In the US, adjuvanted or higher-dose influenza vaccines are preferentially recommended for annual use among adults aged 65 years or older. Adjuvanted and high-dose influenza vaccines have not been compared in a pragmatic randomized study. To assess the relative vaccine effectiveness (rVE) of adjuvanted vs high-dose inactivated influenza vaccine against polymerase chain reaction (PCR)-confirmed influenza in older adults at Kaiser Permanente Northern California (KPNC). In this cluster randomized crossover study, during the 2023 to 2024 influenza season, 65 KPNC facilities were cluster randomized such that approximately half of facilities administered adjuvanted and half high-dose influenza vaccine on the first week of the vaccination season (and thereafter every facility crossed over and alternated formulations weekly). Using Cox proportional hazards regression on a calendar time scale, the rVE of adjuvanted vs high-dose vaccine was estimated for each outcome as 1 minus the hazard ratio, adjusted for age, sex, race and ethnicity, comorbidities, and health care utilization. Study participants included all adults 65 years or older who were vaccinated with adjuvanted or high-dose inactivated influenza vaccine during routine care at a KPNC facility between August 17, 2023, and April 16, 2024. Adjuvanted or high-dose inactivated influenza vaccine receipt during the 2023 to 2024 influenza season. Individuals were considered vaccinated 14 days after immunization. The primary outcome was PCR-confirmed influenza in any clinical setting. Secondary outcomes were PCR-confirmed influenza with hospitalization or emergency department visits and hospitalization for community-acquired pneumonia. Outcomes were assessed starting October 1, 2023, or 14 days after vaccination, whichever came later. This study included 429 595 individuals from the 2023 to 2024 influenza season (mean [SD] age, 75 [7] years; 236 857 [55.1%] female; 86 287 [20.1%] Asian, 22 910 [5.3%] Black, 53 820 [12.5%] Hispanic, 1123 [0.3%] American Indian or Alaska Native, 2562 [0.6%] Pacific Islander, 252 709 [58.8%] White, 1638 [0.4%] multiracial, and 8546 [2.0%] unknown race), of whom 212 875 (49.6%) received adjuvanted and 216 720 (50.4%) received high-dose influenza vaccine. There were 836 cases of PCR-confirmed influenza (3.9 per 1000 persons) identified after adjuvanted and 867 cases (4.0 per 1000 persons) after high-dose vaccine. The rVE of adjuvanted compared with high-dose influenza vaccine was 1.5% (95% CI, -8.4% to 10.5%) against influenza, 9.1% (95% CI, -4.0% to 20.4%) against influenza with hospitalization or emergency department visits, and 1.0% (95% CI, -11.4% to 12.0%) against hospitalizations for community-acquired pneumonia. In the first season of a large, ongoing study in adults 65 years or older, adjuvanted and high-dose influenza vaccines did not differ in effectiveness against laboratory-confirmed influenza during the 2023 to 2024 influenza season. Consistent with Advisory Committee on Immunization Practices recommendations, these results support the equivalency of adjuvanted and high-dose influenza vaccines for adults 65 years or older. ClinicalTrials.gov Identifier: NCT06029933.
The 2024-25 influenza season was the most severe in the United States (US) since 2017-18, with co-circulation of both influenza A virus subtypes (H1N1 and H3N2). Influenza vaccine effectiveness (VE) has varied by season, setting, and patient characteristics. Using electronic healthcare encounter data from eight US states, we evaluated influenza vaccine effectiveness (VE) against influenza-associated hospitalizations and emergency department or urgent care (ED/UC) encounters from October 2024-April 2025 among children aged 6 months-17 years and adults aged ≥18 years. Using a test-negative, case-control design, we compared the odds of influenza vaccination between acute respiratory illness (ARI) encounters with a positive (cases) versus negative (controls) test for influenza by molecular assay, adjusting for confounders. Analyses included 108,618 encounters (5,764 hospitalizations and 102,854 ED/UC encounters) among children and 309,483 encounters (76,072 hospitalizations and 233,411 ED/UC encounters) among adults. Among children across care settings, 17.0% (6,097/35,765) of cases versus 29.4% (21,449/72,853) of controls were vaccinated. Among adults, 28.2% (21,832/77,477) of cases versus 44.2% (102,560/232,006) of controls were vaccinated. VE was 51% (95% confidence interval [95% CI]: 41-60%) against influenza-associated hospitalizations and 54% (95% CI: 52-55%) against influenza-associated ED/UC encounters among children. VE was 43% (95% CI: 41-46%) against influenza-associated hospitalizations and 49% (95% CI: 47-50%) against influenza-associated ED/UC encounters among adults. Influenza vaccination provided protection against influenza-associated hospitalizations and ED/UC encounters among children and adults in the US during the severe 2024-25 influenza season.These findings support influenza vaccination as an important tool to reduce influenza-associated disease. During the 2024-25 influenza season, influenza vaccination provided protection against influenza-associated hospitalizations (43-51%) and emergency department or urgent care encounters (49-54%) among children and adults in the United States.
