Thursday, April 3, 2025

#Genomic #signatures and #host #adaptation of #H5N1 clade 2.3.4.4b: A call for global #surveillance and multi-target antiviral strategies

Highlights

• Phylogenetic analysis of genotype B3.13 and D1.1 across the species.

• Mutations on the receptor binding sites related to receptor preferring.

• Host adaptability differences between B3.13 and D1.1.

• Antivirals resistance mutations emergence of genotype B3.13 and D1.1.


Abstract

The recent report of the first fatality associated with infection by influenza virus H5N1 clade 2.3.4.4b, identified as genotype D1.1, which is distinct from the B3.13 genotype, has sparked fears of a potential human pandemic. However, the genetic relationships between B3.13 and D1.1, as well as their origins, host adaptability, and antiviral resistance, remain poorly understood. Here we conducted a comprehensive phylogenetic and comparative analysis of H5N1 clade 2.3.4.4b across multiple species, in order to identify the molecular characteristics and frequency of resistance mutations in these two genotypes, elucidate their evolutionary trajectories, and assess their implications for public health. Our results demonstrate that B3.13 exhibits mammalian adaptability, while D1.1 retains avian adaptability. Importantly, both genotypes display limited occurrences of human-like signatures, which can help alleviate public anxiety. Additionally, the emergence of the resistance mutations in the clade 2.3.4.4b on the binding sites of antivirals calls for the development of multi-target antiviral strategies to mitigate the risk of resistant strain reassortment.

Source: Current Research in Microbiological Sciences, https://www.sciencedirect.com/science/article/pii/S2666517425000392?via%3Dihub

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A #Wildlife #Health #Outbreak #Response Table-top Exercise for #Pandemic Preparedness #Planning

Abstract

Zoonotic diseases have received significantly more attention over the last few decades, emerging with increasing frequency and causing the majority of notable disease outbreaks in this century, including the COVID-19 pandemic. As human activities and shifting climate patterns induce changes in the environment that alter habitat and range of reservoir species, the potential for human and animal interactions will increase and enhance the opportunity for spillover. Thus, any emergency response preparedness planning must take into account the function and coordination of agencies across the sectors of human, animal and environmental health. Within the Commonwealth of Pennsylvania a table-top exercise was performed to evaluate a multi-agency response during a hypothetical zoonotic disease investigation. The exercise was evaluated by the participants to gain feedback on the overall process and lessons learned. Here, we describe the tabletop exercise scenario and the insights gained. We found that differences in operational structure create challenges for interdepartmental communication and in the ability to resource a coordinated response, highlighting opportunities to develop infrastructure that will facilitate future actions. A set of recommendations are outlined that may enhance cross-agency activities and promote more effective and efficient emergency response.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.04.01.646690v1

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#Germany - #Influenza A #H5N1 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

One red fox in Sachsen and one in Nordrhein-Westfalen States.

Source: WOAH, https://wahis.woah.org/#/in-review/6398

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#NASA #Update on the #Size Estimate and #Lunar #Impact Probability of #Asteroid 2024 #YR4

Since near-Earth asteroid 2024 YR4 was first discovered in December 2024, NASA and the worldwide planetary defense community have continued to observe the asteroid, which was ruled out as a significant impact risk to Earth. New infrared observations from NASA’s James Webb Space Telescope have decreased the uncertainty of the asteroid’s size and 2024 YR4 is now estimated to be 174-220 feet (53-67 meters), about the size of a 10-story building. The previous size estimate of 131-295 feet (40-90 meters) was derived from visible light measurements from ground-based telescopes.  

(...)

Experts at NASA’s Center for Near Earth Object Studies at the agency’s Jet Propulsion Laboratory have updated 2024 YR4’s chance of impacting the Moon on Dec. 22, 2032 from 1.7% as of late February to 3.8% based on the Webb data and observations from ground-based telescopes. There is still a 96.2% chance that the asteroid will miss the Moon. In the small chance that the asteroid were to impact, it would not alter the Moon’s orbit.  

After mid-April, asteroid 2024 YR4 will be too far and faint to be observed by ground-based telescopes but Webb will observe the asteroid again in May.  

Source: NASA, https://science.nasa.gov/blogs/planetary-defense/2025/04/02/nasa-update-on-the-size-estimate-and-lunar-impact-probability-of-asteroid-2024-yr4/

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#India, Andhra Pradesh reports first #human #death owing to #H5N1 virus

{Excerpt}

(...) Samples of a two-year-old girl from Palnadu district’s Narasaraopeta, who died of multi-organ failure at AIIMS-Mangalagiri on March 16, tested positive for H5N1 virus. The confirmation from National Institute of Virology (NIV-Pune) came on March 31. (...)

Source: The Hindu, https://www.thehindu.com/news/national/andhra-pradesh/ap-reports-first-human-death-owing-to-h5n1-virus/article69403347.ece

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Wednesday, April 2, 2025

#Clinical presentation of #Oropouche virus #infection: A systematic review and meta-analysis

Abstract

Background

The recent surge in incidence and geographic spread of OROV infections poses an escalating threat to global public health. However, studies exploring the clinical signs of OROV infection remains exceedingly limited.

Methods

We searched for OROV studies published until June 17, 2024, in several electronic databases including MEDLINE, EMBASE, SCOPUS, and the Cochrane Library.

Results

In total, 15 studies involving 806 patients with OROV infection were eligible for inclusion. General symptoms with fever and headache were the most common. Gastrointestinal disturbances like nausea/vomiting, anorexia, and odynophagia were also prevalent, along with ocular symptoms, mainly retro-orbital pain, photophobia, and redness. Respiratory symptoms, such as cough, sore throat and nasal congestion, are present, and skin-related issues like rash, pruritus, and pallor were also identified.

