#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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Characterization of #oseltamivir-resistant #H5N1 clade 2.3.4.4b, genotype #D1.1 #variants identified in #poultry farms of British Columbia, #Canada

 

ABSTRACT

Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b, genotype D1.1, are responsible for widespread outbreaks in poultry and continue to cause sporadic, sometimes severe, human infections. Herein, we characterized a wild-type (WT) influenza A(H5N1) D1.1 isolate (BC-H5N1-WT) and its H275Y neuraminidase (NA) variant (BC-H5N1-H275Y), both of which emerged on farms in British Columbia, Canada, during the fall 2024 outbreak. In vitro analysis assessed replication kinetics in MDCK cells, with supernatants collected at different days post-infection (p.i.) and titrated by TCID50 and qRT-PCR. Neuraminidase inhibitor (NAI) susceptibility was determined by NA inhibition assays, whereas susceptibility to baloxavir acid (BXA) was evaluated by plaque reduction assay. In vivo virulence was evaluated in BALB/c mice infected with serial 10-fold dilutions of each virus to monitor weight loss and mortality. Viral titers in lungs, brain, nose, kidney, spleen, and heart were quantified at day 4 p.i. The BC-H5N1-WT virus was susceptible to the four antivirals tested, whereas BC-H5N1-H275Y displayed resistance to oseltamivir and peramivir but remained susceptible to zanamivir and BXA. The BC-H5N1-WT exhibited significantly higher viral replication titers than BC-H5N1-H275Y at all tested time points and showed larger plaque sizes. In mice, BC-H5N1-WT was more virulent with LD50 values of 1.78 × 103 PFUs compared to 8.71 × 104 PFUs for BC-H5N1-H275Y, and produced higher viral titers in lungs and other organs. Despite the reduced fitness of the resistant H5N1 D1.1 variant, its emergence in the absence of viral selection pressure underscores the need for continued surveillance.

Source: 

Link: https://www.tandfonline.com/doi/full/10.1080/22221751.2026.2686474

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First #Ecuadorian #Pediatric Case of Multisystem and #Neurological Involvement Associated with #Influenza A #H5N1 Virus—Case Report

 

Abstract

Influenza A (H5N1) is a highly pathogenic zoonotic virus with a human fatality rate of approximately 60%. Pediatric cases and associated neurological manifestations remain poorly documented in Latin America. This report describes the first confirmed Ecuadorian pediatric case of H5N1-associated encephalitis and multisystem organ failure in a previously healthy 9-year-old female following direct contact with infected poultry. The clinical course was characterized by an atypical initial presentation of bilateral periorbital edema and headache, progressing to acute encephalitis, cerebral ischemia, flaccid tetraplegia, central diabetes insipidus, and refractory septic shock. Diagnostic confirmation was achieved via nasopharyngeal RT-PCR, with additional RT-PCR and sequencing performed on cerebrospinal fluid, which identified conserved influenza A M1/M2 gene fragments, while laboratory markers—including marked elevations in IL-6, ferritin, and CRP—indicated a severe hyperinflammatory state. Management involved an intensive multidisciplinary approach utilizing oseltamivir, intravenous immunoglobulin, modulated-dose corticosteroids, desmopressin, and mechanical ventilation. Despite a severe clinical course, the patient achieved a favorable recovery, with a Glasgow Coma Scale score of 15/15 at discharge and only partial residual paresis and left hypoacusia as sequelae. This landmark case provides rare evidence of H5N1 neuroinvasion in a pediatric patient and demonstrates that timely detection combined with aggressive immunotherapy and antiviral treatment can improve survival. Furthermore, it underscores the critical necessity for strengthened regional molecular surveillance and clinical training to recognize atypical presentations of emerging zoonoses in Latin America, especially in cases involving contact with sick poultry.