Seasonal influenza vaccination remains the most effective strategy for reducing influenza burden and preventing severe disease. Despite decades of vaccine development, the seasonal influenza vaccine is administered intramuscularly and provides suboptimal and highly variable effectiveness depending on host factors, pre-existing immunity, and antigenic match between vaccine and circulating strains. Recent advances in vaccine development have highlighted the potential of intranasal vaccine delivery as a strategy to increase protection against influenza virus infection by inducing local and systemic immune responses. Across multiple intranasal platforms under development, mucosal immunity, particularly secretory IgA and T- and B-cell immune responses, plays a central role in shaping protection against influenza virus infection. Live-attenuated influenza vaccines (LAIV) elicit protective immune responses, particularly in the pediatric population, and remain the only currently licensed intranasal seasonal influenza vaccine. However, variable performance in adults, strain-dependent viral fitness, and clinical contraindications have limited their broader applicability. These limitations have driven the development of next-generation intranasal influenza vaccine platforms designed to preserve the immunological advantages of mucosal vaccination while improving consistency, safety, and applicability across diverse populations. This review synthesizes current knowledge on licensed and emerging intranasal influenza vaccine platforms, including replicating viral platforms and non-replicating platforms, and discusses key immunological mechanisms, challenges, and translational progress. Together, these advances underscore the growing potential of intranasal vaccination as a next-generation strategy to improve influenza control.
Respiratory viruses are major contributors to global morbidity and mortality, with influenza viruses having a significant clinical and epidemiological impact. In this study, we examined the virological and epidemiological aspects of influenza infection in comparison with those of other respiratory infections. We further assessed the genetic diversity of circulating influenza viruses and their susceptibility to antivirals. A total of 2,981 nasopharyngeal specimens from patients with acute respiratory illness were tested for 13 different respiratory viruses using multiplex real-time PCR. Representative influenza strains underwent whole-genome sequencing, phylogenetic and amino acid analyses. At least one respiratory virus was detected in 1,635 (54.8%) patients, and 182 (6.1%) had co-infections involving two to four viruses, including six cases of SARS-CoV-2 and influenza co-infection. Influenza A(H3N2) and B/Victoria lineage viruses predominated, with positivity rates of 12.1 and 10.9%, respectively, followed by rhinoviruses (9.0%), whereas SARS-CoV-2 circulation remained low (3.7%). Influenza infections were most prevalent among children aged 5-14 years. Phylogenetic analysis identified multiple genetic subclades, including C.1.9, C.1.9.1, C.1.9.3, C.1.9.4 and D.5 for A(H1N1)pdm09; J.2, J.2.1, and J.2.2 for A(H3N2), and C.5.1, C.5.6, C.5.6.1, and C.5.7 for B/Victoria lineage. Numerous amino acid substitutions were observed across viral proteins, including within hemagglutinin antigenic sites compared to vaccine strains. The 2024-2025 influenza season in Bulgaria was characterized by high influenza activity and substantial genetic heterogeneity of circulating strains. These findings underline the importance of continuous molecular surveillance to monitor viral evolution, inform vaccine strain selection, and guide national public health strategies.
