#Oseltamivir #Resistance in #Human #Influenza #H5N1 and #H7N9 Infections: A Mini Review

 

Abstract

Avian influenza viruses (AIVs) have been reported to cause infections in humans following avian-to-human transmission, resulting in a range of clinical outcomes. A(H5N1) and A(H7N9) infections, which constitute the majority of human AIV cases, are responsible for severe infections leading to high mortality. The neuraminidase inhibitor oseltamivir is expected to play a major role for the control of AIV infections in humans. However, the emergence of resistance may compromise the impact of antiviral therapy. The objective of this article is to review human cases of A(H5N1) and A(H7N9) infections for which mutations of oseltamivir resistance were detected. Neuraminidase mutations rapidly occurred in a subtype-specific manner, with H274Y and N294S substitutions predominating in A(H5N1) cases and the R292K substitution in A(H7N9) cases. Serious clinical outcomes and mortality were seen in most A(H5N1) and A(H7N9) cases despite oseltamivir therapy, thus highlighting the need for improving antiviral strategies against these AIVs.

Source: 

Link: https://academic.oup.com/ofid/article/13/7/ofag393/8722865

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#Autoantibodies against type I #interferons in patients with #zoonotic #H7N9 #influenza: an observational case–control study

 

Summary

Background

The determinants of the species barrier preventing human infections with avian influenza A viruses (IAV) are incompletely understood. We previously identified loss-of-function variants of the interferon-regulated antiviral factor MxA as a genetic factor for increased susceptibility to infections with the H7N9 subtype. Given the central role of type I IFNs (IFN-I) in antiviral defence, we hypothesised that IFN-I-neutralising autoantibodies may similarly predispose to zoonotic H7N9 infection.

Methods

In this observational case–control study, serum samples collected between 2013 and 2017 from 199 Chinese patients with laboratory-confirmed H7N9 infection and 531 healthy, uninfected controls (269 poultry workers, 262 close contacts) were screened for IgG autoantibodies binding IFNα2, IFNβ1b, or IFNω using a multiplex bead-based assay. Positive samples were tested for IFN-neutralising activity in a luciferase-based reporter assay. To confirm their ability to block IFNα2-mediated antiviral activity, selected samples (n = 19) were analysed in IAV infection experiments. Associations between age, sex, H7N9 case status, case fatality, and the presence of neutralising autoantibodies were evaluated by logistic regression. Available whole-genome sequencing data from 26 individuals with neutralising autoantibodies were screened for variants in genes linked to IFN-I autoimmunity.

Findings

Neutralising autoantibodies against at least one IFN-I were detected in 19.1% (38/199) of patients but in only 1.1% (6/531) of controls, consistent with published general population data. Most patient sera targeted IFNα2 and/or IFNω (35/199), and 18.1% (36/199) neutralised even high IFN-I concentrations of 1–10 ng/ml. The presence of neutralising autoantibodies was associated with 8.2- to 25.3-fold higher odds of H7N9 infection (p < 0.0001), depending on antibody specificity and reference group. Autoantibody prevalence increased significantly with age in patients (44.8% ≥70 years; OR = 1.05; 95% CI 1.02–1.07; p = 0.0001), but was not associated with sex (OR for males vs. females = 0.52; 95% CI 0.23–1.14; p = 0.106). All selected sera containing neutralising autoantibodies blocked IFNα2-induced antiviral activity in cell culture. No known genetic predisposition for IFN-I autoimmunity was identified.

Interpretation

Our findings suggest that IFN-I-targeting autoimmunity is associated with susceptibility to zoonotic IAV infection with the H7N9 subtype, and possibly also other subtypes, including panzootic H5N1. Given the ease of implementation, screening for anti-IFN-I autoantibodies could be readily integrated into surveillance or targeted testing. This could be relevant in environments with increased exposure to zoonotic IAVs.

Funding

Shenzhen Medical Research Fund, National Natural Science Foundation of China, Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, Guangdong Provincial Science and Technology Program, Program for Youzuzhikeyan of Shenzhen University, German Research Foundation, Swiss National Science Foundation.

Source: 

Link: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(26)00271-9/fulltext

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#Assessment of #influenza virus and #coronavirus #tropism, #replication competence and disease severity in ex vivo and in vitro cultures of the #human respiratory tract

ABSTRACT

The emergence of animal influenza viruses circulating in poultry and human populations poses a significant public health threat, yet current risk assessment tools that connect surveillance data to human transmission risk and disease severity are lacking. To address this, we employed a semi-quantitative approach to analyze virus tropism and replication competence, conducting risk assessments of influenza and coronavirus adaptation to human transmission in an ex vivo model, and evaluating virus-induced impairment of alveolar fluid clearance (AFC) in vitro as a correlation of disease severity. Our results showed that seasonal influenza A H1N1, H3N2, influenza B, MERS-CoV, and SARS-CoV exhibited productive viral replication and tissue infection in bronchial tissues, whereas wild bird surveillance isolates such as H5N3 and H7N1 showed minimal replication when compared to pandemic H1N1 and highly pathogenic avian influenza (HPAI) H5N1. Notably, differential lung viral replication and tissue tropism were detected for H5N6 and H9N2. HPAI H5N1, H7N9, MERS-CoV, and SARS-CoV caused more severe AFC impairment than seasonal H1N1, H3N2, and influenza B viruses, correlating with their clinical severity. Overall, these findings revealed an important association between viral tropism and human transmissibility in ex vivo explants, as well as the impairment of AFC in vitro, which aligns with the clinical manifestations of disease severity across different viral strains.

Source: 

Link: https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.002281

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Effectiveness of #baloxavir marboxil in nonhuman #primates infected with highly pathogenic avian #influenza #H7N9 virus

 

Summary

Background

Highly pathogenic avian influenza (HPAI) A(H7N9) virus poses a potential public health threat, underscoring the need for effective antiviral options for outbreak preparedness. Baloxavir marboxil (BXM) is a cap-dependent endonuclease inhibitor approved for seasonal influenza, but its in vivo efficacy against HPAI A(H7N9) virus has not been fully evaluated.