Source: 

Link: https://www.mdpi.com/1999-4915/18/7/749

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Evaluation of #antiviral #treatments for highly pathogenic avian #influenza virus #infections in #feline species

 

Abstract

In 2020, highly pathogenic avian influenza (HPAI) isolates from clade 2.3.4.4b emerged in Europe and spread globally, including in bovine hosts in the USA. Viruses from this clade cause minimal disease in dairy cattle, characterized by decreased milk production but low mortality rates. Infections have also occurred in feline hosts. In contrast to cows, infection of cats (and closely related species, including skunks and foxes) can result in severe neurological signs and mortality. Documented feline H5N1 infections from clade 2.3.4.4.b have a mortality rate of approximately 80% following rapid onset of clinical signs. No antiviral compounds have been tested in an experimental feline model; however, anecdotal clinical evidence suggests early treatment with oseltamivir may improve outcomes in felines with HPAI. Here, we show the in vitro efficacy of several influenza inhibitors in feline glial astrocyte (PG-4) and kidney (CRFK) cell culture models using the clade 2.3.4.4.b virus Tx2/24 (H5N1). The neuraminidase inhibitor oseltamivir carboxylate did not effectively inhibit viral replication in either cell line. The cap-dependent endonuclease inhibitor baloxavir exhibited the strongest inhibition of this virus, with EC50 values of 30 nM in PG-4 and 1 μM in CRFK cells. Amantadine and rimantadine, M2 ion channel inhibitors, were unable to completely inhibit viral replication in either cell line at any concentration utilized. The broad-spectrum nucleoside analog GS-441524 demonstrated little to no inhibition of viral replication in either cell line. Additionally, the mutagenic NHC analogs EIDD-1931 and EIDD-2801 successfully inhibited viral replication at the maximum tested concentration of 100 μM but exhibited significant cytotoxicity. Our findings suggest that baloxavir should be considered by veterinary clinicians as the first-line drug of choice when presented with felines or other species infected with HPAI.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

Cornell Feline Health Center, Ithaca, US

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.06.09.730954v1

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A mouse #model of #human-derived #H10N3 #influenza enables preclinical evaluation of #antiviral efficacy

 

Highlights

• Revealing one human-derived H10N3 virus was highly lethal to C57BL/6J, ICR, and BALB/c mice;

• Successfully establishing the first human-derived H10N3-infected mice model.

• In vitro antiviral assay revealed that this human-origin H10N3 virus exhibits natural resistance to oseltamivir, but remains sensitive to peramivir and baloxavir.

• Oseltamivir or BM immediate treatment after infection effectively prevented mortality caused by H10N3,but their efficacy with a 24h delay were significantly weaker than that of peramivir.

• BM one-dose treatment with a 24h delay has no protective effect, but BM combination with NAIs exhibits significant additive effect on mortality caused by H10N3.

• BM and NAIs combination may be a promising therapy for combating novel H10N3 virus infection.

Abstract

    Human infections with avian influenza A (H10N3) have recently been reported, representing a notable global public health concern. To seek effective strategies for emerging H10N3 virus infection and provide tools for vaccine and antiviral drugs development, we established a mouse model with a novel human-derived H10N3 virus. Our findings revealed that this human-derived H10N3 virus was highly lethal to C57BL/6J, ICR, and BALB/c mice. Neuraminidase inhibitors (oseltamivir or peramivir) effectively conferred protection for H10N3 low-lethal infection, but the efficacy of peramivir is superior to that of oseltamivir. One single dose of baloxavir marboxil (BM) treatment at 2 h post-infection provides complete protection against mortality, but BM treatment with a 24h delay has no protective effect against mortality caused by H10N3 virus infection. Furthermore, BM multiple doses treatment with a 24h delay for H10N3 infection remains effective in preventing weight loss and enhancing viral clearance, but its protective efficacy against mortality was significantly attenuated. However, both in vitro and in vivo combination of BM with NAIs exhibit significant additive effect against H10N3 virus infection than BM or NAIs monotherapy. Our findings suggest that combination of BM with NAIs represents a promising therapeutic strategy for emerging H10N3 infections in clinical practice.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S0166354226000951?via%3Dihub

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#Antiviral treatment for #influenza

 

