RARE DISEASE
Avian influenza
Avian influenza
Avian influenza
Drug discovery
1
drug
With orphan designation
Overview
Avian influenza (bird flu) is caused by influenza A viruses (primarily H5N1) that circulate globally in wild birds and sporadically infect mammals, including humans. Transmission occurs through direct contact with infected animals or contaminated environments. High-risk populations include poultry/dairy workers and veterinarians. Symptoms range from mild conjunctivitis to severe pneumonia and ARDS. Early antiviral treatment (≤48 hr) improves outcomes. While human-to-human transmission remains rare, case fatality rates exceed 50% for H5N1 without treatment [1][7][9][13][17].
Burden
Mortality: 54% CFR in Western Pacific H5N1 cases (2003-2024) [8], 40-52% for H7N9 [17].
Economic: $3B USD losses in 2022-2024 US poultry culls [6][15].
Emerging Threats: Multispecies spread (cows, seals) since 2024 with 50+ human cases, though current human cases remain mild with treatment [4][15][19].
Categories: rare infectious diseases, rare respiratory diseases
Research Papers
4,580 drug discovery papers about Avian influenza, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
4,580 drug discovery papers about Avian influenza, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-08-14 | Skuas as sentinels of high pathogenicity avian influenza H5N1 on the Antarctic Peninsula in the 2024/2025 austral summer.
Despite Antarctica's geographic isolation, the first incursion of high pathogenicity avian influenza (HPAI) H5N1 was detected in the 2023/2024 austral summer. Surveillance for HPAI H5N1 in Antarctica remains patchy due to logistical, financial and infrastructure challenges, with many suspected cases remaining unconfirmed and few viral genome sequences available to date. Through the 2024/2025 austral summer, we undertook five sampling expeditions to the South Shetland Islands and Antarctic Peninsula facilitated by cruise ships/operators. Across more than 500 faecal environmental samples collected from apparently healthy penguins and marine mammals, we found no detectable evidence of HPAI H5N1. However, HPAI H5N1 was detected in all but one of the skua carcasses sampled, which, in most cases, were found within metres of penguin sub-colonies. All HPAI H5N1 viral genome sequences from skuas on the Antarctic Peninsula fell within a single lineage, which included those genomes from skuas sampled in the 2024/2025 season from the South Shetland Islands. Genomes were in a different clade to those from the Antarctic Peninsula collected in the 2023/2024 austral summer. Our results confirm that although the prevalence may be low, HPAI H5N1 is recurring in Antarctica, emphasizing the need for ongoing surveillance to monitor and mitigate threats to wildlife, even in the planet's most isolated regions.
2026-08-12 | Epidemiological and clinical characterization of human infections with H9N2 avian influenza virus in Changsha city, China, 2015-2025.
H9N2 avian influenza virus poses a persistent public health concern due to its zoonotic potential. This study investigated the epidemiological and clinical characteristics of human H9N2 avian influenza infection in Changsha City, along with related environmental surveillance data, to provide a scientific basis for disease prevention and control. From January 2015 to December 2025, a total of 11 human H9N2 avian influenza cases were collected from historical surveillance data of the Changsha CDC in Changsha City. Cases occurred sporadically throughout the year; most (90.91%, 10/11) were mild, one severe case was co-infected with two types of respiratory pathogens, and the majority (72.73%, 8/11) were children under 5 years old. Among the 10 cases with available exposure history, 70.00% had been exposed to live poultry or LPMs, with the H9 and N2 subtypes detected in related environmental samples at rates of about 76%. Genetic analysis showed that the H9N2 viruses from human cases were highly homologous to H9N2 viruses found in the live poultry environment in Changsha City, while also exhibiting diverse mutations in key functional sites and domains. Environmental samples from large live poultry markets exhibited a significant year-on-year increase in positive rate (χ2=111.30, P<0.001), resulting in a substantially higher average rate in 2020-2024 versus 2014-2019 (77.11% vs. 47.43%; χ2=158.24, P<0.001). In conclusion, sporadic human H9N2 infections, predominantly affecting children, were mostly associated with live poultry exposure, with no evidence of human-to-human spread, while environmental data revealed a sharply increasing contamination trend in markets, pointing to a heightened risk.