All of the major antigenic changes in influenza A(H3N2) viruses since 1968 have involved mutations at just nine amino acid positions, called cluster transition sites, surrounding the receptor binding region of the hemagglutinin surface protein. During the Northern Hemisphere (NH) 2024-2025 influenza season, A(H3N2) variants emerged with multiple parallel substitutions affecting cluster transition sites 135, 145, 158, and/or 189, with implications for the 2025-2026 season. Using >24,000 global A(H3) sequences between September 2024 and August 2025, we assessed the nature and frequency of amino acid mutations among emerging NH and Southern Hemisphere (SH) A(H3N2) variants relative to the 2024-2025 subclade J and updated 2025-2026 subclade J.2 vaccine reference strains. We contextualized based on historic amino acid variation among >210,000 global A(H3) sequences since 1968 and publicly available antigenic characterization data relative to 2024-2025 and 2025-2026 vaccine reference strains. Virtually all circulating A(H3N2) viruses in 2024-2025 were subclade J.2. In Europe, about one-third had cluster transition site mutations, mostly T135A with S145N. In North America, more than two-thirds had cluster transition site mutations, including T135K or S145N, with a late-season increase in doubly mutated J.2.3 (N158K + K189R) and J.2.5 (S145N + N158K) subclades. The SH 2025 season showed an increase in J.2.3 and emergence of J.2.4 (T135K + K189R), including a further drifted J.2.4.1 variant with additional N158D and other mutations, recently renamed subclade K. A substantial proportion of J.2.3 and J.2.4 viruses are antigenically distinct from the 2025-2026 influenza vaccine. Influenza A(H3N2) variants with a combination of cluster transition site mutations emerged during the NH 2024-2025 season. A further drifted and vaccine-mismatched variant, called subclade K, arose during the SH 2025 season and is projected to predominate among A(H3N2) viruses for the NH 2025-2026 season. While mismatched vaccines can still provide protection, enhanced genetic, antigenic, and epidemiological (eg, vaccine effectiveness, disease burden) monitoring are warranted to inform risk assessment and response. Toutes les modifications antigéniques majeures aux virus de l'influenza A(H3N2) depuis 1968 découlent des mutations de neuf positions d'acides aminés seulement qui entourent la région des récepteurs de liaison de l'hémagglutinine, une protéine de surface. Pendant la saison 2024–2025 de l'influenza dans l'hémisphére Nord (HN), des variants A(H3N2) ont émergé, dotés de multiples substitutions paralléles qui touchent les positions 135, 145, 158 ou 189, ce qui a des conséquences pour la saison 2025–2026 de l'influenza. Entre septembre 2024 et août 2025, les auteurs ont utilisé plus de 24 000 séquences A(H3) globales pour évaluer la nature et la fréquence des mutations d'acides aminés dans les variants A(H3N2) émergents de l'HN et de l'hémisphére Sud (HS) par rapport à celles des souches référence vaccinale du sous-clade J de 2024–2025 et du sous-clade J.2 de 2025–2026. Ils les ont contextualisées d'aprés la variation historique d'acides aminés de plus de 210 000 séquences d'A(H3) globales depuis 1968 et les données de caractérisation antigénique accessibles au public relatives aux souches de référence vaccinales de 2024–2025 et de 2025–2026. Pratiquement tous les virus A(H3N2) en circulation en 2024–2025 faisaient partie du sous-clade J.2. En Europe, environ le tiers comportait des mutations à diverses positions, notamment T135A et S145N. En Amérique du Nord, plus des deux tiers étaient dotés de mutations à diverses positions, y compris T135K ou S145N, et présentaient une augmentation des sous-clades J.2.3 (N158K+K189R) et J.2.5 (S145N+N158K) qui ont subi une double mutation en fin de saison. La saison 2025 en HS a révélé une augmentation du sous-clade J.2.3 et l'émergence du sous-clade J.2.4 (T135K+K189R), y compris un variant du sous-clade J.2.4.1 qui a subi une dérive plus marquée incluant une mutation supplémentaire à la position N158D et d'autres mutations. Ce variant a récemment reçu le nom de sous-clade K. Une proportion substantielle des virus aux sous-clades J.2.3 et J.2.4 sont distincts sur le plan antigénique de ceux contenus dans le vaccin contre l'influenza pour la saison 2025–2026. Des variants de l'influenza A(H3N2) dotés d'une combinaison de mutations aux diverses positions ont émergé pendant la saison 2024–2025 de l'HN. Un variant ayant subi une dérive génétique plus importante et qui ne concorde pas au vaccin, désormais nommé sous-clade K, a émergé pendant la saison 2025 en HS et devrait prédominer parmi les virus A(H3N2) pour la saison 2025–2026 en HN. Bien que des vaccins non concordants puissent offrir une certaine protection, une surveillance génétique, antigénique et épidémiologique des vaccins (p. ex., leur efficacité) s'impose pour mieux évaluer le risque et la réponse s'y rapportant.