Abstract

Seasonal influenza is a widespread acute respiratory infection that causes significant illness and death worldwide. Two major antiviral classes are neuraminidase inhibitors (NAIs) and polymerase inhibitors. NAIs, including oseltamivir, zanamivir, peramivir and laninamivir, block viral release, while polymerase inhibitors such as baloxavir disrupt viral RNA replication. Early administration within 48 h of symptom onset reduces illness duration, severity and complications, particularly in high-risk groups. Oseltamivir is the most widely studied NAI, demonstrating reduced viral shedding, faster symptom resolution and lower complication rates, though gastrointestinal side effects are common. Higher doses generally do not improve outcomes compared to standard dosing. Zanamivir is more effective against influenza B and is inhibitory for most influenza A viruses resistant to oseltamivir, but the inhaled formulation is less suitable for patients with severe illness or airway disease. Intravenous (IV) zanamivir is approved for hospitalized influenza patients in some countries. Peramivir offers IV treatment options, while laninamivir is mainly used in Japan. Baloxavir shows superior viral load reduction and comparable symptom relief to oseltamivir in outpatients, though resistance variants can emerge. Favipiravir and newer polymerase inhibitors are under investigation. Combination therapies may enhance recovery, with limited evidence. Overall, timely antiviral use is critical to reducing influenza’s burden.

This article is part of the Theo Murphy meeting issue ‘Evaluating anti-infective drugs’.

Source: 

Link: https://royalsocietypublishing.org/rstb/article/381/1949/20240344/481548/Antiviral-treatment-for-influenza

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#Genetic and #biological characterization of a #duck-origin clade 2.3.4.4b #H5N6 avian #influenza virus reveals partial #mammalian #adaptation

 

Highlights

• Duck-origin H5N6 virus A/Duck/Jiangsu/628/2022 shares high homology with the human strain A/Yangzhou/125/2022.

• The 628 strain shows mammalian adaptation markers: HA mutations enhance human receptors affinity and NA mutations reduce sensitivity to neuraminidase inhibitors.

• Limited airborne transmission but detectable droplet-mediated spread suggests increased mammalian transmission risk.

Abstract

Clade 2.3.4.4b H5Nx highly pathogenic avian influenza viruses (HPAIVs) have caused extensive outbreaks in poultry worldwide. H5 HPAIVs have caused sporadic but severe human infections in China, representing a persistent zoonotic threat. Here, we identified a duck-origin H5N6 HPAIV (A/Duck/Jiangsu/628/2022) through routine surveillance and assessed its biological characteristics and mammalian pathogenesis. Phylogenetic analysis revealed > 98% nucleotide identity between strain 628 and the concurrent human H5N6 strain A/Yangzhou/125/2022. Molecular characterization identified multiple mammalian adaptation markers: hemagglutinin substitutions (S137A, T160A, T192I) associated with enhanced human receptor binding; neuraminidase mutations (I117T, D198N) linked to reduced neuraminidase inhibitor susceptibility; and polymerase complex changes (PB1-D622G, PA-K142Q) conferring increased mammalian cell replication. In vitro studies demonstrated that 628 virus replicated more efficiently in mammalian than in avian cells and exhibited dual receptor-binding specificity. Mouse pathogenicity assays revealed moderate virulence with progressive lung pathology. Critically, transmission experiments confirmed both direct contact and airborne transmission capabilities of 628 in guinea pigs. These findings demonstrate that circulating H5N6 viruses have acquired partial mammalian adaptation while retaining avian fitness, significantly elevating pandemic potential. Enhanced surveillance of wild bird populations, poultry farms, and live poultry markets is urgently needed to develop effective prevention and control strategies.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S037811352600146X?via%3Dihub

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Antiviral activities of multiple #antivirals against highly pathogenic avian #influenza A #H5N1 in vitro and in mice

 