2026-08-07 | Genetic characterization and zoonotic potential of G1-Lineage H9N2 avian influenza viruses isolated from poultry in Pakistan, 2023.
The H9N2 subtype of avian influenza A virus has been endemic in poultry populations across Asia and the Middle East, posing ongoing economic and public health concerns. Since their initial detection in Pakistan in the 1990s, H9N2 viruses have caused repeated outbreaks in commercial poultry, leading to substantial economic losses and raising concerns about zoonotic transmission. To characterize the recent genetic evolution and zoonotic potential of circulating strains, five H9N2 isolates were obtained from poultry in Pakistan between January and March 2023. Phylogenetic analysis of the haemagglutinin gene revealed that all five isolates belong to the G5.3.2, formerly known as B2, sub-lineage of the G1 Eurasian lineage, in accordance with the revised global classification system for H9 viruses. Comparative genomic analysis confirmed that all eight gene segments were closely related to previously reported Pakistani strains, with no evidence of recent reassortment, suggesting localized persistence and ongoing genetic drift. Notably, several mammalian-adaptive mutations were identified in internal gene segments of the isolates, suggesting a potential risk of cross-species transmission. In addition, all five isolates exhibited dual receptor-binding characteristics, recognizing both α2,3-linked (avian-type) and α2,6-linked (human-type) sialic acid glycans, with a stronger affinity for α2,6-linked glycans. These findings underscore the need for continuous surveillance and risk assessment of H9N2 viruses circulating in Pakistan.
2026-08-06 | Neutralizing and protective monoclonal antibodies identify antigenic sites in influenza H7 hemagglutinin and select for amino acid substitutions rarely observed at the global level.
Avian influenza viruses of the H7 subtype infect a variety of avian as well as mammalian species, and a better understanding of H7 virus antigenicity and immunogenicity is vital to the development of effective countermeasures for a potential H7 pandemic threat. We have developed a diverse panel of murine monoclonal antibodies (mAbs) to the H7 hemagglutinin (HA) and characterized these mAbs for the HA epitope(s) that they bind, their neutralizing activity in vitro against several strains of H7, and their ability to provide protection against virus challenge in vivo. The majority of the isolated mAbs recognized antigenic sites A and B on the globular head of the influenza HA, but mAbs were also isolated to non-canonical sites on HA. Escape viruses generated against the mAbs were used to further define the antigenic sites on the H7 HA, and notably, we find that most amino acid substitutions identified in these escape viruses are rare at the global level. Finally, we used a polyclonal antibody generated by virus infection to assess whether antibody binding and neutralization were impacted by individual amino acid substitutions in the HA of escape viruses generated by the mAbs. The results showed that all of the escape viruses, each of which carried a single amino acid substitution, were still effectively neutralized by polyclonal antibodies, suggesting that the antibody response to H7 infection was broad and redundant.IMPORTANCEInfluenza H7 viruses infect a variety of avian and mammalian species, and present a potential threat to human health. We used a panel of murine monoclonal antibodies (mAbs) to facilitate the identification of important protective epitopes on the H7 hemagglutinin (HA). While most of the antibodies bind to antigenic sites A and B on the H7 HA that correspond to well-characterized cognate sites on influenza H3, some antibodies appear to recognize new epitopes in HA distinct from those known antigenic sites. We also identified amino acid substitutions in escape viruses selected by these mAbs and evaluated their impact in the context of polyclonal responses and natural H7 virus evolution over a >60-year period. Taken together, the results add to our understanding of influenza H7 virus antigenicity and immunogenicity, and may have positive implications for successful H7 vaccine development.
2026-08-04 | Subclass switching enhances protective efficacy of a non-neutralizing H7N9 avian influenza antibody.
