ETIDIOH - NEW

  New human cases {1,2}:  -- From 26 August to 29 September 2025 , based on reporting date, the detection of influenza A(H5) in one human , influenza A(H5N1) in one human , influenza A(H9N2) in eight humans and an influenza A(H1N1) variant ((H1N1)v) virus in one human were reported officially.   Circulation of influenza viruses with zoonotic potential in animals :  -- High pathogenicity avian influenza (HPAI) events in poultry and non-poultry animal species continue to be reported to the World Organisation for Animal Health (WOAH).{3}  -- The Food and Agriculture Organization of the United Nations (FAO) also provides a global update on avian influenza viruses with pandemic potential.{4}  Risk assessment {5}:  -- Sustained human to human transmission has not been reported from these events.  -- Based on information available at the time of this risk assessment update , the overall public health risk from currently known influenza A viruses d...

  Abstract The antigenic relationship between Eurasian avian-like H1N1 swine influenza viruses (EA H1N1) and human pandemic 2009 H1N1 viruses (2009/H1N1) remains a critical question for influenza surveillance and vaccine efficacy . This study systematically investigated the antigenic differences between strains A/swine/Tianjin/312/2016 (TJ312, EA H1N1) and A/Guangdong-Maonan/SWL1536/2019 (GD1536, 2009/H1N1). Cross-hemagglutination inhibition (HI) assays revealed a significant antigenic disparity, with a 16-fold reduction in heterologous versus homologous HI titers . Comparative sequence analysis identified 22 amino acid differences across the five major antigenic sites (Sa, Sb, Ca1, Ca2, and Cb) of the HA1 subunit. Using reverse genetics , a panel of mutant viruses was generated. This study revealed that a single histidine (H)-to-asparagine (N) substitution at residue 128 (H3 numbering) in the Sa antigenic site acts as a primary determinant of antigenic variation , sufficient to ca...

  Abstract Influenza virus cross-subtype antibodies targeting the hemagglutinin (HA) head are rare . Here, we found that a large proportion of monoclonal antibodies (mAbs) isolated from individuals immunized with the 2021-22 seasonal influenza vaccine bound to an epitope on the HA head of both the H1N1 vaccine strain and H3N2 strains from the mid-1990s. These H1/H3 cross-reactive antibodies were also found in polyclonal sera , but only in samples from individuals born in the 1990s . Ferrets sequentially exposed to an H3N2 virus from the 1990s and a contemporary seasonal influenza vaccine produced the same type of H1/H3 cross-reactive antibodies. We found evidence that H1N1 viruses are currently evolving within the human population to abrogate the binding of these antibodies . Together, our study demonstrates how prior influenza virus exposures can influence the specificity of antibodies elicited by entirely different influenza virus subtypes, and how viruses evolve to escape these ...

  Abstract Background :  Avian influenza of the H5N1 subtype shares substantial relatedness in its neuraminidase (NA) surface protein with human influenza A H1N1 viruses of the past century. Understanding variation in pre-existing anti-N1 antibodies against H5N1 is critical to pandemic risk assessment and preparedness.  Methods :  We used anonymized, residual sera collected equally from ten age groups spanning one to >80 years during an August 2024 cross-sectional serosurvey in British Columbia, Canada . We assessed NA inhibition antibody titres by enzyme-linked lectin assay against H5N1 (N=575), H1N1pdm09 (N=250) and H3N2 (N=205). We compared anti-NA titres by birth (imprinting) cohorts defined in relation to historic N1 and/or N2 exposure opportunities.  Results :  Among participants with median age 32 (IQR: 15-62) years, 404 ( 70%) had cross-reactive anti-N1 titre ≥10 against H5N1 , with 260 (45%), 182 (32%) and 98 (17%), having titres ≥40, ≥80 and ≥...

  Abstract Influenza continues to cause significant mortality globally and possesses substantial pandemic potential . Assessing pandemic risk requires a clear understanding of existing population immunity . Leveraging a unique large-scale cohort of human sera , we evaluated total and neutralising antibody -mediated immunity to multiple haemagglutinin (HA) proteins, including those from subtypes with high pandemic potential. Our analysis reveals that population immunity is heterogeneous , with distinct age-dependent differences in responses to H5, H7, and H9 avian influenza subtypes. These shifts align with historical circulation patterns of seasonal H1N1 and H3N2 human viruses. Notably, H7 viruses are primarily neutralised through head domain epitopes , while H5 viruses are targeted mainly via stem epitopes , although in both instances some neutralisation occurred via receptor binding site-adjacent epitopes . Furthermore, H7 responses were dominated by non-glycan-targeted IgG2 anti...

  ABSTRACT Swine influenza A virus (swIAV) is an important zoonotic pathogen with the potential to cause human influenza pandemics . Swine are considered “ mixing vessels ” for generating novel reassortant influenza A viruses . In 2009, a swine-origin reassortant virus (2009 pandemic H1N1, pdm/09 H1N1 ) spilled over to humans , causing a global influenza pandemic . This virus soon spread back into swine herds and reassorted with the circulating swIAVs. We previously reported that the genotype 4 (G4) reassortant Eurasian avian-like (EA) H1N1 virus , which bore pdm/09- and triple reassortant (TR)-derived internal genes, had been predominant in swine populations of China since 2016, posing a threat to both the swine industry and public health . Here, our ongoing surveillance confirmed that G4 EA H1N1 viruses remained the predominant swIAVs in China from 2019 to 2023 and had reassorted with the co-circulating swIAVs, such as the H3N2 virus, to generate novel reassortant EA H1N2 viruses...