ABSTRACT

In 2024, a bovine H5N1 strain was first isolated from dairy cows in Texas and confirmed to transmit cross-species to humans. Therefore, research on treatments for human infection should be accelerated. In our study, the antiviral effects of baloxavir acid (BXA), oseltamivir carboxylate (OSC), EIDD-1931 (NHC), and ribavirin (RBV) against five H5N1 strains were evaluated in vitro. Cell viability and viral replication were measured to assess the antiviral effects. The results showed that the EC50 of BXA treatment was the lowest. The BXA/NHC and BXA/OSC combination treatments showed more potent inhibitory effects than each monotherapy. The 15 mg/kg baloxavir marboxil (BXM) / 125 mg/kg molnupiravir (MNP) and the 15 mg/kg BXM / 10 mg/kg oseltamivir phosphate (OSP) were tested in BALB/c mice. The mice were inoculated with 10 times the 50% mouse lethal dose (10 MLD50) of bovine H5N1 virus. Treatments began 1-day post-infection (1 dpi) and were administered orally twice daily for 5 or 7 days. Changes in body weight, clinical signs, and survival were monitored; lung and brain tissues were collected for virological, immunological, and histological analyses. Most mice died from severe neurological symptoms. Compared with the 5-day treatment, the 7-day treatment effectively inhibited viral replication and increased survival rates to 50% in BXM, BXM/MNP, and BXM/OSP treatments. Mice treated with BXM/MNP or BXM/OSP combination therapy showed lower viral yields in the lungs than those treated with BXM alone. The results provide a reference for human treatment, and extending the 7-day combination treatment should be considered.

Source: Emerging Microbes and Infections, https://www.tandfonline.com/journals/temi20

Link: https://www.tandfonline.com/doi/full/10.1080/22221751.2026.2645843

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Prompt and Intensive #Antiviral #Chemoprophylaxis in Nursing Home #Influenza #Outbreaks

 

Key Points

-- Question:  Is initiation of antiviral chemoprophylaxis with oseltamivir for 70% or more of eligible nursing home (NH) residents within 2 days of outbreak detection associated with lower 14-day and 30-day mortality and hospitalization compared with a nonintensive approach?

-- Findings:  In this cohort study of 404 influenza outbreaks across 318 NHs with 35 086 resident-trial observations using a sequential target trial emulation and the randomize-censor-weight approach, hospitalization but not death was lower at 14 days post outbreak in NHs that implemented intensive antiviral chemoprophylaxis; 30-day estimates were directionally similar but less precise.

-- Meaning:  Results of this study suggest that clinicians should promptly initiate antiviral chemoprophylaxis in at least 70% of NH residents within 2 days of an influenza outbreak to markedly reduce influenza-related hospitalizations.

Abstract

Importance  

Influenza outbreaks in nursing homes (NHs) can cause high morbidity and mortality. Antiviral chemoprophylaxis with oseltamivir is recommended, yet optimal implementation strategies remain unclear.

Objective  

To examine whether initiating antiviral chemoprophylaxis for 70% or more of eligible NH residents within 2 days of influenza outbreak detection is associated with lower all-cause mortality and hospitalization at 14 and 30 days.

Design, Setting, and Participants  

Retrospective cohort study using a sequential cluster-randomized target trial emulation and randomize-censor-weight approach for influenza outbreaks (September 1, 2018–May 31, 2022) in 12 US NH corporations. Eligibility criteria were age 18 years or older, present on the outbreak-detection day, no antiviral use in the preceding 7 days, no influenza in the past 14 days, and complete baseline data. Residents were followed up until hospitalization or death, an NH discharge to a nonacute-care location, or the end of follow-up. Data were analyzed from February 2023 to January 2026.

Exposures  

Intensive antiviral chemoprophylaxis with oseltamivir (≥70% of eligible residents within 2 days of outbreak detection) or nonintensive antiviral chemoprophylaxis (0% to <70% of eligible residents).

Main Outcomes and Measures  

Outcomes were all-cause death and hospitalizations within 14 and 30 days of outbreak detection. Discrete-time hazard models with pooled logistic regression were applied to estimate weighted risks, risk differences (RDs), and risk ratios (RRs).

