlemiss said:

While avian influenza is highly contagious in birds, this is a very rare event and is very specific to the circumstances on this premises.

We took swift action to limit the spread of the disease at the site in question, all infected birds are being humanely culled, and cleansing and disinfection of the premises will be undertaken all to strict biosecure standards. This is a reminder that stringent biosecurity is essential when keeping animals.

We are seeing a growing number of avian flu cases in birds on both commercial farms and in backyard flocks across the country. Implementing scrupulous biosecurity measures will help protect the health and welfare of your birds from the threat of avian influenza and other diseases.

Andrew Gwynne, Minister for Public Health and Prevention, said:

The safety of the public is paramount, and we are monitoring this situation closely.

The risk of wider or onward transmission is very low, however the UK remains prepared and ready to respond to any current and future health threats.

We recently added the H5 vaccine, which protects against avian influenza, to our stockpile as part of our preparedness plans.

UKHSA will publish further details about the confirmed human case in due course.

WOAH: California Reports New H5N9 Reassortant In Ducks

 

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While HPAI H5N1 has remained the dominant H5 subtype around the globe, we've recently seen inroads made by an HPAI H5N5 subtype in Canada and parts of Europe (see The Continued Expansion of HPAI H5N5).  

These new subtypes arise due to reassortment, which occurs when two different flu viruses infect the  same host - share genetic material - and produce a hybrid. 

Most reassortants will be unable to compete with their parental strains, but sometimes a new and viable  subtype is created. HPAI H5N5 has shown some modest success in this regard, but it remains a minor player. 

Today WOAH has reported (#6201) that a new HPAI H5N9 reassortment has been detected at a duck farm in Merced County, California.  This HPAI subtype was last reported during the 2016/2017 H5N8 epizootic in Europe (see DEFRA: Update On HPAI & LPAI Avian Flu Outbreaks in France)

Details are scant, but they provide the following epidemiological data. 

SOURCE OF EVENT OR ORIGIN OF INFECTION

• Unknown or inconclusive

EPIDEMIOLOGICAL COMMENTS

Highly pathogenic avian influenza (HPAI) H5N9, Eurasian lineage goose/Guangdong clade 2.3.4.4b and HPAI H5N1 clade 2.3.4.4b were confirmed in a commercial duck premises in Merced County, CA. This is the first confirmed case of HPAI H5N9 in poultry in the United States. The USDA Animal and Plant Health Inspection Service (APHIS), in conjunction with State Animal Health and Wildlife Officials, are conducting comprehensive epidemiological investigations and enhanced surveillance in response to the HPAI related events.

For now, this appears to be a one-off event, and there is no word on its pathogenicity.  Whether HPAI H5N9 has `legs', and will spread beyond this duck farm - or will spontaneously appear elsewhere - remains to be seen.  

But it does remind us that nature's gain of function (GOF) field experiment continues, and we should be prepared for surprises.