The influenza virus causes seasonal epidemics throughout the world. At the same time, the rapid mutation of the virus renders the use of seasonal vaccines less effective. One of the approaches sought to improve influenza prevention is the use of monoclonal antibodies that are active against a wide range of influenza virus strains. In this study, the virus-neutralizing activity of the monoclonal antibodies CR9114, MHAA4549A, MEDI8852, C585, and 1G01 against the influenza virus was assessed. To this end, recombinant vectors based on adeno-associated virus (rAAV) encoding these antibodies were used. The rAAV vectors were expressed in mice in vivo, and the virus-neutralizing activity of the sera against the H1N1 and H3N2 influenza virus strains was assessed. Administration of rAAV-C585, rAAV-MHAA4549A, and rAAV-1G01 conferred 100% protection to mice challenged with a lethal dose of the H3N2 influenza virus. The efficacy of rAAV-CR9114 and rAAV-MEDI8852 against this influenza virus strain was lower, at 80 and 75%, respectively.
Swine farmers are at increased risk of zoonotic influenza virus transmission. In France, seasonal influenza vaccination is recommended for swine farmers, yet little is known about vaccine uptake in this at-risk group. To assess seasonal influenza vaccination uptake, its determinants, and associated attitudinal factors among swine farm managers in Brittany during the 2023-2024 influenza season. A cross-sectional survey was conducted among a random sample of swine farm managers. Data were collected using a standardized questionnaire, including attitude items according to the French 7C-model of psychological antecedents of vaccination. Among 735 respondents, 14.0% [11.8%-16.4%] declared they have been vaccinated for the 2023-2024 season, and 35.0% [32.1%-38.0%] were unaware of the national recommendation. Only 33.5% demonstrated a knowledge score above 2/4. Vaccine uptake was significantly associated with older age, prior severe influenza (OR: 3.29 [1.97-5.50]), and receiving a vaccination voucher from the agricultural social security system (OR: 2.76 [1.66-4.59]). However, only 31.8% [28.6%-34.8%] reported having received one. Five among the seven components of the 7C-model were associated with vaccine uptake.Unvaccinated unwilling to vaccinate were characterised by low collective responsibility (R2 = 16.98%) and unfavourable benefit-risk calculation (R2 = 16.84%), while unvaccinated willing to vaccinate were mainly influenced by vaccine accessibility (R2 = 17.32%) and negative social conformism (17.20%). Seasonal influenza vaccination uptake among swine farm managers is low. Targeting this population through tailored strategies is essential. These findings are relevant nationally and internationally and can inform One Health coordinated prevention efforts for professionals exposed to zoonotic influenza viruses.
To establish the incidence of developing diabetes mellitus (DM) post hospitalisation with influenza. Retrospective cohort study. Electronic healthcare records from Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics in England. 13 710 adults with a first episode of hospitalised influenza as the primary cause for admission between 1 July 2004 and 1 March 2021 based on ICD-10 codes without pre-existing DM were included. A randomly selected group (a) from CPRD records matched for age, sex and General Practitioner (GP) practice and (b) an unmatched group of hospitalised sepsis patients were used as comparator groups. Patients were followed from 1 day after discharge till either DM diagnosis, death or end of GP record. HRs for incidence of DM were calculated using adjusted Cox regression models. Incidence of DM was 12.5 per 1000 person years. Adjusted HRs (aHR) for developing DM after hospitalised influenza compared with matched controls was 1.54 (95% CI 1.39 to 1.70, p<0.001) and to hospitalised sepsis comparators 1.14 (95% CI 1.03 to 1.26, p=0.013). The greatest risk for developing DM in hospitalised influenza patients was within 90 days of discharge (aHR 2.71 (95% CI 1.94 to 3.77, p<0.001)) compared with matched controls. Risk factors for DM after influenza hospitalisation included being male, pre-existing DM risk, obesity and critical care admission during acute illness. Patients' post hospitalisation with influenza had a greater incidence of DM when compared with both matched controls and patients following hospitalisation with sepsis.
The host immune determinants that distinguish protective from life-threatening responses to influenza are poorly understood. Identifying drivers of immunopathology in the human lung is critical for developing potential therapies. To define the cellular and molecular immune landscape of the lung in mild versus severe influenza and to identify key cellular states and pathways associated with disease severity. We generated a large-scale single-cell atlas by sequencing over 520,000 cells from the bronchoalveolar lavage fluid of 88 non-immunocompromised adult individuals with mild or severe influenza A and healthy controls. Key findings were validated by flow cytometry and protein quantification, and machine-learning models were used to identify predictive signatures. Severe influenza was characterized by profound pulmonary lymphopenia and a massive influx of functionally dysregulated neutrophils. The infiltrating neutrophils were primed for extracellular trap formation, driving a cytokine storm via the S100A8/A9/A12-TLR4 and CXCL8-CXCR1/2 axes. This pathology coincided with the depletion and functional impairment of resident alveolar macrophages and an expansion of pro-inflammatory, monocyte-derived macrophages that amplified neutrophil recruitment. Lymphopenia in severe disease arose from synergistic cell-death programs, while remaining lymphocytes exhibited a dysfunctional state of concurrent exhaustion and hyper-cytotoxicity. Mild influenza featured a coordinated adaptive immune response, distinguished by an enrichment of T follicular helper cells and plasma cells. Machine-earning models identified robust cellular and transcriptional signatures predictive of disease severity. Our atlas defines the divergent immune trajectories in influenza, revealing specific cellular states and pathways that drive immunopathology and provide novel targets for host-directed therapies.