Methods

We evaluated the efficacy of BXM in cynomolgus macaques infected with a reverse genetics-generated HPAI A(H7N9) virus. Animals received either low- or high-dose BXM, single-dose oseltamivir, or vehicle at 4 or 48 h post-infection (hpi). BXM administration was designed to mimic human pharmacokinetics. Viral titres, body temperature, body weight, lung pathology, and treatment-emergent viral substitutions were analysed.

Findings

Early treatment (4 hpi) with BXM significantly reduced viral titres in nasal and tracheal swabs, lessened weight loss, and decreased pulmonary inflammation and alveolar damage compared to untreated or oseltamivir-treated animals. Virus pathogenicity was relatively mild; no animals died. Delayed treatment (48 hpi) showed limited benefit. The PA-I38T (83.8%) and PA-E23G (78.6%) substitutions associated with BXM resistance were detected in one animal, and a PA-K34R (85.4%) substitution was detected in another animal. These substitutions reduce BXM susceptibility and were detected at low titres.

Interpretation

Although the dosing regimen used in this study involved repeat dosing to achieve the plasma drug concentrations after a single dose in humans, these findings highlight the importance of early antiviral intervention and support BXM use as a potential countermeasure against HPAI A(H7N9) virus infection, as resistance-associated substitutions remained limited in the macaque model. BXM may be a valuable therapeutic option for HPAI A(H7N9) virus infections.

Funding

Supported by the Japan Agency for Medical Research and Development (JP20wm0125002, JP223fa627001) and Shionogi & Co., Ltd.

Source: 

Link: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(26)00233-1/fulltext

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Prior #immunity to seasonal #influenza #H3N2 virus confers varying levels of cross - #protection against challenge with clade 2.3.4.4b #H5N1, #H7N9, or #H9N2 virus in a #ferret model

 

ABSTRACT

Evaluating how prior immunity to seasonal influenza viruses influences subsequent zoonotic influenza A virus (IAV) infection in animal models is critical for pandemic preparedness. In this study, we investigated the cross-protective effect of pre-existing A(H3N2) immunity in ferrets challenged with three distinct subtypes of zoonotic IAVs: low pathogenic A(H7N9) and A(H9N2) viruses, and highly pathogenic clade 2.3.4.4b A(H5N1) virus. Our results show that A(H3N2) preimmunity conferred some protection against A(H5N1) and A(H9N2) virus infection, as evidenced by more rapid viral clearance in the upper respiratory tract, reduced virus shedding in the nasal wash on select days post-inoculation, and a lowered frequency of viral detection in specific tissues compared with naive animals. In contrast, A(H3N2) preimmunity provided minimal cross-protection against A(H7N9) infection, as weight loss and viral dissemination in tissues were not significantly reduced in A(H3N2) preimmune ferrets relative to naive animals. These findings highlight the variable breadth and magnitude of cross-protection elicited by prior seasonal IAV immunity against zoonotic influenza virus challenges in the ferret model. Seasonal influenza A(H3N2) preimmunity provided differing levels of cross-protection against zoonotic influenza A virus infections in ferrets.

Source: 

Link: https://journals.asm.org/doi/10.1128/spectrum.03974-25

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A Phase 1/2 Dose-Ranging Safety and Immunogenicity Study of #mRNA-Based Candidate #Pandemic #Influenza #Vaccines in Healthy Adults

 

Abstract

Background

Influenza A viruses pose a persistent pandemic threat. We report safety, reactogenicity, and immunogenicity findings for mRNA-1018 pandemic influenza vaccine candidates from a phase 1/2 study in healthy adults.

Methods

In Part A, participants were randomized to receive 1 of 4 mRNA-1018 candidates at 1 of 3 dose levels across 2 influenza A groups: (1) H5N8/H5-only or (2) H7N9/H7-only. H5N8 and H7N9 candidates were administered at 25, 50, or 100-µg and H5-only and H7-only at 12.5, 25, or 50-µg. Part B participants were randomized to receive 12.5, 25, or 50-µg H5-only-CG. Primary objectives were to evaluate the safety and reactogenicity of vaccine candidates. Secondary objectives included evaluation of humoral immunogenicity through day 205 by hemagglutination inhibition (HAI), neuraminidase inhibition, and microneutralization assays.

Results

Parts A and B comprised 1195 and 304 dosed participants, respectively. Overall, solicited local adverse reactions (ARs) within 7 days of vaccination occurred in 76.8% of participants across vaccine candidates and dose levels, most commonly injection-site pain. Solicited systemic ARs were reported in 62.8% of participants, most frequently fatigue and headache. Solicited ARs were predominantly grade 1–2 in severity, with few grade 3 and no grade 4 events. Post-vaccination immune responses, assessed absolutely, by HAI titers and dynamically, by seroconversion rates, tended to increase with vaccine dose. H5-based candidates induced stronger strain-specific HAI, but with comparable microneutralization titers, versus H7-based candidates.

Conclusions

Vaccine candidates were sufficiently well-tolerated and immunogenic. Further development of mRNA pandemic influenza vaccines is warranted for pandemic preparedness.

Source: 

Link: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciag278/8662346

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#Genomic similarity to quantitatively evaluate the #reassortment #potential of #H7N9 with other subtypes of avian #influenza viruses

 

Abstract

Introduction: 

The H7N9 influenza virus poses a significant public health threat due to its potential for reassortment and cross-species transmission. This study aims to systematically evaluate the genomic similarity between H7N9 and other influenza A subtypes to identify strains with high reassortment potential and characterize their spatiotemporal and host distribution patterns.