  Abstract H5N1 highly pathogenic avian influenza viruses have spread globally and pose a risk for a human pandemic . Prior studies suggest that early life exposures to group 1 influenza viruses (H1N1 and H2N2) prime antibodies that cross-react to the hemagglutinin of H5N1 , which is also a group 1 virus. Less is known about how immune history affects antibody responses against the neuraminidase (NA) of H5N1 viruses. Here, we measured NA inhibition antibodies against multiple H5N1 viruses using sera from 155 individuals born between 1927 and 2016 . We found that individuals primed in childhood with H1N1 viruses were more likely to possess higher levels of antibodies that cross-react with the NA of H5N1 viruses compared to individuals primed in childhood with H2N2 or H3N2 viruses. While young children rarely possessed cross-reactive NA antibodies, we found that childhood infections with contemporary H1N1 , but not H3N2, viruses can elicit them. These data suggest that immune history...

  Abstract In recent years, the four main swine influenza A virus (IAV-S) subtypes circulating in swine in the EU have been H1avN1, H1huN2, H1N1pdm09, and H3N2 . The latter emerged in 1984 from a reassortment event between a human seasonal H3N2 and H1avN1, and is currently detected at low prevalence in swine in Italy . Here, we describe nine H3N2 IAV-S isolates belonging to three novel genotypes , first detected in Italy in 2021 , likely resulting from reassortment events between swine and human IAVs. The first genotype was characterized by a hemagglutinin (H3 HA) of human seasonal origin , a neuraminidase (N2 NA) derived from H1huN2 strains circulating in Italian swine, and an avian-like internal gene cassette (IGC). The second genotype differed in its IGC constellation: PB2, PB1, PA and NP segments were of pandemic origin ( pdm09 ), while NS and M segments derived from the Eurasian avian-like lineage . The third genotype combined a human-derived H3, a Gent/84-derived N2, and a pd...

  Abstract Influenza A virus (IAV) infection is associated with a wide variety of neurological complications , of which mild complications like impaired cognitive functioning are most prominent . Even though several studies have shown that many influenza viruses can enter the CNS, the neuropathogenesis of seasonal ( H3N2 and H1N1 ) and pandemic (pH1N1 2009) IAV infections is poorly understood. Therefore, we aimed to investigate the cellular tropism, replication efficiency and associated functional consequences using a human stem cell-derived neural co-culture model of neurons and astrocytes . All viruses were able to infect neurons in the co-culture model, although this infection did not result in efficient replication and release of progeny virus. In addition, infection did not result in visible cell death or apoptosis. However, functional analyses revealed that IAV inoculation resulted in a reduction of spontaneous neural activity and a partial reduction of neural excitability. T...

  ABSTRACT Influenza A virus (IAV) in swine in the U.S. is surveilled to monitor genetic evolution to inform intervention efforts and aid pandemic preparedness . We describe data from the U.S. Department of Agriculture National Surveillance Plan for Influenza A Virus in Pigs from 2009 to 2022. Clinical respiratory cases were subtyped, followed by sequencing of hemagglutinin (HA) and neuraminidase (NA), and a subset of viruses was whole genome sequenced . Phylogenetic analysis identified geographic and temporal IAV reassortment hotspots . Regions acting as IAV genomic diversity sources or sinks were quantified, and dissemination was qualified and modeled. The dominant IAV clades were H1N2 (1B.2.1), H3N2 (1990.4.a), and H1N1 (H1-1A.3.3.3-c3). Internal genes were classified as triple-reassortant (T) or pandemic 2009 (P), and three genome constellations represented 73.5% of detections across the last 2 years. In some years, the distribution of IAV diversity was so narrow that it presen...

Abstract Background .  Highly pathogenic avian influenza A(H5) viruses pose a pandemic threat , with a history of zoonotic spillovers into humans that are presumed immunologically naive. Whether the general population is currently immunologically naive to circulating A(H5) influenza viruses is unknown.  Methods .  To evaluate the presence of cross-reactive immune responses to emerging A(H5) clade 2.3.4.4b influenza viruses in the general population, we conducted comprehensive immune profiling on cross-sectional samples from healthcare workers (n=107). Samples were collected in August and September 2024 in the scope of an ongoing prospective follow-up study: Surveillance of rEspiratory viruses iN healThcare and anImal workers in the NethErLands (SENTINEL).  Findings .  Low-level antibody responses directed against the A(H5) hemagglutinin (HA) head were detected in a limited number of individuals , but without hemagglutination inhibition activity. Nevertheless, we...

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). ...