The Pragmatic Assessment of Influenza Vaccine Effectiveness in the Department of Defense (PAIVED) study was a clinical trial of three influenza vaccines in military beneficiaries enrolled at 10 military treatment facilities over four influenza seasons (2018/19-2021/22). This secondary analysis aimed to assess the relationship between cigarette smoking and e-cigarette use and influenza-like illness (ILI) incidence and severity. Demographic information, including cigarette smoking and e-cigarette use, was collected at enrollment. ILIs were identified during the influenza season of enrollment using weekly surveys. ILI symptoms were reported using the inFLUenza Patient-Reported Outcome (FLU-PRO) instrument. The relationship between smoking status and risk of reporting an ILI was estimated using Poisson regression; ILI severity was compared by cigarette smoking and e-cigarette use using multivariable linear regression. Among 8,708 participants with cigarette smoking status, 4.3% were current smokers and 11.9% were former smokers. Current cigarette smokers reported higher respiratory domain scores (0.24 (95% CI: 0.07, 0.41)) than non-smokers; former cigarette smokers were at higher risk of reporting an ILI than non-smokers [rate ratio 1.11 (95% CI: 1.02, 1.20)] and reported ILI episodes that were on average 1.23 days longer in duration (95% CI: 0.29, 2.17). Among 8,119 participants with e-cigarette use status, 3.9% were current users and 2.6% were former users. Current e-cigarette users reported more than one additional day with limited activity (1.14 days, 95% CI: 0.10, 2.18) and 0.78 additional days with fever (95% CI, 0.20, 1.35); former e-cigarette users were at higher risk of reporting an ILI than nonusers [rate ratio 1.20 (95% CI, 1.04, 1.38)] and reported higher respiratory domain scores than non-users (0.27 (95% CI 0.08, 0.46)). We observed slightly higher ILI risk in former cigarette smokers and e-cigarette users, longer symptom duration in former cigarette smokers, and higher respiratory symptom scores in current cigarette smokers and former e-cigarette users compared to non-smokers/users. Findings in this secondary analysis are exploratory and hypothesis-generating; additional studies are needed to confirm the relationships reported here.
In October 2024, the Standing Committee on Vaccination (STIKO) adjusted its recommendation on seasonal influenza vaccination for people aged 60 and over. Based on new study data, the MF59-adjuvanted influenza vaccine is now recommended as equivalent to the high-dose vaccine: The MF59-adjuvanted vaccine was shown to be superior in terms of effectiveness compared to non-adjuvanted standard vaccines in older adults. The immune response to the adjuvanted vaccine was broader and stronger than to the standard vaccine. The MF59-adjuvanted vaccine had a similar safety profile to the high-dose vaccine, both showing slightly increased local and systemic reactogenicity compared to the standard vaccine. STIKO believes that recommending both vaccines could increase acceptance and willingness to be vaccinated in the target population. Die Ständige Impfkommission (STIKO) hat im Oktober 2024 ihre Empfehlung zur saisonalen Influenza-Impfung für Personen ab 60 Jahren angepasst. Aufgrund neuer Studiendaten wird der MF59-adjuvantierte Influenza-Impfstoff nun neben dem Hochdosis-Impfstoff gleichwertig empfohlen: Es zeigte sich eine Überlegenheit des MF59-adjuvantierten Impfstoffs hinsichtlich der Effektivität im Vergleich zu nicht-adjuvantierten Standardimpfstoffen bei älteren Erwachsenen. Die Immunantwort auf den adjuvantierten Impfstoff ist mitunter breiter und stärker als gegen Standardimpfstoff. Der MF59-adjuvantierte Impfstoff wies ein ähnliches Sicherheitsprofil auf wie der Hochdosis-Impfstoff, beide zeigten im Vergleich zum Standardimpfstoff leicht erhöhte lokale und systemische Reaktogenität. Die STIKO geht davon aus, dass die Empfehlung beider Impfstoffe Akzeptanz und Impfbereitschaft in der Zielpopulation steigern könnte.