Non-neutralizing antibodies contribute to protection against the H7N9 subtype avian influenza virus through Fc effector functions. Antibody subclass plays a critical role in determining binding affinity to Fc receptors (FcR) and downstream Fc effector functions. In this study, to assess whether antibody subclass switching can enhance antibody protective efficacy, subclass of a non-neutralizing monoclonal antibody (mAb) against the hemagglutinin of H7N9 virus was switched from IgG1 to IgG2a, and their activity and protective efficacy were assessed. Subclass switching caused no significant changes in antigen binding, hemagglutination-inhibition and virus neutralizing activities of the antibody. The hybridoma-derived mAb conferred no protection against H7N9 virus infection. Interestingly, both IgG2a and IgG1 antibodies produced in CHO cells provided full protection against mortality caused by a sublethal H7N9 virus challenge. Upon lethal challenge, IgG2a antibody conferred 70% protection, whereas its IgG1 counterpart only provided 30% protection. However, both antibodies did not decrease virus loads in mouse lungs. Moreover, compared to the IgG1 antibody, affinity of the subclass-switched IgG2a antibody to FcR was significantly increased, as evidenced by enhanced binding of the antibody to recombinant murine FcγRI and to FcRs on murine macrophages. Our findings highlighted a benefit of subclass-engineering to antibody modification and development of therapeutic antibodies.
small molecules
2026-07-26 | Synergistic control of viral persistence via wettability and ion release on antiviral coatings.
Antiviral coating design remains largely empirical due to the lack of quantitative principles linking interfacial properties to viral persistence under realistic conditions. Here, we establish a survival time-based evaluation framework that captures the drying dynamics of 2-μL virus-containing microdroplets and enables quantitative assessment of antiviral coating performance using viral survival time (duration of infectivity) and survival time reduction rate. Using this framework, we identify surface virus density, defined as infectious virus per unit distribution area, as a physical determinant governing viral persistence. When surface virus density was matched, viral survival times converged irrespective of inoculum level or droplet geometry. Accordingly, viral survival time decreased with decreasing surface virus density, and hydrophilic surface design alone reduced viral survival time by approximately 70-80%. Furthermore, we demonstrate that the initial release rate of antiviral metal ions constitutes a complementary chemical control parameter under rapid-drying conditions. Antiviral coatings incorporating amorphous vanadate glass particles enabled rapid release of copper or silver ions within the first 1-5 min following droplet deposition. By integrating wettability-mediated viral redistribution with rapid ion release, synergistic suppression of viral persistence was achieved, reducing viral survival time relative to uncoated surfaces by up to 97.6% for influenza virus, 98.2% for feline calicivirus, and 94.9% for highly pathogenic avian influenza virus. These findings demonstrate that viral persistence can be predictively controlled through the combined physical regulation of surface virus density and chemical inactivation by rapidly released antiviral agents. This antiviral coating strategy may contribute to reducing contact transmission risks in healthcare, agricultural, and community environments.
2026-07-23 | Antiviral and immunomodulatory effects of Siji antiviral mixture against H9N2 avian influenza virus infection in chickens.
The H9N2 subtype avian influenza virus (AIV) is common in poultry and poses significant risks to both the poultry industry and public health. Current control strategies for H9N2 AIV predominantly rely on vaccination; however, these approaches are often undermined by the continuous antigenic drift of hemagglutinin under the pressure of antibodies. This study evaluated the antiviral efficacy of Siji Antiviral Mixture (SAM) against H9N2 infection in specific pathogen-free chickens. Compared with the infected control group, SAM significantly reduced viral loads in multiple tissues, including liver, spleen, lung, kidney, brain, and trachea, demonstrating its direct antiviral activity. Further analysis revealed that SAM modulated H9N2-induced inflammation by downregulating excessive innate immune responses. Specifically, SAM significantly enhanced the expression of antiviral effectors (OASL and MX-1) in the lungs during the early stages of viral infection, while attenuating the production of inflammatory cytokines (IL-6, IL-10) in the later stages. Additionally, SAM regulated the expression levels of pattern recognition receptors (MDA5, TLR3, and TLR7), thereby preventing excessive immune responses. These findings indicate that SAM possesses both antiviral and immunoregulatory effects, highlighting its potential as an effective anti-AIV agent for the management of H9N2 AIV infection.
2026-07-23 | Oseltamivir Resistance in Human Influenza A(H5N1) and A(H7N9) Infections: A Mini Review.