Conclusion

Overall, this study provides a foundational understanding of OROV’s clinical manifestations to guide diagnosis, management, and public health interventions against this neglected tropical disease.


Author summary

In the realm of life sciences, understanding the full scope of infectious diseases is crucial for protecting public health. Oropouche virus (OROV), a relatively under-studied pathogen, has been showing an alarming increase in both incidence and geographical spread recently. Despite its growing threat, our knowledge of the clinical symptoms it causes has been severely lacking. Our study is the first of its kind to comprehensively review and analyze available research on OROV-related symptoms. By pooling 15 studies involving 806 patients, we’ve uncovered a range of symptoms from common fever and headache to less-known ocular, gastrointestinal, and skin - related issues. This new understanding is vital. For scientists, it lays the groundwork for further research into OROV’s biology and disease mechanisms. For non-scientists, it helps in early recognition of the disease, which is key to getting proper medical care and preventing its spread.

Source: PLoS Neglected Tropical Diseases, https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0012962

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Rates of #infection with other #pathogens after a positive #COVID19 test versus a negative test in #US #veterans (November, 2021, to December, 2023): a retrospective cohort study

Summary

Background

SARS-CoV-2 infection leads to post-acute sequelae that can affect nearly every organ system, including the immune system. However, whether an infection with SARS-CoV-2 is associated with increased risk of future infections with other pathogens is not yet fully characterised. In this study, we aimed to test the association between a positive test for COVID-19, compared with a negative test, and rates of future infections with other pathogens.

Methods

We used the US Department of Veterans Affairs health-care databases to build a spatiotemporally aligned cohort of 231 899 people with a positive COVID-19 test and 605 014 with a negative COVID-19 test (test-negative control group) between Nov 1, 2021, and Dec 31, 2023. We first did a discovery approach to map the associations between those with a positive COVID-19 test versus a negative test and laboratory-based outcomes of infectious illnesses. We then compared rates of a prespecified set of infectious disease outcomes between those with and without a positive COVID-19 test. To evaluate the specificity of the findings to COVID-19, we compared the rates of a prespecified set of infectious disease outcomes in a spatiotemporally aligned cohort of people admitted to hospital for COVID-19 (n=12 450) versus those admitted for seasonal influenza (n=3293). Outcomes were ascertained 30 days after the date of the first test until the end of follow-up (365 days after the first test plus 30 days, death, or July 18, 2024, whichever came first). An inverse probability weighting approach was used to balance demographic and health characteristics across cohorts. Log-binomial regression models were used to estimate risk ratios (RRs) and 95% CIs.

Findings

In the 12 months of follow-up, compared with participants who had a negative test for COVID-19, people with COVID-19 who did not require admission to hospital during the acute phase of infection had increased test positivity rates for bacterial infections (in blood, urine, and respiratory cultures) and viral diseases (including Epstein–Barr virus, herpes simplex virus reactivation, and respiratory viral infections). People who were positive for COVID-19 and admitted to hospital also had increased rates of bacterial infections in blood, respiratory, and urine biospecimens, and viral infections in blood and respiratory biospecimens. Analyses of prespecified outcomes showed that, compared with the test-negative control group, participants with a positive COVID-19 test who were not admitted to hospital had significantly increased rates of outpatient diagnosis of infectious illnesses (RR 1·17 [95% CI 1·15–1·19]), including bacterial, fungal, and viral infections; outpatient respiratory infections (1·46 [1·43–1·50]); and admission to hospital for infectious illnesses (1·41 [1·37–1·45]), including for sepsis and respiratory infections; the rates of prespecified outcomes were generally higher among those who were admitted to hospital for COVID-19 during the acute phase. Compared with people admitted to hospital for seasonal influenza, those admitted for COVID-19 had higher rates of admission to hospital for infectious illnesses (1·24 [1·10–1·40]), admission to hospital for sepsis (RR 1·35 [1·11–1·63]), and in-hospital use of antimicrobials (1·23 [1·10–1·37]).

Interpretation

Our results suggest that a positive test for COVID-19 (vs a negative test) was associated with increased rates of diagnosis of various infections in the 12 months following an acute SARS-CoV-2 infection. The putative long-term effects of COVID-19 on the immune system and the propensity for infection with other pathogens should be further evaluated in future studies.

Source: Lancet Infectious Diseases, https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00831-4/abstract?rss=yes

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Dairy #cattle #herds mount a characteristic #antibody response to highly pathogenic #H5N1 avian #influenza viruses

Abstract

An unprecedented outbreak of a highly pathogenic avian influenza virus, H5 clade 2.3.4.4b, was reported in United States dairy cattle during the spring of 2024. It has now spread to hundreds of herds across multiple states. In humans, antibodies to the hemagglutinin (HA) protein confer the strongest protection against infection. Human herd immunity limits viral spread but also drives the emergence of antigenic variants that escape dominant antibody responses. We used store-bought milk to profile the collective H5N1 antibody response of dairy cattle herds. We detected HA binding antibodies in specific samples from states with recent/ongoing outbreaks. These antibodies present in milk neutralized replicating virus expressing dairy cattle HA and neuraminidase (NA). Despite originating from independent vendors, dairies/plants, geographic regions, and time, antibodies present in these samples are remarkably similar in activity and HA binding specificity. The dominant antibody response was clade 2.3.4.4b HA specific, followed by cross-reactivity with other H5s. Whether the uniformity of the response is a pathway to achieve herd immunity or an avenue for antigenic variants to rapidly escape remains to be seen.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.04.01.646587v1

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Highly pathogenic avian #influenza #management in high-density #poultry #farming areas