Recent clinical data on seasonal influenza mRNA vaccines have demonstrated suboptimal efficacy against the influenza B virus (IBV). We employed sequence optimization strategies that successfully enhanced the antigen expression of hemagglutinin (HA), and developed mRNA vaccine candidates targeting the WHOrecommended strains. When administered at a low dose (0.1 μg), both mono-and trivalent influenza A mRNA vaccines induced robust humoral immunity and conferred complete protection against homologous viral challenge in murine models, outperforming the quadrivalent inactivated vaccine (QIV, 2 μg). In contrast, IBV mRNA vaccines at an equivalent dose failed to elicit detectable antibodies and offered no protection, consistent with prior of suboptimal immunogenicity in human trials. These findings highlight strain-specific immunogenicity constraints inherent to conventional mRNA platforms. To overcome these limitations, we systematically compared three distinct RNA vaccine modalities: (1) nucleoside-modified mRNA, (2) self-amplifying RNA (saRNA), and (3) circular RNA (circRNA). Notably, a single 0.1 µg dose of trivalent saRNA vaccine elicited robust humoral immunity and provided complete protection against IBV challenge, whereas mRNA vaccination achieved only 14% survival. Importantly, long-term antibody monitoring over 20 weeks showed that saRNA at the low 0.1 μg dose maintained high antibody levels, with a markedly more durable response to IBV antigens than other platforms. Moreover, the trivalent mRNA vaccine exhibited a favorable safety profile, with no obvious abnormal body weight changes or serum biochemical abnormalities observed after immunization. Our findings advocate for strain-adaptive platform selection: conventional mRNA for generating rapid, high-magnitude responses against influenza A, and next-generation saRNA vaccine for enhanced dose efficiency, particularly against IBV.
The persistent circulation of influenza viruses following the COVID-19 pandemic remains a major public health concern, yet local genomic epidemiology in pediatric populations is not well-defined. In 2024, we collected 490 influenza antigen-positive specimens from a pediatric hospital in Qidong, eastern China, and performed influenza genome enrichment-based whole-genome sequencing, yielding 425 genomes (86.73%) with at least hemagglutinin (HA) and neuraminidase (NA) segments. A/H1N1 (45.41%), A/H3N2 (18.35%), and B/Victoria (36.24%) co-circulated, with two activity peaks in January and December. Phylogenetic analysis assigned these viruses to clades 6B.1A.5a.2a (A/H1N1), 3C.2a1b.2a.2a.3a.1 (A/H3N2), and V1A.3a.2 (B/Victoria). Positively selected sites in HA included lineage-specific residues such as position 210 in B/Victoria and positions 187 and 372 in A/H3N2. The oseltamivir resistance marker NA-H275Y was detected in 7/193 (3.65%) A/H1N1 strains, whereas no detected resistance to RNA polymerase inhibitors. These findings highlight the co-circulation patterns, genetic diversity, and antiviral susceptibility profile of influenza viruses in a pediatric population in eastern China, supporting the importance of sustained genomic surveillance to guide local prevention strategies and clinical management.
The role of glucose restriction in host antiviral defense remains elusive. Here, we investigate the impact of pre-existing hypoglycemia on host susceptibility to influenza infections. We find that mouse models with intermittent hypoglycemia exhibit heightened vulnerability to influenza A virus (IAV) infections at low to moderate exposure levels. This vulnerability is attributed to reduced expression of TRIM5 in the lung subsequent to hypoglycemic stress. Hypoglycemic stress activates AMPK protein to down-regulate ERK1/2 signaling and inhibit the transactivation activity of AP-1, thereby suppressing Trim5 transcription. Diminished expression of TRIM5 renders the animals more susceptible to influenza infections as it compromises pulmonary antiviral immunity by attenuating type I interferon (IFN-I) production and signaling. These findings provide mechanistic insights into how pre-existing hypoglycemia detrimentally impacts host antiviral defense, and establish TRIM5 as a molecular link connecting metabolic stress to innate antiviral immunity.
