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  Abstract I nterspecies transmission of human influenza A viruses (FLUAV) to swine occurs frequently, yet the molecular factors driving adaptation remain poorly understood . Here we investigated how vaccine-induced immunity shapes the evolution of a human-origin H3N2 virus in pigs using an in vivo sustained transmission model . Pigs (seeders) were vaccinated with a commercial inactivated swine vaccine and then infected with an antigenically distinct FLUAV containing human-origin HA/NA . Contact pigs were introduced two days later. After 3 days, seeder pigs were removed, and new contacts introduced. This was repeated for a total of 4 contacts. Sequencing of nasal swab samples showed the emergence of mutations clustered near the HA receptor binding site , enabling immune escape and abolishing binding to N-glycolylneuraminic acid. Mutant viruses recognized α2,6-sialosides with 3 N-acetyllactosamine repeats , which are rare in swine lungs, while the parental virus bound structures wit...

  10 December 2025 Situation at a glance Seasonal influenza (‘the flu’) is an acute respiratory infection caused by influenza viruses that circulate globally and year-round.  It can cause illness ranging from mild to severe , sometimes resulting in hospitalization or death.  Seasonal influenza activity has increased globally in recent months, with an increased proportion of seasonal influenza A(H3N2) viruses being detected.  This rise coincides with the onset of winter in the northern hemisphere and an increase in acute respiratory infections caused by influenza and other respiratory viruses typically observed at this time of year.  Although global activity remains within expected seasonal ranges , early increases and higher activity than typical at this time of year have been observed in some regions.  Seasonal influenza viruses, including A(H3N2) viruses, continually evolve over time.  Since August 2025, there has been a rapid increase of A(H3N2) J.2...

  Editor’s summary Birds operate at body temperatures several degrees higher than those of mammals, and, like mammals, birds are infected by influenza viruses. Influenza viruses can move between animal hosts, often reassorting their gene segments as they transition. Knowing that the body temperature of humans often elevates when sick, Turnbull et al. investigated whether virus gene segments originating from hot-blooded birds may give the virus an advantage in feverish mammals. They found that a viral polymerase containing an avian origin PB1 subunit indeed allowed the virus to replicate at higher temperatures in vitro and in a hyperthermic mouse model. —Caroline Ash Structured Abstract INTRODUCTION Influenza A viruses circulate in diverse species of birds and periodically spill over to cause severe or fatal infections in humans . Avian influenza A viruses are adapted to replicate in the gastrointestinal tract of birds at ~40° to 42°C . By contrast, human-adapted seasonal influenza ...

  Highlights •  Human antibody HB420 cross-reacts with neuraminidases from H3N2 and H5N1 •  HB420 engages the neuraminidase active site via a single Asp residue •  Germline HB420 is N2 specific but gains reactivity to N1 through somatic mutation •  HB420 provides in vivo protection against both H3N2 and H5N1 Summary The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and its occasional spillover to humans have raised concerns about a potential H5N1 pandemic . Although recent studies have shown that pre-existing human antibodies can recognize H5N1 neuraminidase , the molecular basis of how this cross-reactivity develops remains poorly understood. In this study, we used a phage display antibody library derived from 245 healthy donors to isolate an antibody, HB420, that cross-reacts with neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo. Cryogenic electron microscopy analysis r...

  Authors: Freja CM Kirsebom{1}, Catherine Thompson{2}, Tiina Talts{2}, Beatrix Kele{2}, Heather J Whitaker{3}, Nurin Abdul Aziz{1}, Christopher Rawlinson{1}, Rebecca E Green{1}, Catherine Quinot{1}, Nicholas Gardner{1}, Elizabeth Waller{1}, Alex Allen{1}, Conall H Watson{1,4}, Suzanna LR McDonald{1}, Maria Zambon{2}, Richard Pebody{4,5}, Mary Ramsay{6,7}, Katja Hoschler{2}, Anika Singanayagam{*2,4}, Jamie Lopez Bernal{*1,4}  {*} Joint last authors  {1} Immunisation and Vaccine-preventable Diseases Division, UK Health Security Agency, Colindale, London  {2} Respiratory Virus Unit (RVU), UK Health Security Agency, Colindale, London  {3} Modelling Division, UK Health Security Agency, Colindale, London  {4} NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London, United Kingdom  {5} Epidemic and Emerging Infections Directorate, UK Health Security Agency, Colindale, London  {6} Public Health Programmes Directorate, UK H...