Results  

Among 404 outbreaks in 318 NHs, 35 086 resident-trial observations (29 683 residents; median age 78 [IQR, 68- 86] years; 60% women; 81% White; 76% vaccinated) met eligibility criteria. Intensive oseltamivir prophylaxis was randomized to 17 155 observations; 17 931 were randomized to nonintensive care. At 14 days, intensive prophylaxis vs nonintensive yielded an RD of –0.06% (95% CI, −0.73% to 0.93%) and an RR of 0.96 (95% CI, 0.56-1.57) for death, and an RD of –0.96% (95% CI, −1.78% to −0.19%) and an RR of 0.79 (95% CI, 0.64-0.96) for hospitalization. At 30 days, the hospitalization differences persisted but were less precise and there continued to be no difference in death.

Conclusions and Relevance  

Study results suggest that clinicians should initiate antiviral chemoprophylaxis for at least 70% of eligible NH residents within 2 days of outbreak detection to lower risk of hospitalization.

Source: 

Link: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2846967

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Use of #baloxavir as adjunctive #antiviral #therapy to neuraminidase inhibitors in severely immunocompromised individuals infected with #influenza

 

ABSTRACT

Immunocompromised patients are at risk of developing severe influenza, with protracted viral shedding and development of resistance-associated mutations under antiviral treatment. We report a case series of severely immunocompromised hematology patients, including allogeneic hematopoietic cell transplantation (HCT) recipients, treated with both baloxavir and oseltamivir and describe clinical and virological outcomes and the safety profile of prolonged combination therapy. Allogeneic HCT recipients with influenza infection treated with baloxavir were retrieved via institutional databases. All hospitalized allogeneic HCT patients treated with a combination therapy of baloxavir and oseltamivir over five influenza seasons between October 2019 and May 2025 were included. Six influenza-infected hematology patients (5/6 allogeneic HCT recipients) were treated with combination therapy of oseltamivir and baloxavir. All patients presented with lower respiratory tract infections. Oseltamivir treatment duration ranged from 5 to 31 days, and the number of administered baloxavir doses ranged between one and five. Baloxavir administration was well tolerated, and no adverse events could be attributed to the administered antiviral treatment. All-cause mortality at 3 months post-infection was 66% (4/6), mainly driven by underlying disease. In two patients with protracted shedding, combination therapy did not prevent the development of resistance mutation(s). Combination treatment with prolonged courses of oseltamivir and repeated doses of baloxavir was well tolerated. No definitive conclusions on the efficacy of this approach could be drawn from this study. More data are required on the best treatment of hematology patients infected with influenza.

Source: 

Link: https://journals.asm.org/doi/10.1128/aac.01659-25

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#Oseltamivir aziridines are potent #influenza #neuraminidase #inhibitors and imaging agents

 

Significance

Influenza remains a major global health threat. We introduce oseltamivir-based aziridines that unite transition-state mimicry for tight binding with aziridine-enabled covalent capture of the catalytic tyrosine. This dual function yields potent, mechanism-based neuraminidase inhibition and enables activity-based quantification of active enzyme directly in complex samples. Across N1, N2, and influenza B enzymes, selected compounds show high potency against diverse viral neuraminidases and in live virus replication assays. By combining a clinically grounded scaffold with a reactivity handle, these molecules bridge therapeutic and diagnostic needs and offer a practical platform for neuraminidase imaging and antiviral development.

Abstract

Influenza neuraminidase (NA) is a critical target for seasonal and pandemic antivirals, including the strains of current concern. Current treatments, such as Zanamivir and Oseltamivir, are limited by noncovalent binding and emerging resistance. We hypothesized that Oseltamivir aziridines would unite transition-state mimicry for tight binding, with aziridine-enabled covalent capture of the catalytic tyrosine, thereby supporting both therapy and activity-based quantification. Here, we present oseltamivir-based aziridines, inspired by cyclophellitol chemistry, that act as covalent inhibitors and activity-based probes via an N-acylaziridine warhead. Free-energy calculations, and NMR observations, indicate a 4H5 half-chair preference consistent with the NA transition state, and selected analogues inhibit multiple NA subtypes with low nanomolar binding constants. Diverse evidence establishes covalency: time-dependent inactivation, inhibitor washout, intact-mass shifts, MS/MS identification of a tyrosine adduct, and QM/MM reaction profiles, while cryoEM of N1 aligns with the proposed binding mode, revealing an elimination product. The inhibitors demonstrate formidable activity against diverse viral neuraminidases, including H5N1, and further enable imaging and quantification of active NA. With their dual therapeutic and diagnostic potential, these first-in-class inhibitors indeed benefit from transition state mimicry and covalency, and thus offer a powerful platform for antiviral development and neuraminidase imaging, addressing urgent global health needs in influenza treatment and prevention.