Methods: 

We analyzed nearly 4,000 H7N9 sequences from GISAID and NCBI, alongside representative sequences of other influenza A subtypes. Open reading frames were extracted, and a genomic similarity index was constructed using Euclidean distance, dot product, and cosine similarity measures, with weights optimized via principal component analysis. The index was applied to quantify inter-subtype similarity and predict reassortment-prone strains.

Results: 

High sequence similarity was observed between H7N9 and cognate subtypes (e.g., H7N3, H15N9), with H7N3 exhibiting the highest similarity index (1.00). Validation using known reassortant strains, such as A/Yixing/805/2022 (H3N2), confirmed that strains with high reassortment potential showed significantly elevated similarity scores across all gene segments (p< 0.001). High-similarity outliers analysis identified 581 spillover events, temporally concentrated during 2014–2017, and spatially clustered in regions like the United States, Europe, and Hong Kong. Host analysis highlighted birds—especially chickens, ducks, and turkeys—as key reservoirs for reassortment.

Discussion: 

The genomic similarity index effectively identifies influenza A subtypes with high reassortment potential, supported by retrospective validation and spatiotemporal congruence with documented outbreaks. The concentration of high-similarity strains in specific hosts and regions underscores the role of ecological factors in viral evolution. These findings provide a predictive framework for monitoring emergent reassortants and inform targeted surveillance strategies.

Source: 

Link: https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2026.1777911/full

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#Birth #imprinting effects on the #antibody responses of #H7N9 patients from 2013-2018 in #China

 

Abstract

Background

There is an urgent need to understand the immune correlates of protection against avian influenza viruses (AIV), where pre-existing immunity may be limited.

Methods

Here, we characterized the antibody response in 12 severely ill A(H7N9) patients and examined its association with early-life imprinting and clinical outcome.

Results

We find that A(H7N9) patients imprinted with A(H2N2) during early life show minimal H7-IgM and a rapid IgG response across diverse hemagglutinin subtypes. They also have more high avidity H7-antibodies compared to older or younger patients. Early antibody titers against seasonal H1, H3, and conserved stalk domains trend negatively with clinical severity in A(H7N9) infection, while an inverse pattern is observed following severe A(H1N1) infection, potentially suggesting a different mechanism of immune regulation between seasonal and avian influenza virus infections.

Conclusions

These data provide direct serological evidence that birth imprinting profoundly shapes the humoral immune landscape during zoonotic influenza infection and may influence subsequent disease outcome.

Source: 

Link: https://www.nature.com/articles/s43856-026-01554-1

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#Online monitoring and early #detection of #influenza #outbreaks using exponentially weighted spatial lasso: a case study in #China during 2014–2020

 

Abstract

Influenza poses a persistent public health threat in China, with substantial impacts on health and the economy, especially during seasonal epidemics and emerging outbreaks. Seasonality, local clustering, and serial correlation inherent in influenza data introduce spatio-temporal complexities that traditional statistical process control (SPC) methods cannot adequately capture. This study introduces a novel nonparametric framework for real-time influenza monitoring across 300+ Chinese cities from 2014 to 2020. Reference periods are selected to establish baseline incidence patterns and fit a nonparametric spatio-temporal model to estimate mean and covariance structures. These estimates enable the setting of dynamic outbreak thresholds. Next, exponentially weighted spatial LASSO (EWSL) charting statistics are computed for the monitoring period, prioritizing recent observations and detecting subtle mean shifts in small, clustered regions - well-suited to influenza's progression dynamics. Charting statistics exceeding control limits trigger timely outbreak warnings. Results demonstrate that our method consistently outperforms alternative methods, and existing literature corroborates that its early signals correspond to actual outbreaks - including those for H7N9 strains, influenza A and B viruses, and the initial spread of COVID-19. These findings highlight the potential of our approach as an effective epidemic monitoring tool, addressing complex spatio-temporal patterns and supporting timely, data-driven public health interventions.

Source: 

Link: https://www.tandfonline.com/doi/full/10.1080/02664763.2025.2534915

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#Taiwan: First locally acquired #human case of novel avian #H7 #influenza virus has been detected (MoH, edited)

 

The Taiwan Centers for Disease Control (CDC) announced today (March 2nd) the first locally transmitted case of novel H7 subtype avian influenza in Taiwan. 

The patient is a man in his 70s from central Taiwan who works in poultry farming and has a history of chronic illness. 

He developed symptoms of runny nose, cough, and body aches on March 20th and sought medical attention at a hospital on March 22nd due to fever. 

He was admitted to the hospital on the same day. 

Imaging examination revealed pneumonia. 

Based on clinical symptoms, test results, and the patient's contact history, the doctor reported the case as a novel H7 avian influenza and administered antiviral medication. 

Further testing and gene sequencing by the CDC confirmed the virus as H7 subtype avian influenza. 

Sequence analysis showed that this H7 belongs to the Eurasian lineage and is similar to the H7 subtype avian influenza viruses monitored in wild birds (mainly ducks and anadidae) in Taiwan over the years. 

However, it is different from the H7N9 subtype avian influenza virus that circulated in mainland China from 2013 to 2019, and is a low-pathogenic avian influenza virus. 

This morning, the CDC convened a meeting with agricultural authorities and relevant medical and veterinary experts to discuss the case and, based on the test results, confirmed it as a case of novel H7 avian influenza in humans. 

The patient's condition has improved and they are continuing isolation and treatment. 

The Centers for Disease Control (CDC) stated that after the first locally transmitted case of H7 subtype novel influenza A was detected in Taiwan, health and agricultural authorities immediately launched a joint epidemic prevention operation to carry out relevant investigations and prevention measures. 

Health authorities, with the assistance of epidemiologists and the Health Bureau, conducted on-site epidemiological investigations at the patient's residence, poultry farm, and hospital. 

Currently, 33 close contacts are under health monitoring and management, and 3 have been given preventative medication based on risk assessment. 

Tests were conducted on 6 family members, all of whom tested negative. 

Agricultural authorities immediately implemented movement restrictions at the poultry farm, and animal testing results were negative for avian influenza virus. 