Abstract

The continuous spread of highly pathogenic avian influenza H5 viruses poses significant challenges, particularly in regions with high poultry farm densities where conventional control measures are less effective. Using phylogeographic and phylodynamic tools, we analysed virus spread in Southwestern France in 2020-21, a region with recurrent outbreaks. Following a single introduction, the virus spread regionally, mostly affecting duck farms, peaking in mid-December with a velocity of 27.8 km/week and an effective reproduction number between farms (Re) of 3.8, suggesting the virus can spread beyond current control radii. Transmission declined after late December following preventive culling. Farm infectiousness was estimated around 9 days. Duck farm density was the main driver of virus spread and we identified farm density and proximity thresholds required to maintain effective control (Re < 1). These findings offer actionable guidance to support regional biosecurity and to improve the robustness of the poultry sector to mitigate future outbreaks.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.25.645233v1

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Tuesday, April 1, 2025

Intranasal #influenza virus-vectored #vaccine offers protection against clade 2.3.4.4b #H5N1 #infection in small animal #models

Abstract

The highly pathogenic avian influenza (HPAI) H5N1 virus has been endemic in aquatic birds since 1997, causing outbreaks in domestic poultry and occasional human infections worldwide. Recently, the cross-species transmission of a new reassortant variant from clade 2.3.4.4b of H5N1 to cattle in the US has heightened concerns regarding the expansion of host range and potential human infection. As eradicating the H5N1 virus from its reservoir is impossible, it is essential to prepare for a potential pandemic caused by an H5N1 derivative. Utilizing a deleted-NS1 live attenuated influenza viral vector vaccine system (DelNS1 LAIV), a system we have previously used in the development of a COVID-19 vaccine, we have rapidly developed an intranasal vaccine for cattle H5N1 and related clade 2.3.4.4b strains, based on publicly available sequences. Our research demonstrates that a single intranasal immunization can provide effective protection against lethal challenges from HPAI cattle or mink H5N1 variants, offering strong, sustained immunity after two months in female mouse and male hamster models. Immunogenicity analysis reveals that intranasal vaccination with DelNS1 LAIV induces robust neutralizing antibody, mucosal IgA and T cell responses in mice. It is crucial to further evaluate the DelNS1-H5N1 LAIV system to prepare for potential future H5N1 outbreaks in humans.

Source: Nature Communications, https://www.nature.com/articles/s41467-025-58504-z

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#Denmark - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

On 31 March 2025 a clinical suspicion was reported to the Danish Veterinary and Food Administration. The affected poultry holding consists of 24 hens. On 1 April 2025 highly pathogenic avian influenza subtype H5N1 was confirmed by the national reference laboratory. A 3 km protection zone and a 10 km surveillance zone has been established. The culling was completed on 1 April 2025. Carcasses will be disposed of by rendering.

Source: WOAH, https://wahis.woah.org/#/in-review/6392

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#India - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

 Death was observed in Guinea Fowl in Jharkhand State.

Source: WOAH, https://wahis.woah.org/#/in-review/6376

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#India - #Influenza A #H5N1 viruses of high pathogenicity (Inf. with) (non-poultry including wild birds) (2017-) - Immediate notification

House Crows in Bihar State.


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#PA and #PAX: two key #proteins from segment 3 of the #influenza viruses

Abstract

In recent years, the influenza viruses have posed an increasingly severe threat to public health. It is essential to analyze the virulence and pathogenesis of influenza viruses to prevent and control them, as well as create antiviral drugs. Previous studies have revealed that influenza virus segment 3 codes for not only the PA protein but also a novel protein, PA-X. PA protein is one subunit of the polymerase of influenza viruses and plays a critical role in its life cycle. PA presented endonuclease activity, the transcription and replication of the viral genome, viral virulence, protein degradation, and host immune response by interacting with viral proteins, including PB2, PB1, and host factors, including ANP32A, CHD6, HAX1, hCLE, HDAC6, MCM complex. PA mutations were involved in the viral replication, pathogenicity, and transmission of influenza viruses in poultry, mammals, and humans. PA-X is an open reading frame generated by +1 ribosomal code shift at the N-terminal amino acids of segment 3 and possesses the shutoff activity of host gene expression, regulating the host immune response, viral virulence and transmission. Therefore, PA is one ideal target for the development of antiviral drugs against influenza viruses. Baloxavir marboxil (BXM) and Favipiravir are two very effective anti-influenza virus drugs targeting the PA endonuclease domain of influenza A viruses. In this review, we summarized the structures, viral replication, virulent determinants and transmission, host factors, innate immunity, and antiviral drugs involved in PA and PA-X. The information is of great value for underlying the mechanism of viral replication and developing novel effective strategies to prevent and control influenza infection and the pandemic.

Source: Frontiers in Cellucal and Infection Microbiology, https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1560250/full

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Introducing a #framework for within-host #dynamics and #mutations modelling of #H5N1 #influenza infection in #humans

Abstract

Avian influenza A(H5N1) poses a public health risk due to its pandemic potential should the virus mutate to become human-to-human transmissible. To date, reported influenza A(H5N1) human cases have typically occurred in the lower respiratory tract with a high case fatality rate. There is prior evidence of some influenza A(H5N1) strains being a small number of amino acid mutations away from achieving droplet transmissibility, possibly allowing them to be spread between humans. We present a mechanistic within-host influenza A(H5N1) infection model, novel for its explicit consideration of the biological differences between the upper and lower respiratory tracts. We then estimate a distribution of viral lifespans and effective replication rates in human H5N1 influenza cases. By combining our within-host model with a viral mutation model, we determine the probability of an infected individual generating a droplet transmissible strain of influenza A(H5N1) through mutation. For three mutations, we found a peak probability of approximately 10(^-3) that a human case of H5N1 influenza produces at least one virion during the infectious period. Our findings provide insights into the risk of differing infectious pathways of influenza A(H5N1) (namely avian-human vs avian-mammal-human routes), demonstrating the three-mutation pathway being a cause of concern in human cases.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2024.09.01.24312235v3