Avian influenza viruses (AIVs) have been reported to cause infections in humans following avian-to-human transmission, resulting in a range of clinical outcomes. A(H5N1) and A(H7N9) infections, which constitute the majority of human AIV cases, are responsible for severe infections leading to high mortality. The neuraminidase inhibitor oseltamivir is expected to play a major role for the control of AIV infections in humans. However, the emergence of resistance may compromise the impact of antiviral therapy. The objective of this article is to review human cases of A(H5N1) and A(H7N9) infections for which mutations of oseltamivir resistance were detected. Neuraminidase mutations rapidly occurred in a subtype-specific manner, with H274Y and N294S substitutions predominating in A(H5N1) cases and the R292K substitution in A(H7N9) cases. Serious clinical outcomes and mortality were seen in most A(H5N1) and A(H7N9) cases despite oseltamivir therapy, thus highlighting the need for improving antiviral strategies against these AIVs.
2026-07-10 | Preclinical characterization of HEC116094, an oral inhibitor of the influenza A virus polymerase PB2 subunit.
Influenza A virus remains a global health threat due to its high mutation rate and its resistance to existing neuraminidase and polymerase inhibitors. The polymerase basic protein 2 (PB2) subunit is a promising target for novel therapeutics due to its critical role in inhibiting viral transcription and replication. Here, we reported the preclinical characterization of HEC116094, a novel PB2 inhibitor, against influenza A virus. HEC116094 exhibited potent in vitro activities against multiple laboratory strains (IC50: 0.012-0.069 nM) and the highly pathogenic avian influenza strains H5N1 and H7N9 (IC50: 0.071-0.122 nM). These activities are more potent than VX-787 (Pimodivir) and oseltamivir. Our studies demonstrated that HEC116094 treatment could reduce the extent of weight loss and maintain a 100% survival rate in BALB/c mice, even when initiated 72 h post-infection. In addition, HEC116094 exerted potent in vitro synergy and in vivo therapeutic benefits when combined with oseltamivir. Furthermore, HEC116094 displayed minimal kinase inhibition and excellent PK characteristics. Superior preclinical activity demonstrated that HEC116094 was a more potent PB2 inhibitor against influenza A virus than VX-787 in this study. Currently, HEC116094 is under evaluation in Phase I clinical studies.
2026-07-10 | Optimizing an avian influenza vaccine using a novel Bacterial Enzymatic Combinatorial Chemistry (BECC) TLR4 adjuvant.
The development of broadly protective and dose-sparing influenza vaccines remains a critical challenge, particularly for zoonotic H5N1 strains with pandemic potential. This study evaluates BECC470s, a synthetic TLR4 adjuvant, for its ability to enhance the immunogenicity and protective efficacy of recombinant H5 hemagglutinin (rHA) vaccination in murine models. BECC470s-adjuvanted rHA elicited robust IgG1/IgG2a antibody responses and complete survival following homologous 2004 H5N1 challenge in a prime-boost model. Although BECC470s broadened antibody binding to both variable HA head and conserved stalk domains by ELISA, functional neutralizing antibody responses were restricted to the matched 2004 H5N1 isolate, with no detectable neutralization of H5N1 viruses isolated in 2022 or 2024. These data indicate that BECC470s enhances the magnitude and apparent cross-reactivity of binding antibody responses while maintaining strain-specific neutralizing activity, supporting its potential as an adjuvant for next-generation influenza vaccines while underscoring the need for further optimization to achieve true cross-neutralizing protection.IMPORTANCEBECC470s is a synthetic TLR4 agonist adjuvant that enhances the breadth and potency of recombinant H5 hemagglutinin vaccination in mice. By driving balanced antibody responses, complete protection against homologous challenge, and neutralizing activity targeting both HA head and stalk, BECC470s outperforms the comparator TLR4 adjuvant. These preliminary findings indicate that BECC470s enables antigen sparing while increasing antigen immunogenicity, supporting its potential translational application to current H5N1 vaccines.
vaccines
2026-08-17 | A novel candidate vaccine virus derived from Japan's first mammalian case of clade 2.3.4.4b A/H5N1 highly pathogenic avian influenza virus.