To clarify the source of infection, today's expert meeting resolved to request the farm to expand testing at nearby poultry farms and to cooperate with wild bird associations to collect droppings from surrounding wild birds. 

Furthermore, the CDC will continue to cooperate with the farm to obtain the gene sequence of the H7 virus detected in Taiwan for further comparison. 

Health and agricultural authorities will continue to strengthen surveillance of humans and animals, including respiratory viruses and influenza/novel coronavirus pneumonia surveillance in medical institutions, active surveillance of poultry farms and migratory birds, and will cooperate with farmers to promote personal protective measures for poultry farmers and public health education. 

They have also contacted duck farming associations to distribute 40,000-50,000 masks free of charge to duck farmers. 

The Centers for Disease Control (CDC) pointed out that, based on current epidemiological investigations and test results, the genetic analysis of this case shows a low-pathogenic avian influenza virus, without any mutations increasing the risk of avian-to-human transmission, and it remains a common avian virus. 

The initial assessment is that this case is an isolated incident. 

Considering the patient's improved condition after treatment, the lack of mutations increasing the risk of avian-to-human transmission in the preliminary genetic analysis, the negative test results at the poultry farm, and the absence of any other family members showing symptoms after the patient's onset, the risk is assessed as controllable, and there is no immediate risk of the outbreak expanding. 

However, to understand the potential risks of this case, they will continue to track the symptoms and test results of contacts, further analyze the virus and trace possible sources of infection, and have activated a joint working group on the risk assessment of zoonotic infectious diseases between agriculture and health authorities to conduct a comprehensive risk assessment. 

The Taiwan Centers for Disease Control (CDC) will notify the World Health Organization (WHO) today through the IHR contact window in accordance with the International Health Regulations (IHR).

According to surveillance data, since the novel influenza A virus was classified as a Category 5 notifiable infectious disease in Taiwan in 2014, a total of 5 sporadic cases have been reported. Besides this case, the others were reported in 2017 (H7N9, imported from outside China), 2021 (H1N2v), 2022 (H1N2v), and 2023 (H1N2v). In addition, there were 4 confirmed cases of H7N9 imported from outside China in 2013-2014; none of the contacts were infected.

The CDC explained that the H7N9 sequence in today's reported case is only closely related to one other human case, H7N4, reported in Jiangsu, China in 2018. The case involves a 68-year-old woman with a history of coronary heart disease and hypertension. She developed symptoms such as cough, weakness, and muscle aches on December 25, 2017, and was hospitalized for pneumonia on January 1, 2018, and discharged on January 22 after recovery. Prior to the onset of illness, the patient had contact with live poultry. Her close contacts did not develop any suspected symptoms during the observation period. The virus remains avian and has not shown resistance to existing antiviral drugs.

The Centers for Disease Control (CDC) reminds workers involved in poultry and livestock farming to implement self-protection measures during operations and to conduct thorough disinfection after work to reduce the risk of infection with the novel influenza A. If symptoms of acute respiratory infection or conjunctivitis appear, seek medical attention immediately and proactively inform healthcare professionals of your occupational history of contact with animals to facilitate early diagnosis. The public is advised to implement the "5 Dos and 6 Don'ts" epidemic prevention principles in daily life:

"5 Dos": Cook meat and eggs thoroughly with soap; wash hands thoroughly with soap; if symptoms appear, wear a mask, seek medical attention immediately, and inform the doctor of your occupation and contact history; those who have long-term contact with poultry and livestock should get vaccinated against influenza; maintain a balanced diet and exercise appropriately.

"6 Don'ts": Don't eat raw poultry, eggs, or poultry products; don't smuggle or buy meat of unknown origin; don't touch or feed poultry and livestock; don't release or discard poultry and livestock indiscriminately; don't mix poultry and livestock with other poultry and livestock; and don't go to places with poor air circulation or crowded places.

For related information, please visit the Taiwan Centers for Disease Control website (https://www.cdc.gov.tw/) or call the toll-free epidemic prevention hotline 1922 (or 0800-001922).

Source: 

Link: https://www.cdc.gov.tw/Bulletin/Detail/bZE85LXA9ZGdCvEJKZe6Cg?typeid=9

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14th Meeting of #WHO #Expert Working Group of the Global #Influenza #Surveillance and Response System (GISRS) for Surveillance of #Antiviral Susceptibility (March 20 '26)

Weekly epidemiological record 

20 MARCH 2026, 101th YEAR, No 12, 2026, 101, 53–56

http://www.who.int/wer 

Executive Summary 

The WHO Expert Working Group on Surveillance of Influenza Antiviral Susceptibility (AVWG) supports the WHO GISRS by providing practical guidance for monitoring antiviral susceptibility of seasonal and emerging influenza viruses through global surveillance efforts. 

The 14th WHO-AVWG meeting was held in virtual format on 10-12 June 2025. 

Update on susceptibility of seasonal influenza viruses to approved antiviral agents 

From approximately May 2024 to May 2025, five WHO Collaborating Centres (CCs) and two National Influenza Centres (NICs) reported co-circulation of influenza A(H1N1) pdm09, A(H3N2), and B/Victoria viruses. 

A(H1N1)pdm09 dominated in Eastern Asia{1}. Elevated frequency of influenza neuraminidase (NA) inhibitor (NAI) reduced inhibition/ highly reduced inhibition (RI/HRI) was identified among A(H1N1)pdm09 viruses, largely conferred by the NA-H275Y substitution. 

Reporting frequency was 3.8% in China, lower (≤1%) in other reporting regions, but still measurable and were in some cases a result of prior antiviral use or specific local outbreaks (e.g., a hospital in Iceland with a NA-H275Y+S247N cluster, a primary school classroom outbreak in Japan{2}. The NA-S247N substitution (≤3.3%) was also noted by three centres, but these viruses exhibited normal inhibition (NI) by NAIs when available isolates were tested. 