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Monday, March 31, 2025

#Population #Immunity to #HA Head, Stalk and #NA of HP Avian #Influenza 2.3.4.4b A(#H5N1) viruses in #USA and Impact of Seasonal Influenza on A(H5N1) Immunity

Abstract

The unprecedented 2.3.4.4b A(H5N1) outbreak in dairy cattle, poultry, and spillover to humans in the United States (US) poses a major public health threat. Population immunity is a critical component of influenza pandemic risk assessment. We conducted a comprehensive assessment of the population immunity to 2.3.4.4b A(H5N1) viruses and analyzed 1794 sera from 723 people (0.5-88 yrs) in multiple US geographic regions during 2021-2024. Low pre-existing neutralizing and hemagglutinin (HA) head binding antibodies and substantial cross reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1) were detected in US population. Antibodies to group 1 HA stalk were also prevalent with an age-related pattern. A(H1N1)pdm09 infection and influenza vaccination did not induce neutralizing antibodies but induced significant rise of NA inhibition (NAI) antibodies to N1 of 2.3.4.4b A(H5N1), and group 1 HA stalk antibodies. Understanding population susceptibility to novel influenza is essential for pandemic preparedness.

Source: MedRxIV, https://www.medrxiv.org/content/10.1101/2025.03.30.25323419v1

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#Germany - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

 A poultry farm in Sachsen-Anhalt Region.

Source: WOAH, https://wahis.woah.org/#/in-review/6378

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#India - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

Backyard and Farmed Poultry in Karnataka State.

Source: WOAH, https://wahis.woah.org/#/in-review/6366

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#Influenza at the #human - #animal #interface - #Summary and #risk #assessment, from 21 January to 19 March 2025 {WHO}



Influenza at the human-animal interface Summary and risk assessment, from 21 January to 19 March 2025{1} 


New human cases{2}: 

From 21 January to 19 March 2025, based on reporting date, the detection of influenza A(H5N1) in five humans, influenza A(H9N2) virus in four humans, influenza A(H1N1) variant ((H1N1)v) virus in one human, and influenza A(H1N2)v virus in one human were reported officially. 

Circulation of influenza viruses with zoonotic potential in animals: 

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

Risk assessment{5}: 

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

Risk management

-- New candidate vaccine viruses (CVVs) for zoonotic influenza viruses for pandemic preparedness purposes were selected for development at the February 2025 WHO consultation on influenza vaccine composition for use in the northern hemisphere 2025-2026 influenza season. A detailed summary of zoonotic influenza viruses characterized since September 2024 is published here and updated CVVs lists are published here. 

IHR compliance

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


Avian influenza viruses in humans 

Current situation:  

Since the last risk assessment of 20 January 2025, one laboratory-confirmed human case of A(H5N1) infection was reported to WHO from Cambodia, one from the United Kingdom of Great Britain and Northern Ireland and three from the United States of America (USA).  

A(H5N1), Cambodia 

On 26 February 2025, Cambodia notified the WHO of a human case of influenza A(H5N1) in a boy from Prey Veng Province. The case had onset of fever, cough and fatigue on 17 February. He was initially seen at a local private clinic and given medication, but as his condition did not improve, he was transferred to Phnom Penh and hospitalized at a private hospital on 20 February. The case’s condition deteriorated, and he developed shortness of breath and was transferred on 24 February to a national hospital, which is a sentinel surveillance site for severe acute respiratory infection (SARI). Upon admission the case was isolated, nasopharyngeal (NP) and oropharyngeal (OP) swab specimens were collected and oseltamivir administered. On 25 February, the specimens tested positive for influenza A(H5N1) by reverse transcription-polymerase chain reaction (RT-PCR) at the National Institute of Public Health of Cambodia. The results were later confirmed by the Institut Pasteur du Cambodge (IPC) on 26 February. Sequence analysis of the HA gene revealed the virus belongs to clade 2.3.2.1e (previously classified as clade 2.3.2.1c){7}, and is similar to viruses circulating among birds, including poultry, and detected in human cases since late 2023 in Cambodia. The case was reported to have had exposure to sick and dead backyard chickens. Samples collected from the backyard chickens tested positive for A(H5N1). The case died on 25 February. No further cases were detected among the contacts of the case. This case is the second human infection with influenza A(H5N1) reported in Cambodia in 2025. 

A(H5N1), United Kingdom  

On 25 January 2025, the United Kingdom reported to WHO the detection of A(H5N1) in one individual in England who was sampled as part of a zoonotic influenza surveillance study launched by the UK Health Security Agency (UKHSA) in March 2023 to monitor people with close contact to infected birds. The individual was recruited to the surveillance study while working at a farm where birds were infected with A(H5N1) viruses and was found to be symptomatic. A sample collected on 23 January was confirmed A(H5)-positive at the national reference laboratory on 24 January. One symptomatic household contact tested negative. Sequencing of virus from the infected birds the case had contact with were determined to be of A(H5N1) clade 2.3.4.4b and the DI.2 genotype, which is prevalent within Europe at the current time. The DI.2 genotype is distinct from the A(H5) clade 2.3.4.4b genotypes that have been detected in North America.{8}  The UKHSA has previously notified WHO (in May, June, and July 2023) about four individuals who tested positive for influenza A(H5) virus as part of the UKHSA Zoonotic Influenza Surveillance Study.{9} 