The development of candidate vaccine viruses (CVVs) for pre-pandemic preparedness requires attenuation of pathogenicity while maintaining immunogenicity. In this study, we developed and characterized NIID-002, a reassortant virus derived from A/Ezo red fox/Hokkaido/1/2022 (H5N1; clade 2.3.4.4b), to evaluate its suitability as a candidate vaccine. NIID-002 exhibited markedly reduced pathogenicity compared with its parental strain, while retaining broad antigenic reactivity and protein yield comparable to other clade 2.3.4.4b CVVs. In mammalian models, NIID-002 demonstrated strong attenuation, causing no lethal infection in mice and only minimal weight loss with limited viral replication in ferrets. Antisera raised against NIID-002 reacted broadly with recent wild-type H5N1 isolates, suggesting potential broad protection. Protein yield analysis confirmed a production efficiency comparable to that of other CVVs within the same clade, supporting its feasibility for large-scale vaccine manufacturing. Overall, NIID-002 fulfills the key requirements for the pandemic preparedness of CVV, combining reduced pathogenicity, broad antigenic reactivity, and adequate production efficiency. These findings highlight its potential as a candidate H5N1 vaccine and underscore the continued need for surveillance and refinement of influenza vaccine strategies to address evolving viral threats.
2026-08-14 | Impact of prior low-pathogenicity avian influenza H7N7 exposure on susceptibility and protection against homologous high-pathogenicity avian influenza H7N7 challenge in chickens.
Circumstances driving the transition from low-pathogenicity to high-pathogenicity avian influenza viruses (LPAIVs to HPAIVs) remain poorly understood. In July 2015, a UK layer outbreak revealed circulation of an H7N7 LPAIV (H7N7-LP), which subsequently mutated into a high-pathogenicity H7N7 virus (H7N7-HP) at the same farm. The emergent H7N7-HP caused high mortality, though prior H7N7-LP exposure provided partial protection in some chickens. We experimentally assessed the protective effect of prior H7N7-LP exposure upon subsequent H7N7-HP challenge. In the absence of an isolated H7N7-LP direct-precursor to this H7N7-HP outbreak strain, eight chickens were directly-inoculated with an H7N7-LP which was closely genetically related to the outbreak H7N7-HP. At 1-day post-infection (dpi), eight naïve contact chickens were introduced to assess H7N7-LP transmission. All (100%) directly inoculated chickens became H7N7-LP infected, whereas only 3/8 contacts (37.5%) acquired infection. At 14 dpi, these 16 chickens, together with eight immunologically naïve controls, were challenged with H7N7-HP. Among the naïve controls and the previously H7N7-LP contact-exposed chickens, all 16 (100%) shed H7N7-HP, with 62.5% and 50% mortality, respectively. In contrast, none of the chickens previously directly-inoculated with H7N7-LP subsequently shed H7N7-HP, where all remained healthy and survived. Therefore, direct H7N7-LP inoculation induced effective immunity against antigenically related H7N7-HP. However, the more limited H7N7-LP infection acquired via contact exposure resulted in all shedding H7N7-HP, with reduced clinical protection. This sequential infection model highlighted how the route and timing of initial LPAIV exposure, along with acquired immunity, differed in influencing susceptibility to an emergent HPAIV, reflecting outcomes observed during layer outbreaks.
2026-08-11 | Protective effect of A(H5N8) stockpiled vaccine against a virus genetically identical to a human isolate of bovine A(H5N1) influenza virus.
Since early 2024, highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b have caused extensive outbreaks in dairy cattle in the United States, with spillover into mammalian species, including humans. A bovine-derived A(H5N1) virus isolated from a human case retains high pathogenicity and transmissibility in mammalian models, highlighting its pandemic potential. Stockpiled pre-pandemic influenza vaccines are intended to provide early protection before strain-matched vaccines are available; however, their protective efficacy against bovine A(H5N1) viruses has not been directly evaluated in vivo. In this study, we assessed the protective efficacy of an AS03-adjuvanted A/Astrakhan/3212/2020 (H5N8) clade 2.3.4.4b-based influenza vaccine stockpiled in Japan using mouse and ferret models. Vaccinated and unvaccinated animals were challenged with a virus genetically identical to a human isolate of bovine A(H5N1) virus. Neutralising antibody responses, viral replication in organs, and survival were evaluated. Vaccination with the AS03-adjuvanted A(H5N8)-based stockpiled vaccine induced robust neutralising antibody responses in both animal models, significantly suppressed viral replication, and conferred complete protection against lethal challenge. In contrast, all unvaccinated mice and ferrets succumbed to infection. These findings demonstrate that the AS03-adjuvanted A(H5N8)-based stockpiled vaccine provides strong cross-protective efficacy against bovine A(H5N1) viruses. An AS03-adjuvanted A(H5N8)-based vaccine stockpiled in Japan could serve as an immediate countermeasure against bovine A(H5N1) viruses during the early phase of a pandemic. This work was supported by grants from the Japan Program for Infectious Diseases Research and Infrastructure (JP20wm0125002) and the Japan Initiative for World-leading Vaccine Research and Development Centers (JP223fa627001) from the Japan Agency for Medical Research and Development.