Incidence of RI/HRI or NA-associated markers were less frequently reported for A(H3N2) and B/Victoria viruses than A(H1N1)pdm09 viruses. 

Markers and incidence of reduced susceptibility to baloxavir was detected at low frequencies of 0.07 to 2.2%, where the latter value represented a small sample set of only 2 of 89 viruses in Japan. 

Reduced susceptibility or amino acid markers indicative of reduced susceptibility were observed only in influenza A viruses and not influenza B. 

Update on susceptibility of zoonotic and animal influenza viruses  to approved antiviral agents 

From approximately May 2024 to May 2025, global surveillance data from WHO CCs, NICs, and associated partners including WHO Essential Regulatory Laboratories and the OFFLU (WOAH/FAO Network of Expertise on Animal Influenza) network reported that most zoonotic and avian influenza viruses, particularly circulating A(H5N1/x) HA clade 2.3.4.4b and 2.3.2.1a/e viruses, were broadly susceptible to NAIs and baloxavir. 

A(H5N1) 2.3.4.4b virus oseltamivir inhibitory concentrations remain elevated vs. seasonal N1 viruses. 

Small and isolated incidence of NAI associated RI/HRI or markers included: NA-D199G mediated oseltamivir/zanamivir RI detected in A(H5N1) 2.3.4.4b poultry in the Russian Federation (February 2024, reported June 2025), NA-N295S in poultry in India A(H5N1) 2.3.2.1a isolates, and 8 poultry farms in British Columbia, Canada exhibiting A(H5N1) 2.3.4.4b with NA-H275Y. 

Only two viruses with reduced baloxavir susceptibility were identified, 1 human virus with PA-I38M (California, USA) and 1 environmental virus isolate with PA-V100I (China, Hong Kong Special Administrative Region). 

Beyond A(H5N1/x), nearly 30 avian influenza subtypes including A(H9N2), A(H7N2), A(H7N7), and A(H7N9), and A(H10N7) were analysed across surveillance sites in the Bangladesh, Egypt, the Netherlands and the United States of America (USA). 

They generally lacked NA or PA genotypic markers of reduced drug susceptibility and when available for phenotypic testing, were susceptible to both NAIs and baloxavir. 

A(H7N2) and A(H7N7) viruses from the Netherlands displayed oseltamivir RI compared to human seasonal references, but this may be due to foldchange comparison to a mismatched NA subtype. 

Swine-origin variant viruses (A(H1N1)v, A(H1N2)v, A(H3N2)v) tested across the USA and Europe were largely free of genotypic or phenotypic indicators of reduced susceptibility/inhibition to NAIs or baloxavir. 

Some viruses (the  Netherlands) showed slightly higher NAI median inhibitory concentrations to historical or human seasonal baselines, but all remained below NAI RI thresholds. 

Update of protocols and guidance for GISRS laboratories 

Both genotypic and phenotypic assays may be used as tools to monitor susceptibility of influenza viruses to NAIs and baloxavir. 

The WHO-AVWG routinely reviews and updates influenza NA and PA amino acid substitutions associated with reduced susceptibility to NAIs and baloxavir; updated tables for the previous reporting period were included on the WHO website{3–5}. 

The US CDC continues to update and ship reference virus panels that can be used for NAI and baloxavir susceptibility testing, available via the International Reagent Resource{6} 

Further guidance on baloxavir and other PA inhibitor testing included the Influenza Replication Inhibition Neuraminidase-based Assay (IRINA), published by the Centers for Disease Control and Prevention, USA{7} and included on the WHO website{8}. 

The WHO AVWG continues to develop algorithms for NICs to aid in influenza response planning (zoonotic, pandemic, and antiviral resistance-specific events), guidance to aid in decisions making for testing strategies (genotypic vs. phenotypic), and guidance for consideration of baloxavir and PA inhibitor specific amino acid substitutions associated with reduced drug susceptibility{9}. 

Additionally, the WHO-AVWG has worked with GISAID to continue to refine and implement modifications to existing tools to facilitate identification of NA and PA substitutions upon sequence submission. 

Outbreak and pandemic preparedness with clinicians’ perspectives 

Two physicians, Profs. Prof. David Hui and Bin Cao, were invited to present recently updated WHO guidance on clinical practice guidelines for influenza{10}. 

Significant updates and discussion surrounded inclusion of baloxavir, which was conditionally recommended for non-severe disease high-risk patients and post-virus exposure prophylaxis (PEP) including influenza viruses associated with high mortality. 

Conditional recommendation against any NAI or baloxavir intervention remains for non-severe disease low-risk patients or seasonal virus PEP. 

Data was presented on multiple PA inhibitors rapidly moving through late-stage clinical trials in China which may have implications on expanded usage of this newer class of influenza drugs. 

Review of External Quality Assessment Programme (EQAP) panels 

EQAP was initiated in 2007 to monitor the quality of GISRS, NICs, other national influenza reference laboratories’ capacity for influenza diagnosis and detection. 

An optional antiviral phenotypic NAI panel was introduced in 2013, and genotypic baloxavir susceptibility was introduced in 2020. 

Results for the 2024 Global EQAP panel were reported during the 14th WHO-AVWG meeting. 

Of the 194 participating laboratories, 26.3% participated in NAI susceptibility testing. 

Results and subsequent discussion from this year’s panel were used by members of WHO-AVWG to assess the training needs of NICs. 

Way forward 

The 2020–2023 Annual Global Update on the Susceptibility of Influenza Viruses (Global AVS) manuscript was published{11} and drafting of a 2023–2025 publication is underway. The next WHO-AVWG meeting will be held in June 2026.

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{1} World Health Organization. Influenza Transmission Zones. 2026. https://cdn.who.int/media/docs/ default-source/influenza/influenzaupdates/2025_09_24_influenza-transmission-zones. pdf?sfvrsn=22361408_3&download=true. 