A(H5N1), USA{10,11,12,13} 

In the USA, one laboratory-confirmed A(H5) infection was reported in an adult from the state of Ohio who worked at a commercial poultry facility where HPAI A(H5N1) virus had been detected in birds and was involved in depopulation activities. The individual had respiratory symptoms, was hospitalized, discharged and recovering at the time of the update. Genetic sequencing of the virus from this individual identified an avian influenza A(H5N1) virus from clade 2.3.4.4.b belonging to the genotype D1.3 genotype and no markers known that would impact the effectiveness of influenza antivirals or existing candidate vaccine viruses or changes associated with mammalian adaptation were identified.  Another laboratory-confirmed A(H5) infection was reported in an adult from the state of Wyoming who had direct contact with poultry infected with avian influenza A(H5) virus that died on their property. The individual was reported to have underlying health conditions that can be risk factors for severe influenza illness. This person has been discharged from the hospital and was recovering at the time of the update. Initial upper respiratory specimens were negative for influenza viruses; a lower respiratory specimen collected several days later in the hospital was positive for avian influenza A(H5N1) virus. Genetic sequencing of the virus from this individual identified an avian influenza A(H5N1) virus from clade 2.3.4.4.b belonging to the genotype D1.1, and the genetic mutation in the polymerase basic 2 (PB2) protein (E627K) that has previously been associated with more efficient virus replication in people and other mammals and has been detected in viruses from past human infections with A(H5) viruses.  Additionally, one laboratory-confirmed case was reported in an adult from the state of Nevada who worked at a commercial dairy cattle farm in an area where HPAI A(H5N1) viruses had been detected in cows. This individual developed conjunctivitis and recovered. Genetic sequencing of the virus from this individual identified an avian influenza A(H5N1) virus from clade 2.3.4.4.b also belonging to genotype D1.1, with a sequence nearly identical to that of the viruses that USDA reported from dairy cows in Nevada that the person worked with.{14} Sequencing also identified the D701N genetic mutation in the PB2 protein that has previously been associated with more efficient virus replication in mammalian cells and has been detected in viruses from past human infections with A(H5) viruses. Low pathogenicity and high pathogenicity avian influenza viruses have been detected in birds in the United States.  Since 2022, the HPAI A(H5) virus has been detected in commercial and backyard flocks in 48 states, impacting over 100 million birds. To date, 71 people have tested positive for A(H5) virus in the United States since 2022, with all but one of these cases occurring in 2024. All cases have been associated with exposure to either A(H5N1)-infected poultry or dairy cattle, except for two cases where the exposure source could not be identified.{15} To date, no human-to-human transmission of influenza A(H5) virus has been identified in the USA. A(H5N1) virus infections in dairy cattle and wild and domestic birds continue to be reported in the USA.{16} According to reports received by WOAH, various influenza A(H5) subtypes continue to be detected in wild and domestic birds in the Americas, Asia and Europe. Infections in non-human mammals are also reported, including in marine and land mammals.{17} A list of bird and mammalian species affected by HPAI A(H5) viruses is maintained by FAO.{18}


Risk Assessment for avian influenza A(H5) viruses:  

1. What is the current global public health risk of additional human cases of infection with avian influenza A(H5) viruses?  

-- Most human cases so far have been infections in people exposed to A(H5) viruses, for example, through contact with infected poultry or contaminated environments, including live poultry markets, and occasionally infected mammals and contaminated environments. While the viruses continue to be detected in animals and related environments humans are exposed to, further human cases associated with such exposures are expected but unusual. The impact for public health if additional cases are detected is minimal. The current overall global public health risk of additional human cases is low. 

2. What is the likelihood of sustained human-to-human transmission of currently circulating avian influenza A(H5) viruses?  

-- No sustained human-to-human transmission has been identified associated with the recent reported human infections with avian influenza A(H5). There has been no reported human-to-human transmission of A(H5N1) viruses since 2007, although there may be gaps in investigations. In 2007 and the years prior, small clusters of A(H5) virus infections in humans were reported, including some involving health care workers, where limited human-to-human transmission could not be excluded; however, sustained human-to-human transmission was not reported.  Available evidence suggests that influenza A(H5) viruses circulating have not acquired the ability to efficiently transmit between people, therefore the likelihood of sustained human-to-human transmission is thus currently considered unlikely at this time.  

3. What is the likelihood of international spread of avian influenza A(H5) viruses by travellers?  

-- Should infected individuals from affected areas travel internationally, their infection may be detected in another country during travel or after arrival. If this were to occur, further communitylevel spread is considered unlikely as current evidence suggests these viruses have not acquired the ability to transmit easily among humans.  


A(H9N2), China 

Since the last risk assessment of 20 January 2025, four human cases of infection with A(H9N2) influenza viruses were notified to WHO from China on 7 February 2025. All four cases were detected through the influenza-like illness (ILI) surveillance system. The cases were detected in Guangdong (one), Hunan (two) and Sichuan (one) provinces. One case, in an adult, had underlying conditions at the time of illness and was hospitalized with pneumonia. The other cases (two children and one adult) had mild illnesses. Each case had a known history of exposure to poultry prior to the onset of symptoms. Environmental samples collected from areas associated with two cases (live poultry markets) tested positive for influenza A(H9) virus while samples from the environments associated with the other two cases (backyard areas) tested negative. No further cases were detected among contacts of these cases and there was no epidemiological link between the cases.  