Source: 

Link: https://www.pnas.org/doi/10.1073/pnas.2504045123

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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.

___

{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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#Report on #influenza viruses received and tested by the #Melbourne #WHO CC for #Reference and Research on #Influenza during 2024

 

Abstract

As part of its role in the World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne received 12,180 human influenza-positive samples during 2024. Viruses were analysed for their antigenic, genetic, and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or embryonated hens’ eggs for potential use in seasonal influenza virus vaccines. During 2024, influenza A(H1N1)pdm09 and A(H3N2) viruses predominated, accounting for 33% and 42%, respectively, of all viruses received, compared to 5% for influenza B/Victoria. Of note, one influenza A(H5N1) virus was also received in 2024. The majority of A(H1N1)pdm09 (98%), A(H3N2) (88%) and influenza B (100%) viruses analysed at the Centre were found to be antigenically and genetically similar to the respective WHO recommended vaccine strains for the Southern Hemisphere in 2024. Of 4,007 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, twelve A(H1N1)pdm09 viruses and one B/Victoria virus showed highly reduced inhibition against oseltamivir or zanamivir. Of 3,294 total samples sequenced for baloxavir susceptibility, 18 of the 1,825 A(H3N2) samples were identified with genetic evidence of reduced susceptibility to baloxavir marboxil in the PA gene.

Source: 

Link: https://ojs.cdi.cdc.gov.au/index.php/cdi/article/view/3449

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#Baloxavir outperforms #oseltamivir, #favipiravir, and #amantadine in treating lethal #influenza #H5N1 HA clade 2.3.4.4b #infection in #mice

 

Abstract

Intercontinental spread of highly pathogenic avian influenza A(H5N1) viruses poses significant pandemic risks and necessitates strong protective countermeasures. We evaluated the therapeutic efficacy of the neuraminidase inhibitor oseltamivir, the polymerase inhibitors baloxavir and favipiravir, and an ion-channel blocker amantadine, against severe influenza A(H5N1) virus infection in female BALB/c mice. Baloxavir (≥10 mg/kg, 1 dose) fully protected mice from death, significantly reduced virus respiratory replication, and prevented neuroinvasion. Oseltamivir (≥100 mg/kg/day for 5 days) provided limited survival benefits, reduced lung titers but failed to prevent viral neuroinvasion. Favipiravir (≥100 mg/kg/day for 5 days) provided partial protection, although did not reduce viral titers in lungs and brain. Amantadine provided no benefits. Although all drugs inhibited A(H5N1) viruses in vitro, in vivo correlations did not extend beyond baloxavir. Our results indicate that baloxavir is the most reliable treatment to address both respiratory replication and systemic spread of contemporary A(H5N1) viruses in mice and should be considered in pandemic planning.

Source: 

Link: https://www.nature.com/articles/s41467-026-69721-5

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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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Genomic #Evolution of #Influenza A Virus During the 2024-2025 Season, the Johns Hopkins Health System: Antigenic Drift Reduces Serum Neutralization

 

Abstract

Introduction

Seasonal influenza causes significant global morbidity, mortality, and economic burden. Ongoing viral evolution can lead to vaccine mismatch and the emergence of antiviral resistance, highlighting the importance of genomic surveillance. The 2024–2025 influenza season was characterized by high incidence and increased hospitalizations.

Methods

We analyzed influenza A virus (IAV) genomes and clinical characteristics from the 2024–2025 season. Whole-genome sequencing was performed on 648 influenza A–positive clinical specimens collected between October 2024 and April 2025.