{2} Takashita E, Shimizu K, Usuku S, Senda R, Okubo I, Morita H, et al. An outbreak of influenza A(H1N1) pdm09 antigenic variants exhibiting cross-resistance to oseltamivir and peramivir in an elementary school in Japan, September 2024. Euro Surveill. 2024;29(50).

{3} World Health Organization. Summary of neuraminidase (NA) amino acid substitutions assessed for their effects on inhibition by neuraminidase inhibitors (NAIs). 2025. https://cdn.who.int/media/docs/default-source/ influenza/laboratory---network/quality-assurance/human-nai-marker-table_ for-publication_final_20240918.pdf. 

{4} World Health Organization. Summary of neuraminidase (NA) amino acid substitutions assessed for their effects on inhibition by NA inhibitors (NAIs) among avian influenza viruses of Group 1 (N1, N4, N5, N8 subtypes) and Group 2 (N2, N3, N6, N7, N9 subtypes) NAs. 2025. https://cdn.who.int/media/ docs/default-source/influenza/avwg/avian-nai-marker-whotable__10-10-2025.pdf?sfvrsn=bc0d1e9a_10 

{5} World Health Organization. Summary of polymerase acidic protein (PA) amino acid substitutions assessed for their effects on PA inhibitor (PAI) baloxavir susceptibility. 2025. https://cdn.who.int/media/docs/default-source/influenza/ laboratory---network/quality-assurance/antiviral-susceptibility-influenza/ pa-marker-who-table_28-11-2025_updated.pdf?sfvrsn=5307d6fe_4. 

{6} International Reagent Resource. 2026. https://www. internationalreagentresource.org/. 

{7} Patel MC, Flanigan D, Feng C, Chesnokov A, Nguyen HT, Elal AA, et al. An optimized cell-based assay to assess influenza virus replication by measuring neuraminidase activity and its applications for virological surveillance. Antiviral Res. 2022;208:105457. 

{8} World Health Organization. Baloxavir Susceptibility Assessment using Influenza Replication Inhibition Neuraminidase-based Assay (IRINA). https:// cdn.who.int/media/docs/default-source/influenza/avwg/cdc-phenotypic-lp492rev01d---baloxavir-susceptibility-assessment-using-irina.pdf? 

{9} Patel MC, Nguyen HT, Mishin VP, Pascua PNQ, Champion C, Lopez-Esteva M, et al. Antiviral susceptibility monitoring: testing algorithm, methods, and f indings for influenza season, 2023-2024. Antiviral Res. 2025;244:106299. 

{10} World Health Organization. Clinical practice guidelines for influenza 2024. https://www.who.int/publications/i/item/9789240097759.

{11} Hussain S, Meijer A, Govorkova EA, Dapat C, Gubareva LV, Barr I, et al. Global update on the susceptibilities of influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2020-2023. Antiviral Res. 2025:106217.

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Source: 

Link: https://iris.who.int/server/api/core/bitstreams/1ea408da-cd90-438b-b80c-b00aaf4e7315/content

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Systematic Identification of the Functional lncRNAs During #H7N9 Avian #Influenza Virus #Infection in Mice

 

Abstract

Accumulating studies have identified the pivotal role of long non-coding RNAs (lncRNAs) in participating in host–virus interactions during virus infections. However, the regulatory roles of lncRNAs in influenza A virus (IAV) infection are still not fully elucidated. In this study, using high-throughput sequencing, we comprehensively compared the expression profiles of lncRNAs and mRNAs in mouse lungs infected either with the nonpathogenic parental (SDL124) H7N9 virus or its moderately pathogenic mouse-adapted (S8) variant. A total of 7636 significantly differentially expressed (SDE) lncRNAs were obtained in the S8-infected group compared to the mock group. As for the SDL124 group, 1042 SDE lncRNAs were identified. Subsequently, the mRNAs co-expressed with SDE lncRNAs were subjected to functional annotation and pathway enrichment analysis. The results indicated that the target mRNAs regulated by the S8 virus were mainly enriched in various immunological processes and exhibited a strong correlation with inflammatory-related signaling pathways. Moreover, 12 lncRNAs and 10 mRNAs co-expressed with SDE lncRNAs were selected and successfully verified by RT-qPCR. Among these lncRNAs, NONMMUG032982.2 and NONMMUG032328.2 exhibited strong antiviral activity against IAV. Additionally, these two lncRNAs were chosen for further in-depth bioinformatics analysis, including transcription factor prediction, coding capacity assessment, genomic location, construction of secondary structure, and prediction of potential interacting proteins. Taken together, these findings provide a cluster of lncRNAs probably associated with the virulence of IAV in mice and shed light on the anti-IAV effects of two functional lncRNAs, establishing a molecular foundation for further exploring the regulatory mechanisms of lncRNAs in IAV infection.

Source: Viruses, https://www.mdpi.com/journal/viruses

Link: https://www.mdpi.com/1999-4915/18/3/353

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Evolutionary #lineage and #host origin influence #virulence and #mammalian adaptation of #H7N9 avian #influenza viruses

 

Abstract

The H7N9 avian influenza virus (AIV) has posed a major global public health concern since its first detection in China in 2013. Transmitted among wild birds and poultry, this virus has crossed the species barrier to infect humans, causing severe respiratory disease and high mortality. Although the widespread use of H7 vaccines has markedly reduced human infections, the ongoing circulation and adaptive evolution of the virus in poultry remain a serious threat. In this study, we analyzed three highly pathogenic H7N9 isolates collected in China in 2022, representing two hemagglutinin (HA) gene evolutionary lineages: Group.y.2.3 (isolate 229-4, chicken origin; isolate 782-2, quail origin) and Group.y.2.4 (isolate 621, quail origin). Pathogenicity was compared through phylogenetic analysis, molecular characterization, and infection experiments in both avian and mammalian models. Group.y.2.3 isolates displayed stronger replication and pathogenicity in chickens and mice, with isolate 782-2 being the most virulent. The chicken-origin isolate 229-4 caused more severe weight loss and higher viral loads in the lungs of mice, indicating that host origin influences cross-species transmission potential. Molecular analyses revealed that all isolates possessed multiple basic cleavage sites and mutations linked to mammalian adaptation, including HA 186 V. Some isolates also harbored newly acquired glycosylation sites associated with immune evasion. Overall, our findings demonstrate that both genetic lineage and host origin shape the biological characteristics of H7N9 isolates. Group.y.2.3 isolates warrant priority in surveillance, providing critical insights for vaccine updates and risk assessment.