Risk Assessment for avian influenza A(H9N2):  

1. What is the global public health risk of additional human cases of infection with avian influenza A(H9N2) viruses?  

-- Most human cases follow exposure to the A(H9N2) virus through contact with infected poultry or contaminated environments. Most human infections of A(H9N2) to date have resulted in mild clinical illness in most cases. Nearly 130 human infections with A(H9N2) cases have been reported to date since 2003, and six of these have been severe or fatal and three of these were known to have underlying medical conditions. Since the virus is endemic in poultry in multiple continues in Africa and Asia{19}, further human cases associated with exposure to infected poultry are expected but remain unusual. The impact to public health if additional cases are detected is minimal. The overall global public health risk of additional human cases is low

2. What is the likelihood of sustained human-to-human transmission of avian influenza A(H9N2) viruses?  

-- At the present time, no sustained human-to-human transmission has been identified associated with the event described above. Current evidence suggests that influenza A(H9N2) viruses from these cases have not acquired the ability of sustained transmission among humans, therefore sustained human-to-human transmission is thus currently considered unlikely.  

3. What is the likelihood of international spread of avian influenza A(H9N2) virus by travellers?  

-- Should infected individuals from affected areas travel internationally, their infection may be detected in another country during travel or after arrival. If this were to occur, further community level spread is considered unlikely as current evidence suggests the A(H9N2) virus subtype has not acquired the ability to transmit easily among humans.  


Swine Influenza Viruses   

Current situation:    

Since the last risk assessment of 20 January 2025, one detection of an influenza A(H1N1)v virus was reported from China and one detection of an influenza A(H1N2)v was reported from the USA.  


Influenza A(H1N1)v, China 

On 7 February 2025, China notified WHO of a human case of Eurasian avian-like swine influenza A(H1N1) virus in a child from Yunnan Province. She developed mild upper respiratory tract symptoms on 12 November 2024 and a respiratory sample was collected on 13 November 2024 as part of routine influenza-like illness (ILI) surveillance. Close contacts remained asymptomatic and tested negative for influenza. She had exposure to backyard pigs however samples collected from the pigs tested negative for Eurasian avian-like swine influenza A(H1N1) viruses. The virus from this case was a clade 1C.2.3 virus. 


Influenza A(H1N2)v, USA  

A laboratory-confirmed human infection with an influenza A(H1N2)v virus was reported in an adult from the state of Iowa. The individual sought health care during the week ending 18 January 2025, was hospitalized, and recovered. An investigation by public health officials did not identify direct or indirect swine contact. No further cases were identified associated with this case. The virus from this case belonged to clade 1B.2.1 which is known to circulate in swine in the USA. 


Risk Assessment:   

1. What is the public health risk of additional human cases of infection with swine influenza viruses?    

-- Swine influenza viruses circulate in swine populations in many regions of the world. Depending on geographic location, the genetic characteristics of these viruses differ. Most human cases are exposed to swine influenza viruses through contact with infected animals or contaminated environments. Human infection tends to result in mild clinical illness in most cases. Since these viruses continue to be detected in swine populations, further human cases are expected but remain unusual. The impact for public health if additional cases are detected is minimal. The overall risk of additional human cases is low.    

2. What is the likelihood of sustained human-to-human transmission of swine influenza viruses?    

-- No sustained human-to-human transmission was identified associated with the events described above. Current evidence suggests that contemporary swine influenza viruses have not acquired the ability of sustained transmission among humans, therefore sustained human-to-human transmission is thus currently considered unlikely.     

3. What is the likelihood of international spread of swine influenza viruses by travelers?    

-- Should infected individuals from affected areas travel internationally, their infection may be detected in another country during travel or after arrival. If this were to occur, further community level spread is considered unlikely as current evidence suggest that these viruses have not acquired the ability to transmit easily among humans.   

For more information on zoonotic viruses, see the report from the WHO Consultation on the Composition of Influenza Virus Vaccines for Use in the 2025-2026 Northern Hemisphere Influenza Season held on 24-27 February 2025 at the following link: Antigenic and genetic characteristics of zoonotic influenza A viruses and development of candidate vaccine viruses for pandemic preparedness in the 2025-2026 northern hemisphere influenza season.  


Overall risk management recommendations

Surveillance and investigations 

• Due to the constantly evolving nature of influenza viruses, WHO continues to stress the importance of global strategic surveillance in animals and humans to detect virologic, epidemiologic and clinical changes associated with circulating influenza viruses that may affect human (or animal) health. Continued vigilance is needed within affected and neighbouring areas to detect infections in animals and humans. Close collaboration with the animal health and environment sectors is essential to understand the extent of the risk of human exposure and to prevent and control the spread of animal influenza. 

• As the extent of influenza virus circulation in animals is not clear, epidemiologic and virologic surveillance and the follow-up of suspected human cases should continue systematically. Guidance on investigation of non-seasonal influenza and other emerging acute respiratory diseases has been published on the WHO website. 

• Countries should increase avian influenza surveillance in domestic and wild birds, enhance surveillance for early detection in cattle populations in countries where HPAI is known to be circulating, include HPAI as a differential diagnosis in non-avian species, including cattle and other livestock populations, with high risk of exposure to HPAI viruses; monitor and investigate cases in non-avian species, including livestock, report cases of HPAI in all animal species, including unusual hosts, to WOAH and other international organizations, share genetic sequences of avian influenza viruses in publicly available databases, implement preventive and early response measures to break the HPAI transmission cycle among animals through movement restrictions of infected livestock holdings and strict biosecurity measures in all holdings, employ good production and hygiene practices when handing animal products, and protect persons in contact with suspected/infected animals.{20}  

• When there has been human exposure to a known outbreak of an influenza A virus in domestic poultry, wild birds or other animals – or when there has been an identified human case of infection with such a virus – enhanced surveillance in potentially exposed human populations becomes necessary. Enhanced surveillance should consider the health care seeking behaviour of the population, and could include a range of active and passive health care and/or communitybased approaches, including: enhanced surveillance in local influenza-like illness (ILI)/SARI systems, active screening in hospitals and of groups that may be at higher occupational risk of exposure, and inclusion of other sources such as traditional healers, private practitioners and private diagnostic laboratories. 

