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  Highlights •  Human influenza A virus N2 neuraminidases were analyzed by antigenic cartography •  N2 antigenic evolution was discordant with antigenic evolution of H3 hemagglutinin •  Important epitopes were identified at the NA active site but also elsewhere in NA •  Changes in charge, volume, and hydropathy of epitope residues caused antigenic drift Summary Human influenza A viruses escape antibody-mediated immunity through changes in the hemagglutinin (HA) and neuraminidase (NA) glycoproteins . HA antigenic evolution has been studied extensively, with more recent interest in NA due to its importance in influenza vaccine efficacy. Here, the antigenic properties of the NA of more than 300 A( H3N2 ) and A( H2N2 ) viruses isolated since 1957 were quantified with a NA inhibition enzyme-linked lectin assay and visualized using antigenic cartography , with follow-up molecular studies using recombinant viruses. The antigenic evolution of N2 NA was more gradual than...

  Abstract Selection of advantageous mutations drives the emergence of dominant variants during seasonal influenza epidemics . However, within-host detection of such variants remains rare , limiting our understanding of how selection operates at the scale of individual hosts. In this study, we used a controlled human infection model to examine the within-host evolutionary dynamics in thirteen participants intranasally infected with a seasonal H3N2 influenza A virus . Although this clinical trial is ongoing , our work represents a pre-planned, interim, exploratory analysis. Results in this system were contrasted with those observed in a ferret model of infection. The inoculum, used in both humans and ferrets, carried standing diversity that enabled evaluation of variant trajectories during infection. Although the dynamics were variable among participants, in humans , the minor variants in the PA and NP gene segments tended to increase in frequency as infection progressed. Variant dy...

  Boston — The Massachusetts Department of Public Health (DPH) is reporting very high and rising levels of influenza activity statewide as the Commonwealth moves through peak flu season .  Thousands of residents have become ill , forcing them to miss work, school, and other activities.  Many are experiencing serious complications , leading to increased visits to urgent care centers and emergency departments, and high levels of hospitalization .  The current widespread burden of illness underscores the importance of taking preventive measures , especially vaccination , to reduce severe disease and protect individuals, families, and communities. Tragically, influenza has already been reported to be associated with the deaths of three pediatric patients in Massachusetts during recent weeks.  In addition, there have been 29 adult influenza deaths reported so far this season.  While COVID-19 and respiratory syncytial virus (RSV) rates currently remain low, cases...

  ABSTRACT Avian influenza virus cross-species infection in humans poses a major threat to global public health . Species-specific differences between avian ANP32A and mammalian ANP32 proteins create a natural barrier against viral cross-species infection by directly impairing the functional interaction between the avian-origin viral RNA polymerase and mammalian ANP32 proteins , thereby restricting viral genome replication . The key to overcoming this barrier lies in the adaptation of viral RNA polymerase to host ANP32 family proteins . This mini-review summarizes the mechanisms and variations in influenza virus adaptation to ANP32 proteins across different species. Influenza viruses adapt to species-specific ANP32 proteins through various mutations and display distinct preferences for specific ANP32 family members within the same host. Additionally, alternative splicing variants of ANP32A within a single species further modulate viral RNA polymerase adaptability. Despite this dive...

  {Abstract} Background :  Emerging threats such as highly pathogenic influenza strains like H5N1 emphasize the need for vaccines that induce cross-reactive immunity against conserved epitopes. Existing influenza vaccines primarily elicit strain-specific responses , leaving gaps in protection against pandemic subtypes. This study aimed to evaluate T cell responses to seasonal influenza A and H5N1 and compare them to SARS-CoV-2 specific T cell responses to understand differences shaped by distinct exposure histories and vaccination strategies. Methods :  T cell responses were assessed in 41 laboratory workers who received annual seasonal influenza vaccines using ELISpot to quantify responses to peptide pools derived from influenza ( H1N1 hemagglutinin [HA], H3N2 HA, H5N1 HA, matrix protein 1 [MP1], nucleoprotein [NP]) and SARS-CoV-2 (spike [S2S], nucleocapsid [S2N]). Ten-day expansion assays were used to evaluate functional cross-reactivity between H1, H3, and H5 HA. Intra...

  Abstract We characterized influenza A(H1N1)pdm09, A(H3N2), and B/Victoria viruses circulating in Japan during 2023–2024 , focusing on lineage placement relative to WHO-recommended vaccine strains and on baloxavir resistance (PA/I38T substitutions). We enrolled 210 outpatients with influenza-like illness across eight clinics in six prefectures (October 2023–September 2024). Of these, 209 had an analyzable pre-treatment respiratory specimen for RT-PCR; hemagglutinin (HA) and neuraminidase (NA) genes were sequenced by next-generation sequencing (NGS). PA/I38T substitutions that confer baloxavir resistance were assessed by cycling-probe RT-PCR, Sanger sequencing, and NGS. HA phylogenies were constructed with global datasets and WHO vaccine reference strains. Of 209 pre-treatment specimens, 181 were influenza-positive (A(H1N1)pdm09 44.2%, A(H3N2) 37.6%, B/Victoria 18.2%); 51 follow-up specimens were collected ≈4–5 days after baloxavir or neuraminidase inhibitor therapy . HA phylogeny ...

  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 ≥...