2026-08-05 | Heterologous prime-boost vaccination against H5 avian influenza: Safety and immunogenicity of a MF59-adjuvanted, cell-culture derived H5N6 vaccine.
With increasing H5 avian influenza cases reported globally and the potential for pandemic emergence, induction of cross-reactive antibody responses may represent an important attribute of an effective vaccine. This phase 2 extension study evaluated immunogenicity and safety of MF59-adjuvanted, cell culture-derived H5N6 vaccine (aH5N6c) in adults primed with MF59-adjuvanted, cell culture-derived H5N1 vaccine (aH5N1c) and in unprimed adults. Adults previously primed with two doses of aH5N1c in the parent study V89_18 were randomized to receive two aH5N6c doses (Group 1) or one aH5N6c and one placebo (Group 2) 3 weeks apart. Unprimed adults received two aH5N6c doses (Group 3). Immunogenicity was assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays against the priming (H5N1) and booster (H5N6) strains on Days 1, 8, 22, 43, and 202. Among 258 exposed participants, primed subjects (Groups 1 and 2) showed higher HI geometric mean titers against both strains than unprimed (Group 3) subjects, with MN responses similarly enhanced. Heterologous H5N1 responses were robust in primed subjects (Day 43 HI GMTs: 333-343; seroconversion rates >89%) but minimal in unprimed subjects, with responses persisting to Day 202. Solicited adverse events were mild or moderate, comparable between groups, and consistent with other MF59-adjuvanted pandemic vaccines; no vaccine-related serious adverse events occurred. Heterologous H5N6 booster vaccination in H5N1-primed adults elicited strong cross-reactive immunity against the priming strain, demonstrating long-lasting immune memory for at least 6 y and supporting heterologous prime-boost strategies for pandemic preparedness against emerging H5 outbreaks.
2026-08-03 | A bivalent inactivated influenza vaccine incorporating epitope-optimized surface proteins confers cross-protective immunity against H9N2 influenza virus.
AbstractThe H9N2 avian influenza virus (AIV) has caused substantial economic losses to the global poultry industry and poses a zoonotic threat to humans. Vaccination constitutes a pivotal strategy for the prevention and control of H9N2 AIVs. However, the ongoing antigenic evolution of the virus poses a persistent challenge to the protective efficacy of existing vaccines. Therefore, the development of a broadly protective H9N2 influenza vaccine capable of eliciting cross-reactive immune responses is crucial for mitigating both the disease burden and the risk of pandemics. Here, we developed a bivalent chimeric inactivated vaccine, designated cHANA, by combining two individually rescued chimeric inactivated viruses, cHANA1 and cHANA2. Each recombinant virus carries one set of Epigraph-designed HA and NA immunogens, and the two sets were computationally optimized from global H9N2 HA and NA sequence datasets to complement each other in epitope coverage across the H9N2 viral population. Compared to the WHO-recommended candidate vaccine virus (CVV), AL/39, cHANA elicited more potent cross-reactive antibody responses and T cell immunity in mice. Furthermore, it elicited effective cross-protection against lethal challenge with heterologous H9N2 virus and significantly reduced pulmonary viral loads of mice. By conferring broad protective immunity, this vaccine represents a promising universal candidate for controlling H9N2 outbreaks.
proteins
2026-08-13 | Identification and characterization of PB2 mutations associated with mammalian adaptation of highly pathogenic H5N1 avian influenza viruses.