Co-circulation of multiple influenza subtypes poses a major challenge to global public health. However, its specific impact on non-stationary epidemic sequences and coupling relationships with environmental drivers remains poorly understood. By integrating STL, Adaptive Fourier Decomposition, Continuous Wavelet Transform, and Wavelet Coherence, we analyzed 323 weekly influenza surveillance time series from China (2011-2025). The study identifies a fundamental regime shift during co-circulation periods, transitioning from ordered single-dominant transmission to a chaotic state. This instability is characterized by significant dominant periodicity dispersion, amplified seasonality shifts, and high-intensity anomalies in residual components, with overall seasonal strength dropping by 28%. Crucially, we uncover a marked north-south mechanistic divergence: northern regions exhibited "Environmental Locking," remaining strongly constrained by climates during co-circulation; conversely, southern regions demonstrated "Environmental Decoupling" (H3N2 phase consistency with soil moisture plummeted from R=0.45 to 0.07), where viral ecological competition overshadowed environmental drivers. Influenza co-circulation acts as a systemic perturbation reshaping transmission dynamics. Our findings highlight the necessity for context-adaptive strategies: northern regions can maintain reliance on meteorological warnings, while southern regions must dynamically shift focus toward real-time virological surveillance during co-circulation to capture rapid ecological shifts.
Background Although the hemagglutination inhibition (HAI) titer remains the gold standard correlate of protection against influenza, it does not fully capture the broader antibody responses that contribute to immunity. We analyzed immune responses in paired pre-infection and convalescent sera from 306 RT-PCR-confirmed A/H3N2 infections from two household studies (2014-18) in Managua, Nicaragua. Antibody responses were measured by HAI and enzyme-linked immunosorbent assays (ELISAs) against full-length hemagglutinin (HA), the HA stalk, and neuraminidase (NA). Participants were classified as HAI responders (≥4-fold HAI rise), alternate responders (no HAI rise but ≥4-fold boost in ≥1 ELISA), or no-response individuals (no ≥4-fold rise in any assay). We compared demographic, clinical, and pre-infection antibody characteristics across these groups. We also analyzed predictors of an NA response. Overall, 77% of participants had HAI seroconversion or a 4-fold rise. Among the 23% HAI non-responders, 62% had alternate antibody responses. No-response individuals had the highest pre-infection HAI and full-length HA titers (p < 0.0001), the lowest viral loads, and the fewest fever or influenza like illness (ILI) symptoms (p < 0.01). An NA response was more common among symptomatic individuals (p = 0.0483) and those with low or high baseline NA titers. High baseline HAI titers can limit detectable 4-fold rises and are associated with milder illness. Evaluating additional immune responses may capture a more complete picture of the host response to infection, thereby improving surveillance and informing vaccine development.
Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b continues to circulate globally across wild birds, poultry, and an expanding range of mammalian hosts, highlighting the need for antiviral strategies that address the animal-environment-human interface. The influenza A polymerase acidic (PA) endonuclease, a key enzyme in viral transcription, represents a conserved antiviral target across host species. In this study, we present a computational prioritization framework integrating homology modeling, molecular docking, molecular dynamics simulations, and physicochemical filtering to identify candidate PA endonuclease inhibitors relevant to a One Health context. Homology models of contemporary H5N1 clade 2.3.4.4b PA sequences were constructed based on the crystallographic template 6FS8 and used for cross-host docking against a targeted ligand library. Docking analysis identified baloxavir, a reference inhibitor, and entecavir, a nucleoside analog, as compounds of interest, with entecavir demonstrating favorable binding behavior, particularly in the poultry-associated model. Molecular dynamics simulations of the poultry PA-entecavir complex indicated stable interaction over 170 ns, supported by low structural deviation and favorable binding free energy (ΔG ≈ -85 kJ/mol). Physicochemical profiling suggested that entecavir possesses properties such as high polarity and predicted aqueous solubility, which were considered within the translational filtering step of this computational workflow. However, these properties do not establish antiviral efficacy or practical suitability for field use. The study provides a structured framework for integrating cross-host structural analysis with basic translational considerations, supporting the identification of candidate compounds for further biochemical and virological evaluation within the context of H5N1 control.