Source: 

Link: https://www.sciencedirect.com/science/article/pii/S0032579126002555?via%3Dihub

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#Prognostic factors in #H7N9 avian #influenza: a systematic review based on case reports

 

Abstract

Objective

The H7N9 avian influenza virus, identified in China in 2013, has posed a significant threat to public health due to its high mortality rate. This systematic review aims to evaluate the clinical characteristics and mortality risk factors of H7N9 patients.

Methods

English and Chinese databases (PubMed, Web of Science, Embase, CNKI, VIP, Wanfang) were searched for studies on laboratory-confirmed H7N9 cases with available data on symptom onset, diagnosis time, clinical features, oseltamivir administration, and outcomes. Univariate and multivariate analyses were performed on the pooled case data to assess the relationship between clinical factors and mortality risk.

Results

A total of 166 studies including 237 H7N9 cases were analyzed, with an overall mortality rate of 41.77%. Univariate analysis showed higher mortality in patients with advanced age ≥ 66 years (62.50%), those with underlying diseases (60.20%), those who received oseltamivir ≥ 8 days after symptom onset (54.17%), and those diagnosed ≥ 11 days after onset (62.75%), whereas patients treated with oseltamivir within 2 days of onset had the lowest mortality (17.39%). Multivariate analysis identified advanced age ≥ 66 years (OR = 3.10, 95% CI: 1.07–8.99, P = 0.037) and delayed oseltamivir administration after symptom onset (OR = 4.63, 95% CI: 1.12–19.18, P = 0.034) as independent predictors of mortality, while sex, underlying diseases, and onset-to-diagnosis time were not statistically significant.

Conclusion

Older age and delayed initiation of oseltamivir are key independent predictors of mortality in H7N9 infection. Prompt diagnosis is crucial to facilitate early antiviral treatment, which may improve survival. Future prospective studies are needed to validate these findings and optimize clinical management.

Clinical trial registration

Not applicable.

Source: 

Link: https://link.springer.com/article/10.1186/s12879-026-12908-4

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Intranasal #replicon #vaccine establishes mucosal #immunity and protects against #H5N1 and #H7N9 #influenza

 

Abstract

Seasonal and pandemic influenza viruses are continuous threats to human health, requiring rapid development of vaccines to multiple evolving viral strains. RNA vaccine technologies have the adaptability and manufacturability to facilitate pandemic preparedness but have limited flexibility in their route of administration, reducing the ability to establish local protective immune responses such as respiratory mucosal immunity. Here, we describe monovalent and bivalent replicon vaccines against A/Vietnam/1203/2004 H5N1 and A/Anhui/PA-1/2013 H7N9. These replicon vaccines express either H5 or H7 hemagglutinin and are formulated with a nanostructured lipid carrier (NLC) that permits both intramuscular (IM) and intranasal (IN) dosing. In mice, IM vaccination established systemic humoral and cellular responses but no detectable mucosal response, while IN administration induced robust systemic and mucosal immunity. The replicon-NLC vaccines protected against morbidity and mortality in ferret challenge models, establishing this intranasally-administered replicon-NLC vaccine platform as a potential pandemic response tool.

Source: 

Link: https://www.nature.com/articles/s41467-025-64829-6

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Expanding Horizons: #Host Range #Evolution and #Treatment Strategies for Highly Pathogenic Avian #Influenza #H5N1 and #H7N9

 

Abstract

Avian influenza viruses (AIVs), including H5N1 and H7N9, from the Orthomyxoviridae family present substantial public health concerns. The predominant circulating clade 2.3.4.4b has demonstrated enhanced capacity for mammalian adaptation, raising concerns about potential reassortment with human seasonal influenza viruses. Unlike H7N9’s limited host range, H5N1 infects birds, various mammals, and humans. Recent concerns include widespread H5N1 infection of U.S. dairy cattle across 18 states, affecting over 1000 herds with 71 human infections (70 H5N1 and 1 H5N5). Key observations include cow-to-cow transmission, viral presence in milk, and transmission to humans, mainly through occupational exposure. Evidence of mammal-to-mammal transmission has been documented in European and Canadian foxes and South American marine mammals. Standard pasteurization effectively inactivates the virus in milk. The continuing mammalian adaptations, particularly mutations like PB2-E627K, PB2-D701N, and PB2-M535I, suggest potential for further evolution in new hosts, emphasizing the need for enhanced surveillance to mitigate pandemic risks.

Source: 

Link: https://www.mdpi.com/1999-4915/18/1/54

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Highly Pathogenic Avian #Influenza: #Tracking the #Progression from IAV #H5N1 to IAV #H7N9 and Preparing for Emerging Challenges

 

Abstract

Highly Pathogenic Avian Influenza (HPAI) viruses, particularly IAV (H5N1), continue to pose a major global threat due to their widespread circulation and high mortality rates in birds. Management of HPAI is complicated by challenges in conserving migratory bird populations, sustaining poultry production, and uncertainties in disease dynamics. Structured decision-making frameworks, such as those based on the PrOACT model, are recommended to improve outbreak response and guide critical actions, especially when HPAI virus (HPAIV) detections occur in sensitive areas like wildlife refuges. Surveillance data from late 2024 to early 2025 show persistent HPAI activity, with 743 detections across 22 European countries and beyond, and notable outbreaks in poultry in nations like Hungary, Iceland, and the UK. The proximity of poultry farms to water sources increases environmental contamination risks. Meanwhile, HPAI A(IAV (H5N1)) and other H5Nx viruses have been detected in a wide range of mammalian species globally, raising concerns about mammalian adaptation due to mutations like E627K and D701N in the PB2 protein. Human infections with IAV (H5N1) have also been reported, with recent cases in North America highlighting zoonotic transmission risks. Molecular studies emphasize the importance of monitoring genetic variations associated with increased virulence and antiviral resistance. Preventive strategies focus on biosafety, personal protective measures, and vaccine development for both avian and human populations. Ongoing genetic characterization and vigilant surveillance remain critical to managing the evolving threat posed by HPAI viruses.