Results

Hemagglutinin (HA) sequences were recovered from 74.23% (481/648) of samples and used for subtyping and phylogenetic analysis. A(H1N1)pdm09 and A(H3N2) viruses co-circulated, representing 55.5% and 44.5% of cases, respectively. Among A(H1N1)pdm09 viruses, the HA1 substitution T120A, located near the Sa antigenic site, increased more than twofold compared with the prior season. Circulating A(H3N2) viruses belonged to multiple HA subclades and exhibited distinct amino acid substitutions at key antigenic sites. Neutralization assays using sera from individuals vaccinated with the 2024–2025 seasonal influenza vaccine demonstrated reduced neutralization of three dominant A(H1N1)pdm09 isolates and two A(H3N2) isolates compared with vaccine strains, consistent with antigenic drift. In addition, the neuraminidase substitution S247N, previously associated with reduced oseltamivir susceptibility, was detected in 13.9% of A(H1N1)pdm09 samples.

Discussion

These findings demonstrate ongoing antigenic drift and the presence of antiviral resistance–associated mutations during the 2024–2025 influenza season, underscoring the need for continued genomic surveillance to guide vaccine and antiviral strategies.

Source: 

Link: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiag069/8461561#google_vignette

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#Oseltamivir and #baloxavir monotherapy and combination #therapy efficacy against clade 2.3.4.4b #H5N1 #influenza virus infection in #ferrets

 

Abstract

Neuraminidase inhibitors (NAIs) and cap-dependent endonuclease inhibitors (CENIs) represent two classes of antiviral drugs recommended for early treatment of patients with seasonal influenza A virus (IAV) infections. However, only limited human data, particularly on combination antiviral treatment, are available to inform optimal dosing regimens against novel IAVs, including highly pathogenic avian influenza A(H5N1) virus, associated with severe disease. Clade 2.3.4.4b A(H5N1) viruses have caused outbreaks in avian and mammalian species worldwide, highlighting the need to assess antiviral drug efficacy against these strains. We challenged ferrets with a D1.1 genotype A(H5N1) virus and treated infected animals with the NAI oseltamivir phosphate (OST) and the CENI baloxavir acid (BXA), alone or in combination, with treatment onset commencing pre- or post-symptom onset (24- or 48-hours post-inoculation (p.i.), respectively). When administered pre- or post-illness onset, BXA, but not OST, monotherapy provided significant reduction of clinical signs and significantly decreased infectious viral levels (in both respiratory and extrapulmonary specimens) compared with mock-treated animals. Combination OST/BXA treatment, when administered pre- or post-symptom onset, resulted in significant improvements in both metrics versus OST monotherapy. These data support continued investigation of antiviral treatment modalities that include both NAI and CENI for patients with mild and severe A(H5N1) disease.

Source: 

Link: https://www.nature.com/articles/s42003-026-09607-w

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#Clinical Features and #Management of a Critical #Human Case of #H10N3 Avian #Influenza: A Case Report and Literature Review

 

Highlights

• Nonspecific early signs hinder prompt diagnosis of H10N3 infection.

• H10N3 human infection remains rare but with high clinical severity.

• All patients had bird exposure and developed fever, cough, and dyspnoea.

• Diagnosis was confirmed by sequencing; imaging revealed viral pneumonia.

Abstract

Background

Since the first human case of H10N3 Avian Influenza in Jiangsu, China (April 2021), three cases have been reported globally. However, clinical and treatment data remain limited. Therefore, we describe the fourth patient’s epidemiology, clinical manifestations, diagnostics, treatment.

Case presentation

A 23-year-old woman, previously well, presented on 12 Dec 2024 with fever, dry cough and breathlessness after pig and chicken contact. CT showed bilateral pneumonia. Despite high-flow oxygen and broad-spectrum antibiotics she deteriorated, requiring intubation, lung-protective ventilation and VV-ECMO. Bronchoalveolar lavage isolated H10N3 influenza virus. Treatment with oseltamivir and baloxavir plus prone-position ventilation led to clinical improvement.

Conclusion

Due to its nonspecific early symptoms, H10N3 is difficult to diagnose promptly, increasing the risk. Early recognition, antiviral therapy, and aggressive support are essential in managing severe infections.