Virus-associated pulmonary aspergillosis is a life-threatening secondary infection that substantially increases morbidity and mortality in critically ill patients with respiratory virus infections. Influenza A virus (IAV) and SARS-CoV2 are known to disrupt pulmonary homeostasis, the mechanisms by which these perturbations render the host susceptibility to Aspergillus fumigatus (Af) remain incompletely understood. Here, we integrate an established murine model of influenza-associated pulmonary aspergillosis (IAPA) with single-cell RNA sequencing (scRNA-seq) to define the myeloid cell dysfunction that underlies IAPA establishment and progression. Single-cell transcriptomic profiling of pulmonary monocytes and macrophages revealed that IAV- Af coinfection drives a marked shift away from interferon-mediated antiviral and antigen presentation programs toward stress-associated and redox-regulatory transcriptional states. Pathway analyses demonstrated coordinated suppression of phagocytic and interferon signaling pathways alongside enrichment of oxidative stress and mitochondrial metabolic signatures - changes that closely recapitulate transcriptional defects previously reported in human IAPA patients. Myeloid cells from IAV- Af coinfected mice further exhibited increased oxidative phosphorylation alongside reduced glycolytic and phagocytic activity, consistent with impaired antifungal effector function. To elucidate how prior IAV infection generates a pulmonary microenvironment permissive to Af growth, we evaluated airway iron availability - a critical determinant of both fungal pathogenicity and immune regulation. IAV infection alone produced a significant elevation in bronchoalveolar iron levels accompanied by induction of iron-associated inflammatory mediators. Paradoxically, during IAV- Af coinfection, myeloid cells displayed markedly reduced expression of iron-sequestering and storage genes, revealing a fundamental disconnect between iron burden and cellular iron-handling capacity. Functionally, elevated iron accelerated Af germination and impaired macrophage-mediated fungal killing. Collectively, these findings identify IAV-induced pulmonary iron accumulation as a key driver of immunometabolic reprogramming in myeloid cells, resulting in compromised antifungal immunity and heightened susceptibility to secondary Af infection.
Poultry disease outbreaks are frequently multifactorial, involving complex interactions between infectious agents and environmental stressors. This report describes a case of avian influenza (AI) co-infection in a commercial broiler farm located in Majalengka, West Java, Indonesia, where a total of 11,000 birds exhibited increased mortality during the grow-out period. Diagnostic investigations included pathological examination, serological testing-such as hemagglutination inhibition (HI) assays for AI H5 and H9, enzyme-linked immunosorbent assay (ELISA) for infectious bronchitis, and rapid testing for Mycoplasma gallisepticum-Polymerase Chain Reaction (PCR) analysis, fecal flotation for coccidiosis, and an environmental assessment measuring ammonia levels, humidity, and heat stress index. Pathological findings revealed tracheitis, airsacculitis, thymitis, bursitis, perihepatitis, ascites, petechial hemorrhages, nephromegaly, and enteritis, indicating a complex disease process. Serological results demonstrated exposure to AI H9 and H5, with differing infection dynamics, while the uneven distribution of infectious bronchitis antibodies suggested field challenges. Additionally, partial exposure to Mycoplasma gallisepticum was observed. PCR results were negative at the time of sampling, consistent with post-infection phases. Environmental evaluation revealed elevated ammonia levels, excessive humidity, and a high heat stress index. In conclusion, the increased mortality was associated with avian influenza co-infection, complicated by secondary infections and adverse environmental conditions.
In the context of a rapidly aging global population, influenza vaccine hesitancy among Chinese older adults remains a critical public health issue. Concurrently, the proliferation of digital health information has raised concerns about the negative effects of information overload and cyberchondria. However, the psychological pathways linking these digital phenomena to vaccine hesitancy, particularly for older adults, remain underexplored. This study aims to examine the association between health information overload on excessive online search (cyberchondria) and influenza vaccine hesitancy among Chinese older internet users. Grounded in the Stereotype Embodiment Theory (SET), the study specifically examines the mediating role of self-perceptions of aging. A self-reported online questionnaire was distributed to 791 Chinese internet users aged 55 or older. The research hypotheses were tested using Partial Least Squares Structural Equation Modeling (PLS-SEM) in SmartPLS. Results indicate that health information overload was significantly correlated with cyberchondria (β = 0.501, p < 0.001), psychological growth (β = -0.236, p < 0.001), physical change (β = -0.229, p < 0.001), and psychosocial loss (β = 0.254, p < 0.001). Similarly, cyberchondria was a significant predictor of psychological growth (β = -0.184, p < 0.001), physical change (β = -0.312, p < 0.001), and psychosocial loss (β = 0.285, p < 0.001). Finally, physical change (β = -0.209, p < 0.001) and psychosocial loss (β = 0.247, p < 0.001) showed a significant statistical relationship with vaccine hesitancy. The findings highlight the critical importance of fostering positive aging attitudes in health communication strategies. Health practitioners and policymakers should develop age-friendly digital environments and educational campaigns that not only provide accurate information but also empower older adults to perceive aging more rationally, thereby potentially encouraging proactive health behaviors.