Abstract The H1N1 swine influenza viruses CQ91 and CQ445, isolated from pigs in China, exhibited distinct virulence in mice despite sharing similar genomic constellations. CQ91 demonstrated higher pathogenicity (MLD50: 5.4 log10 EID50) and replication efficiency in mice compared to CQ445 (MLD50: 6.6 log10 EID50). Through reverse genetics, we found that the attenuation of CQ445 was due to a single substitution of glutamic acid (E) with lysine (K) at position 343 in the PB2 protein . Introducing the CQ445-PB2 (343K) into CQ91 significantly reduced viral replication and pathogenicity in mice, while replacing CQ445-PB2 with CQ91-PB2 (343E) restored virulence. In vitro studies showed that the K343E mutation impaired viral replication in MDCK and A549 cells and reduced polymerase activity in minigenome assays. Mechanistically, the amino acid at position 343 in the PB2 affects the transcription stage of the viral replication process . Structural modeling indicated that the charge reversal cau...

Abstract Highly pathogenic avian influenza of the H5N1 subtype has shown recent unprecedented expansion in its geographic and host range , increasing the pandemic threat . The younger age of H5N1 versus H7N9 avian influenza in humans has previously been attributed to imprinted pre-immunity to hemagglutinin stalk (HA2) epitopes shared with group 1 ( H1N1, H2N2 ) versus group 2 ( H3N2 ) influenza A subtypes predominating in the human population before versus after 1968, respectively. Here we review the complex immuno-epidemiological interactions underpinning influenza risk assessment and extend the imprinting hypothesis to include a potential role for cross-protective neuraminidase (NA) imprinting . We compare H5N1 distributions and case fatality ratios by age and birth cohort (as proxy for HA2 and/or NA imprinting epoch) not only to H7N9 but also H5N6 and H9N2 avian influenza, representing more varied conditions of zoonotic influenza relatedness to human subtypes of the past century. We...

Abstract Background From 1918 to 1920, the largest influenza A virus (IAV) pandemic known to date spread globally causing between 20 to 100 million deaths . Historical records have captured critical aspects of the disease dynamics , such as the occurrence and severity of the pandemic waves . Yet, other important pieces of information such as the mutations that allowed the virus to adapt to its new host can only be obtained from IAV genomes. The analysis of specimens collected during the pandemic and still preserved in historical pathology collections can significantly contribute to a better understanding of its course. However, efficient RNA processing protocols are required to work with such specimens. Results Here, we describe an alternative protocol for efficient ancient RNA sequencing and evaluate its performance on historical samples, including a published positive control. The phenol/chloroform-free protocol efficiently recovers ancient viral RNA , especially small fragments , an...

Abstract The Eurasian avian-like swine (EA) H1N1 virus has been widely prevalent in the Chinese swine population and has caused infections in human . However, knowledge regarding its pathogenic mechanisms remains limited. In this study, we analyzed the pathogenic determinants of two G4 genotype EA H1N1 viruses (A/Swine/Guangdong/SS12/2017 and A/Swine/Jiangxi/1110/2017) with differing pathogenicity by constructing a series of reassortant and mutant viruses . The HA-G219A mutation was found to be determinant of pathogenicity in mice. Subsequent analyses revealed that this mutation enhances viral replication in human cells , improves thermal stability , reduces HA activation pH, and alters receptor-binding properties . Furthermore, HA-G219A mutation may be an adaptive mutation that facilitates influenza virus adaptation to swine , with its prevalence increasing in the swine population. This mutation may support cross-species transmission of EA H1N1 swine influenza viruses or genetic excha...

Abstract The ecological factors that led to the 1918 influenza pandemic remain unknown. We hypothesise that horses acted as intermediate hosts spreading a pre-pandemic avian-origin virus before 1918. This is supported by reports describing a large epizootic of unusually severe equine influenza beginning in 1915. Furthermore, the high horse demand during WWI resulted in one of the biggest equine mobilisations in North America between 1914 and 1918. This extensive movement of horses provided abundant opportunities for virus reassortment between pre-pandemic avian and human influenza viruses. Archived equine tissues or serum samples will be needed to test this hypothesis. Source: Journal of Infectious Diseases,  https://academic.oup.com/jid/advance-article-abstract/doi/10.1093/infdis/jiaf197/8115353?redirectedFrom=fulltext&login=false ____

Influenza at the human-animal interface Summary and risk assessment, from 21 January to 19 March 2025 {1}  New human cases {2}:  From 21 January to 19 March 2025, based on reporting date , the detection of influenza A( H5N1 ) in five humans, influenza A( H9N2 ) virus in four humans, influenza A( H1N1 ) variant ((H1N1)v) virus in one human, and influenza A( H1N2 )v virus in one human were reported officially.  • Circulation of influenza viruses with zoonotic potential in animals:  -- High pathogenicity avian influenza (HPAI) events in poultry and non-poultry continue to be reported to the World Organisation for Animal Health (WOAH).{3}  The Food and Agriculture Organization of the United Nations (FAO) also provides a global update on avian influenza viruses with pandemic potential.{4}  • Risk assessment {5}:  -- Sustained human to human transmission has not been reported from these events. Based on information available at the time of the risk assessmen...