• Vigilance for the emergence of novel influenza viruses of pandemic potential should be maintained at all times including during a non-influenza emergency. In the context of the cocirculation of SARS-CoV-2 and influenza viruses, WHO has updated and published practical guidance for integrated surveillance. Notifying WHO 

• All human infections caused by a new subtype of influenza virus are notifiable under the International Health Regulations (IHR, 2005).{21} State Parties to the IHR (2005) are required to immediately notify WHO of any laboratory-confirmed{22} case of a recent human infection caused by an influenza A virus with the potential to cause a pandemic{23}. Evidence of illness is not required for this report. 

• WHO published the case definition for human infections with avian influenza A(H5) virus requiring notification under IHR (2005): https://www.who.int/teams/global-influenzaprogramme/avian-influenza/case-definitions. 


Virus sharing and risk assessment 

• It is critical that these influenza viruses from animals or from people are fully characterized in appropriate animal or human health influenza reference laboratories. Under WHO’s Pandemic Influenza Preparedness (PIP) Framework, Member States are expected to share influenza viruses with pandemic potential on a timely basis{24} with a WHO Collaborating Centre for influenza of GISRS. The viruses are used by the public health laboratories to assess the risk of pandemic influenza and to develop candidate vaccine viruses.  

• The Tool for Influenza Pandemic Risk Assessment (TIPRA) provides an in-depth assessment of risk associated with some zoonotic influenza viruses – notably the likelihood of the virus gaining human-to-human transmissibility, and the impact should the virus gain such transmissibility. TIPRA maps relative risk amongst viruses assessed using multiple elements. The results of TIPRA complement those of the risk assessment provided here, and those of prior TIPRA analyses will be published at http://www.who.int/teams/global-influenza-programme/avian-influenza/toolfor-influenza-pandemic-risk-assessment-(tipra).  


Risk reduction 

• Given the observed extent and frequency of avian influenza in poultry, wild birds and some wild and domestic mammals, the public should avoid contact with animals that are sick or dead from unknown causes, including wild animals, and should report dead birds and mammals or request their removal by contacting local wildlife or veterinary authorities.  

• Eggs, poultry meat and other poultry food products should be properly cooked and properly handled during food preparation. Due to the potential health risks to consumers, raw milk should be avoided. WHO advises consuming pasteurized milk. If pasteurized milk isn’t available, heating raw milk until it boils makes it safer for consumption. 

• WHO has published practical interim guidance to reduce the risk of infection in people exposed to avian influenza viruses. 


Trade and travellers 

• WHO advises that travellers to countries with known outbreaks of animal influenza should avoid farms, contact with animals in live animal markets, entering areas where animals may be slaughtered, or contact with any surfaces that appear to be contaminated with animal excreta. Travelers should also wash their hands often with soap and water. All individuals should follow good food safety and hygiene practices.  

• WHO does not advise special traveller screening at points of entry or restrictions with regards to the current situation of influenza viruses at the human-animal interface. For recommendations on safe trade in animals and related products from countries affected by these influenza viruses, refer to WOAH guidance.  


Links:  

-- WHO Human-Animal Interface web page https://www.who.int/teams/global-influenza-programme/avian-influenza 

-- WHO Influenza (Avian and other zoonotic) fact sheet https://www.who.int/news-room/fact-sheets/detail/influenza-(avian-and-other-zoonotic) 

-- WHO Protocol to investigate non-seasonal influenza and other emerging acute respiratory diseases https://www.who.int/publications/i/item/WHO-WHE-IHM-GIP-2018.2 

-- WHO Public health resource pack for countries experiencing outbreaks of influenza in animals:  https://www.who.int/publications/i/item/9789240076884 

-- Cumulative Number of Confirmed Human Cases of Avian Influenza A(H5N1) Reported to WHO  https://www.who.int/teams/global-influenza-programme/avian-influenza/avian-a-h5n1-virus 

-- Avian Influenza A(H7N9) Information https://www.who.int/teams/global-influenza-programme/avian-influenza/avian-influenza-a-(h7n9)virus 

-- World Organisation of Animal Health (WOAH) web page: Avian Influenza  https://www.woah.org/en/home/ 

-- Food and Agriculture Organization of the United Nations (FAO) webpage: Avian Influenza https://www.fao.org/animal-health/avian-flu-qa/en/ 

-- OFFLU http://www.offlu.org/ 

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{1} This summary and assessment covers information confirmed during this period and may include information received outside of this period. 

{2} For epidemiological and virological features of human infections with animal influenza viruses not reported in this assessment, see the reports on human cases of influenza at the human-animal interface published in the Weekly Epidemiological Record here.  

{3} World Organisation for Animal Health (WOAH). Avian influenza. Global situation. Available at: https://www.woah.org/en/disease/avian-influenza/#ui-id-2. 

{4} Food and Agriculture Organization of the United Nations (FAO). Global Avian Influenza Viruses with Zoonotic Potential situation update. Available at: https://www.fao.org/animal-health/situation-updates/global-aiv-withzoonotic-potential. 

{5} World Health Organization (2012). Rapid risk assessment of acute public health events. World Health Organization. Available at: https://iris.who.int/handle/10665/70810. 

{6} World Health Organization. Case definitions for the 4 diseases requiring notification to WHO in all circumstances under the International Health Regulations (2005). Case definitions for the four diseases requiring notification in all circumstances under the International Health Regulations (2005).   

{7} Ort JT, Zolnoski SA, Lam TT, Neher R, Moncla LH. Development of avian influenza A(H5) virus datasets for Nextclade enables rapid and accurate clade assignment. bioRxiv [Preprint]. 2025 Feb 3:2025.01.07.631789. doi: 10.1101/2025.01.07.631789. PMID: 39829835; PMCID: PMC11741357. 