Source: 

Link: https://www.mdpi.com/2076-2607/14/1/12

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#Ecology of low pathogenicity avian #influenza virus #H7 in wild #birds in south-eastern #Australia prior to emergence of high pathogenicity avian influenza H7 in #poultry

 

Abstract

Adding to the global burden of high pathogenicity avian influenza (HPAI) H5N1, an unprecedented five HPAI H7 outbreaks occurred globally in 2024. Of these, three occurred in southeast Australia, with the independent emergence of HPAI H7N9, H7N8, and H7N3, resulting in the destruction of 2 million poultry. Historical data demonstrates that H7 outbreaks in Australia do not occur randomly, rather, there is a strong association between the timing of the previous H7 outbreaks and rainfall patterns in southeastern Australia. We aimed to address a hypothesis wherein prior to H7 outbreaks in poultry, there was a detectable change in H7 prevalence and/or virus diversity in wild bird populations. We addressed this using virological and serological surveillance data generated from multiple programs. Despite the collection of thousands of samples, there was only weak evidence to support our hypothesis, which provides strong incentive to evaluate current surveillance approaches for the purposes of risk prediction. However, in alignment with a previous analysis, there is strong support for a relationship between H7 outbreak probability and rainfall patterns across southeast Australia. Overall, improved understanding of the ecology and evolution of H5 and H7 viruses in wild bird reservoirs is pivotal to global disease preparedness and response.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

Australian Department of Agriculture Fisheries and Forestry

Australian Department for Health and Aged Care

Source: 

Link: https://www.biorxiv.org/content/10.64898/2025.12.08.693062v1

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Direct #airway delivery of a humanized anti - #H7N9 neutralizing #antibody broadly protects against divergent #H7 #influenza viruses in the mouse model

 

ABSTRACT

Passive administration of broadly neutralizing anti-influenza monoclonal antibodies (mAbs) before or after virus infection can prevent or alleviate disease. Unlike seasonal influenza, infection with zoonotic avian influenza viruses can lead to acute respiratory distress syndrome and high mortality in humans. Respiratory tract-targeting antibody delivery appears to be more clinically relevant and effective for zoonotic influenza treatment. In this study, the efficacy of an anti-H7N9 murine mAb 4B7 and its humanized form (chi4B7) against H7 subtype influenza viruses administered through the intranasal route was investigated in mice. 4B7 recognizes critical residues in the vestigial esterase domain and receptor-binding sites in the hemagglutinin of H7N9 virus. The antibody had cross-H7 binding, hemagglutination inhibition, and neutralizing activities. In particular, the dose of 4B7 required for prophylactic protection against H7N9 infection was significantly reduced in mice treated locally (intranasal) compared with those treated systemically (intraperitoneal). Intranasal delivery of the antibody also enhanced therapeutic efficacy against H7N9 infection compared to intraperitoneal administration. Chi4B7 generated by grafting the variable regions onto the human IgG1 backbone sustained cross-reactivity with different H7 viruses of the parental murine antibody. Airway-delivered chi4B7 provided broad prophylactic and therapeutic protection against divergent H7 viruses in mice. Moreover, intranasal administration of chi4B7 had a long effective prophylaxis window against H7N9 infection. Our results suggest that airway delivery of the humanized anti-H7 antibody is a favorable approach for broad-spectrum prophylaxis and therapy against the H7 subtype influenza.

Source: 

Link: https://journals.asm.org/doi/10.1128/jvi.01327-25

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Structural basis for a potent #human neutralizing #antibody targeting a conserved epitope on the #H7 #hemagglutinin head

 

Significance

The high-resolution cryo-EM structure indicates that the human antibody 6Y13 binds strongly to a conserved pan-H7 epitope on the hemagglutinin head, distinct from the receptor-binding site and lateral patch. However, 6Y13 can broadly neutralize H7 viruses, fully protect H7N9-infected mice, and potently block receptor binding through mechanisms, independent of Fc-mediated steric hindrance.

Abstract

Zoonotic H7N9 avian influenza virus infection remains a global concern because of its pandemic potential. Therefore, developing effective antibodies and vaccines against H7N9 is vital for preventing and controlling major outbreaks. Here, we isolated a human VH3-30 gene-encoded antibody, designated 6Y13, from a survivor of H7N9 infection. This antibody recognized the hemagglutinins (HAs) of the representative H7 subtype zoonotic viruses spanning two decades of antigenic evolution and potently neutralized epidemic H7N9 viruses in vitro. Moreover, 6Y13 conferred complete protection in mice against lethal H7N9 challenge in both prophylactic and therapeutic experiments. Structural analysis by cryoelectron microscopy indicated that 6Y13 binds to a unique conserved site on the HA head, distinct from the receptor-binding site and lateral patch. Nevertheless, 6Y13 efficiently blocked viral receptor binding without interfering with HA receptor binding, independent of Fc-mediated steric hindrance. Our findings provide a promising therapeutic candidate against pan-H7 subtype viruses and are beneficial for the design of H7 subtype influenza vaccine immunogens.

Source: Proceedings of the National Academy of Sciences of the United States of America, https://www.pnas.org/doi/10.1073/pnas.2503008122

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