  ABSTRACT Subtype H3N2 influenza A viruses (IAVs), which emerged in 1968 to cause a pandemic, have shown continual circulation and adaptation that has necessitated frequent updates of candidate vaccine viruses . Here, we sought to determine how genetic changes in the hemagglutinin (HA) and neuraminidase of 21 antigenically distinct H3N2 IAVs isolated from 1968 to 2019 correlate with mammalian fitness and adaptation. We found a surge of adaptation between 1997 and 2002 , resulting in the emergence of A/Fujian/411/2002 (H3N2) and poor vaccine efficacy , leading to an epidemic during the 2003–2004 season. This surge was characterized by a large reduction in binding to mammalian-type α2,6-linked sialic acids and increased infectivity and replication kinetics in humanized Madin-Darby canine kidney cells. HA glycosylation also increased most rapidly from 1968 to 2004 and then plateaued. Symptomatic infections were only evident in mice following inoculation with viruses isolated in the 1...

  ABSTRACT An increase in the number of human cases of influenza A/H5N1 infection in the USA has raised concerns about the pandemic potential of the virus. Pre-existing population immunity is a key determinant for risk assessment and pandemic potential for any virus. Antibody responses against the bovine A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins were measured among a population of influenza-vaccinated or influenza-infected individuals. Modest titers of bovine A/H5N1 HA-binding antibodies and low to undetectable neutralizing antibody titers were detected in a cohort of 73 individuals . Conversely, bovine A/H5N1 NA-binding and neuraminidase-inhibiting antibody titers were comparable to those against a human A/H1N1 NA at baseline . Seasonal influenza vaccination failed to significantly increase antibody titers against both HA and NA glycoproteins of bovine A/H5N1. Recent infection with human A/H1N1 but not A/H3N2 viruses induced significant increases in bovine A/H5N1-n...

  Highlights •  Human antibody HB420 cross-reacts with neuraminidases from H3N2 and H5N1 •  HB420 engages the neuraminidase active site via a single Asp residue •  Germline HB420 is N2 specific but gains reactivity to N1 through somatic mutation •  HB420 provides in vivo protection against both H3N2 and H5N1 Summary The ongoing spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b virus in animals and its occasional spillover to humans have raised concerns about a potential H5N1 pandemic . Although recent studies have shown that pre-existing human antibodies can recognize H5N1 neuraminidase , the molecular basis of how this cross-reactivity develops remains poorly understood. In this study, we used a phage display antibody library derived from 245 healthy donors to isolate an antibody , HB420, that cross-reacts with neuraminidases of human H3N2 and avian H5N1 clade 2.3.4.4b viruses and confers protection in vivo . Cryogenic electron microscopy analysis...

  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 The polymerase acidic (PA) protein is a subunit of the trimeric influenza A virus (IAV) RNAdependent RNA polymerase and the target of the anti-influenza drug baloxavir marboxil (BXM). As with other direct-acting antivirals , treatment with BXM can lead to selection of viruses carrying resistance mutations . If these mutations have negligible fitness costs , resistant viruses can spread widely and render existing treatments obsolete. Multiple BXM resistance mutations in the nuclease domain of PA have been identified, with I38T and I38M amino acid substitutions occurring frequently. These mutations have minimal to no effects on viral polymerase activity , virus replication , or transmission . However, for reasons that are not well understood, viruses with BXM resistance substitutions have not been able to compete with parental wild-type strains . The IAV genome segment encoding PA also encodes the host shutoff nuclease PA-X , which shares the endonuclease domain with PA bu...

  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 Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera , measuring ~10,000 total titers . There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution . Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influen...

  Abstract Human H3N2 influenza viruses, introduced during the 1968 pandemic, have evolved to recognize human-type sialic acid-containing receptors (Neu5Acα2-6Gal) extended with at least three LacNAc (Galβ1-4GlcNAc) repeats. To investigate this restriction in the context of virus attachment to the airway epithelium , we comprehensively analyzed the glycome of human nasal and tracheal epithelial cells . Using a synthetic N-glycan library that reflects the structural diversity of the human airway glycome, we found that only bi-antennary N-glycans with extended human-type receptors on at least one branch serve as receptors for the recent H3 hemagglutinins (HAs). Such receptors are found on tracheal epithelium but are deficient in nasal epithelium. Immunofluorescence analysis on human trachea reveals that recent H3 HAs preferentially attach to ciliated cells , consistent with single-cell RNA sequencing analysis indicating that these cells express glycosyltransferases that produce exten...

  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...