{8} UKHSA. Human case of avian flu detected in England, 27 January 2025. Available at: https://www.gov.uk/government/news/human-case-of-avian-flu-detected-in-england. 

{9} UKHSA. Investigation into the risk to human health of avian influenza (influenza A H5N1) in England: technical briefing 5, Updated 14 July 2023. Available at: https://www.gov.uk/government/publications/avian-influenzainfluenza-a-h5n1-technical-briefings/investigation-into-the-risk-to-human-health-of-avian-influenza-influenzaa-h5n1-in-england-technical-briefing-5. 

{10} US CDC. Weekly US Influenza Surveillance Report: Key Updates for Week 6, ending February 8, 2025. Available at: https://www.cdc.gov/fluview/surveillance/2025-week-06.html. 

{11} US CDC. Weekly US Influenza Surveillance Report: Key Updates for Week 7, ending February 15, 2025. Available at:  https://www.cdc.gov/fluview/surveillance/2025-week-07.html. 

{12} US CDC. CDC A(H5N1) Bird Flu Response Update, February 26, 2025. Available at: https://www.cdc.gov/birdflu/spotlights/h5n1-response-02262025.html. 

{13} US CDC. CDC A(H5N1) Bird Flu Response Update March 19, 2025. Available at https://www.cdc.gov/birdflu/spotlights/h5n1-response-03192025.html. 

{14} USDA. The Occurrence of Another Highly Pathogenic Avian Influenza (HPAI) Spillover from Wild Birds into Dairy Cattle. Available at:https://www.aphis.usda.gov/sites/default/files/dairy-cattle-hpaitech-brief.pdf 

{15} United States Centers for Disease Control and Prevention. H5 Bird Flu: Current Situation. Available at: https://www.cdc.gov/bird-flu/situationsummary/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fbird-flu%2Fphp%2Favian-flusummary%2Findex.html. 

{16}  United States Department of Agriculture. Highly Pathogenic Avian Influenza (HPAI) Detections in Livestock, 19 July 2024. Available at: https://www.aphis.usda.gov/livestock-poultry-disease/avian/avian-influenza/hpaidetections/livestock. 

{17}  World Organisation for Animal Health (WOAH). Avian influenza. Global situation. Available at: https://www.woah.org/en/disease/avian-influenza/#ui-id-2. 

{18} Food and Agriculture Organization of the United Nations. Global Avian Influenza Viruses with Zoonotic Potential situation update. Available at: https://www.fao.org/animal-health/situation-updates/global-aiv-withzoonotic-potential/bird-species-affected-by-h5nx-hpai/en. 

{19} Food and Agriculture Organization of the United Nations (FAO). Global Avian Influenza Viruses with Zoonotic Potential situation update. Available at: https://www.fao.org/animal-health/situation-updates/global-aiv-withzoonotic-potential. 

{20} World Organisation for Animal Health. Statement on High Pathogenicity Avian Influenza in Cattle, 6 December 2024. Available at: https://www.woah.org/en/high-pathogenicity-avian-influenza-hpai-in-cattle/. 

{21} World Health Organization. Case definitions for the four diseases requiring notification in all circumstances under the International Health Regulations (2005).    

{22} World Health Organization. Manual for the laboratory diagnosis and virological surveillance of influenza (2011). Available at: https://apps.who.int/iris/handle/10665/44518 

{23} World Health Organization. Pandemic influenza preparedness framework for the sharing of influenza viruses and access to vaccines and other benefits, 2nd edition. Available at: https://iris.who.int/handle/10665/341850 

{24} World Health Organization. Operational guidance on sharing influenza viruses with human pandemic potential (IVPP) under the Pandemic Influenza Preparedness (PIP) Framework (2017). Available at: https://apps.who.int/iris/handle/10665/25940 

Source: World Health Organization, https://www.who.int/publications/m/item/influenza-at-the-human-animal-interface-summary-and-assessment-19-march-2025

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A #Human #H5N1 #Influenza Virus Expressing Bioluminescence for Evaluating Viral #Infection and Identifying #Therapeutic Interventions

Abstract

A multistate outbreak of highly pathogenic avian influenza virus (HPAIV) H5N1 in dairy cows was first reported on March 25, 2024, in the United States (US), marking the first discovery of HPAIV H5N1 in cattle. Soon after, a dairy worker on an affected dairy farm became the first human case linked directly to this outbreak. Studies with influenza A virus (IAV) require secondary methods to detect the virus in infected cells or animal models of infection. We modified the non-structural (NS) genome segment of the human A/Texas/37/2024 (HPhTX) H5N1 virus to create a recombinant virus expressing nanoluciferase (HPhTX NSs-Nluc), enabling the tracking of virus in cultured cells and mice via in vitro, ex vivo, and in vivo imaging systems (IVIS). In vitro, HPhTX NSs-Nluc showed growth and plaque characteristics similar to its wild-type (WT) counterpart. In vivo, HPhTX NSs-Nluc allowed tracking viral infection in the entire animals and in the organs of infected animals using in vivo and ex vivo IVIS, respectively. Importantly, the morbidity, mortality, and replication titers of HPhTX NSs-Nluc were comparable to those of the WT HPhTX. In vitro, HPhTX NSs-Nluc was inhibited by Baloxavir acid (BXA) to levels observed with WT HPhTX. We also demonstrate the feasibility of using HPhTX NSs-Nluc to evaluate the antiviral activity of BXA in vivo. Our findings support that HPhTX NSs-Nluc represents an excellent tool for tracking viral infections, including the identification of prophylactics or therapeutics for the treatment of the HPAIV H5N1 responsible of the outbreak in dairy cows.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.03.28.646035v1

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