Source: 

Link: https://www.ijidonline.com/article/S1201-9712(26)00002-0/fulltext

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A case of #H10N3 avian #influenza in a young woman

 

Context and significance

The avian influenza A virus subtype H10N3 is a possible candidate for causing a fatal flu and may present a serious public health threat. Research increasingly shows that the avian influenza virus H10N3 can be transmitted from birds to humans, causing severe viral pneumonia and potentially leading to acute respiratory distress syndrome and respiratory failure. Researchers at the Fourth People’s Hospital of Nanning (China) provide evidence supporting the cross-species transmission of the avian influenza virus H10N3 to humans, which can give rise to severe pneumonia. The authors report that a female patient with avian influenza virus H10N3 infection, who was suffering from severe pneumonia, respiratory failure, pneumothorax, and numbness and dysesthesia in her feet, recovered after receiving appropriate therapy and was discharged from the hospital.

Highlights

• A young woman contracted the avian influenza virus H10N3

• Secondary infections, pneumothorax, and foot numbness developed consecutively

• Baloxavir marboxil and oseltamivir were administered

Summary

Background

Avian influenza viruses, frequently identified in wild waterfowl and poultry, have occasionally been transmitted to humans, causing severe respiratory diseases. This report covers the fourth case of a human contracting the H10N3 subtype of avian influenza virus.

Methods

A case of novel avian influenza virus subtype H10N3 was detected in a female patient hospitalized in Nanning, China, in December 2024. Blood, feces, urine, and bronchoalveolar lavage fluid were collected from the patient for medical analysis during the hospitalization.

Findings

A case of novel avian influenza virus subtype H10N3 was detected in a female patient hospitalized in Nanning, China, in December 2024. She also had a history of exposure to live poultry. This case represents the fourth documented instance of H10N3 infection in humans. She was treated with a combination of baloxavir marboxil and oseltamivir. She exhibited extensive lung lesions. Additionally, she presented complicating factors, including secondary infection, pneumothorax, and numbness in her feet. She recovered and was discharged on March 27, 2025, amid comprehensive supportive care, which included therapy with baloxavir marboxil, oseltamivir, fluconazole, tigecycline, amikacin, extracorporeal membrane oxygenation, and rehabilitation therapy.

Conclusions

The virus was effectively cleared by the combination therapies. The internal genes of the H10N3 virus in this patient were highly homologous to the corresponding genes from the A/Yunnan/2024 virus (GenBank accession numbers, hemagglutinin [HA] [GenBank: PP555669] and PB-2 [GenBank: PP555666]).

Funding

This work was funded by the Fourth People’s Hospital of Nanning - Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) Clinical Treatment Center of Guangxi (Nanning).

Source: Med., https://www.cell.com/med/abstract/S2666-6340(25)00272-7

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Differential modulation of #Interferon and Cell Death Responses defines #Human vs Avian #Influenza A Virus Strain-Specific Virulence and guides Combination #Therapy.

Abstract

Influenza A virus (IAV) poses a significant global health risk, with highly pathogenic strains like H5N1 (CFR ~52%) causing severe disease compared to less lethal but more transmissible strains like H1N1 (CFR 0.01-0.03%). Although IAV primarily infects lung epithelial cells, causing cell death and tissue damage, the molecular basis of strain-specific pathogenesis remains poorly understood. Here we show that in cell culture, H5N1 induced more rapid and extensive cell death than H1N1. Since Interferon (IFN) signaling is key to innate immunity, we examined its role in virus-induced cell death using STAT1-knockout A549 cells and JAK/STAT pathway inhibitors like Baricitinib. Both approaches reduced cell death across various IAV strains, including H1N1, H5N1, H7N9, and H3N2. However, inhibition increased viral titers, raising concerns about its clinical use in isolation. To overcome this, we tested a combination of Oseltamivir (antiviral) and Baricitinib (anti-inflammatory). Post-infection treatment in a murine model reduced lung inflammation and improved survival. Given that both drugs are FDA-approved, this approach has strong translational potential for clinical IAV treatment.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

Wellcome Trust/DBT India Alliance, IA/I/18/1/503613

Indian Council of Medical Research, IIRPIG-2023-0000978

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2025.07.31.667854v1

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