The highly pathogenic avian influenza virus (HPAIV) subtype H5N1 has been continuously circulating among wild bird populations and domestic poultry. It's ongoing circulation has led to outbreaks in poultry and U.S. dairy cattle populations, as well as sporadic severe infections in individuals engaged in poultry and dairy farming. These occurrences have raised concerns about the potential evolution of this virus into a pandemic strain. To elucidate the molecular determinants facilitating H5N1 cross-species adaptation and to evaluate its implications for public health, we conducted serials of sequence analysis and specific-site mutations on the viral polymerase subunit PB2 to determine its effect on polymerase activity and viral infectivity. The results showed that three mutations in the PB2 protein (E362G, D441N and M631L) were presented cooperative effects associated with enhanced viral replication in mammalian cells. Compared to the original isolated strain of the 2.3.4.4b clade, A/chicken/NL/FAV-0033/2021, these three mutations were predominantly identified in isolates obtained from cattle and other mammalian hosts between 2021 and 2024. The M631L mutation, identified as the primary determinant of increased polymerase activity in mammalian cells, significantly enhanced the binding affinity of PB2 to ANP32A. The mutation E362G and D441N did not increased polymerase activity and viral replication significantly but enhanced binding affinity of PB2 to ANP32A. The combined mutations with E362G, D441N and M631L resulted in a significantly increased polymerase activity and viral replication in H5N1 virus, and significantly elevated viral loads and aggravated pulmonary pathology in lungs of mice with H5N1 infection. These findings indicate that the PB2-M631L mutation constitutes a crucial molecular marker for the adaptation of H5N1 to mammalian hosts, whereas the E362G and D441N mutations likely function as supportive modulatory factors that optimize this host-adaptation process.
2026-08-11 | Identification and functional characterization of a novel antiviral chicken interferon-υ.
Interferons are critical mediators of antiviral immunity in vertebrates. While type IV interferon (IFN-υ) has been identified in fish and amphibians, its existence and function in chickens remained unknown. Through systematic genomic screening, we identified and cloned a novel chicken interferon gene, designated ChIFN-υ. Phylogenetic analysis placed ChIFN-υ within a distinct clade alongside zebrafish and clawed frog IFN-υ, confirming its identity as a type IV interferon, with minimal homology to classical type I, II, or III IFNs. Expression profiling revealed constitutive ChIFN-υ expression in mucosal and immune tissues of healthy chickens, exhibiting a distinct developmental shift: highest in trachea and small intestine in 1-day-old chicks, shifting to spleen and lung in 4-week-old chickens. ChIFN-υ expression was strongly upregulated following H9N2 AIV infection. Functionally, recombinant ChIFN-υ protein activated the interferon-stimulated response element (ISRE) and Mx promoter in a dose-dependent manner and significantly inhibited the replication of both vesicular stomatitis virus (VSV) and H9N2 AIV in DF-1 cells. In vivo, early treatment with exogenous ChIFN-υ significantly reduced pulmonary and tracheal viral loads and decreased oropharyngeal and cloacal virus shedding in H9N2-infected chickens. In conclusion, this study identifies and functionally characterizes the type IV interferon in chickens, elucidating the evolutionary status, regulated expression, and antiviral efficacy of ChIFN-υ. These findings highlight its potential as a candidate for developing interferon-based therapies against avian viral diseases.
2026-06-26 | Avian Foxp3 acts as a switch for IL-10 by directly binding the T3G motif: revealing a novel epigenetic modulation paradigm.
Foxp3 is the master transcription factor for regulatory T (Treg) cell differentiation and function, essential for immune homeostasis and tolerance. While its role is well-characterized in mammals, its functional mechanisms in avian species remain poorly understood. We conducted comparative genomic and functional analyses of chicken Foxp3 (chFoxp3). DNA-binding specificity was determined using motif analysis and genome-wide scanning. An H9N2 avian influenza challenge model was used to assess Foxp3 expression dynamics and CD4⁺CD25⁺ T cell frequency in vivo. The transcriptional regulation of IL-10 by chFoxp3 was investigated through promoter binding and transactivation assays, with key domains mapped via mutagenesis. Avian Foxp3 has evolved independently from its mammalian ortholog. Unlike human Foxp3, which binds the FKHM motif, chFoxp3 specifically recognizes a T3G microsatellite motif. Genome-wide scanning identified potential targets enriched in the FoxO signaling pathway, including IL-10. In an H9N2 infection model, Foxp3 expression and CD4⁺CD25⁺ T cell frequency exhibited biphasic dynamics. Mechanistically, chFoxp3, but not human FoxP3, directly binds the T3G motif in the IL-10 promoter to activate transcription. This transactivation function critically depends on the HNT linker within its Fork-head domain. Our study reveals a novel mode of transcriptional regulation by chFoxp3 via T3G motif recognition, underscoring its functional diversification during evolution. These findings provide a foundation for understanding immune regulation in birds under both physiological and pathological conditions, such as avian influenza infection.
2026-06-17 | The N-terminal region of pdm09/H1N1 PA synergizes with its cognate NP to enhance mammalian adaptation of avian-origin H9N2 canine influenza virus.
The PA gene of the 2009 pandemic H1N1 (pdm09/H1N1) lineage is derived from avian influenza virus (AIV). Together with other polymerase subunits, it enhances the adaptation of avian-origin influenza virus to mammals. However, the functional region of the PA protein remains unclear. Using reverse genetics, we mapped functional domains of pdm09/H1N1 PA in an avian-origin H9N2 canine influenza virus (CIV) background. The N-terminal 169-252 region conferred high intrinsic polymerase activity yet failed to support efficient viral replication alone, revealing a dissociation between catalytic potential and replicative fitness. In contrast, the 85-168 region enabled robust replication despite lower activity. Importantly, synergy between the 169-252 region and its cognate pdm09/H1N1 NP drove high polymerase activity and replication. This pairing also enhanced viral growth in vitro, increased viral titers in mouse lungs and nasal turbinate, and induced pulmonary damage. Mechanistically, the 169-252 region interacts with NP, accelerating nuclear import and cRNA synthesis, thereby optimizing viral RNA replication timing. Thus, PA-NP co-evolution is a key driver of mammalian adaptation, moving beyond single mutations and highlighting internal gene compatibility as a determinant of viral fitness and pandemic potential.
2026-06-17 | Molecular cloning and antiviral function analysis of pigeon interferon lambda(piIFN-λ).
Type III interferons (IFN-λ) are critical components of the interferon system, serving as key antiviral cytokines in the innate immune response of epithelial cells. However, the biological role of pigeon IFN-λ (piIFN-λ) remains poorly understood. In this study, we cloned and characterized the biological effects of piIFN-λ. Our results reveal that the open reading frame (ORF) of piIFN-λ is 561 base pairs long, encoding a protein consisting of 186 amino acids. The amino acid sequence of piIFN-λ shares 76.3%, 65.1%, 64%, 60.2%, and 31.2% identity with those of shearwater, chicken, duck, goose, and human IFN-λ, respectively. Notably, recombinant piIFN-λ, expressed in a prokaryotic system, exhibited dose‑dependent antiviral activity against both vesicular stomatitis virus (VSV) and H9N2 avian influenza virus (AIV). Mechanistically, luciferase reporter assays indicated that recombinant piIFN-λ activated the Mx and ISRE promoters and enhanced Mx, OAS and PKR mRNA expression in a dose‑dependent manner in DF-1 cells. These findings suggest that piIFN-λ may hold potential as a therapeutic agent for avian viral diseases.
other
2026-07-30 | Capless self-amplifying mRNA vaccine induces dose-sparing protective immunity against HPAI clade 2.3.4.4 H5 virus in mice.
Self-amplifying mRNA (samRNA) vaccines can induce potent immune responses at lower doses than conventional non-replicating mRNA vaccines; however, large RNA size and manufacturing considerations associated with 5' capping remain important challenges. Here, we developed a capless samRNA (CLsamRNA) vaccine platform derived from a Coxsackievirus B5 replicon that uses internal ribosome entry site-mediated cap-independent translation. Systematic optimization of key genetic elements enhanced antigen expression from the CLsamRNA backbone. Using reporter RNAs, LNP-formulated CLsamRNA showed rapid early expression and RNA amplification, with expression kinetics distinct from VEEV-based saRNA and nucleoside-modified mRNA comparators. When encoding the hemagglutinin antigen of highly pathogenic avian influenza clade 2.3.4.4 H5 viruses, CLsamRNA induced potent immune responses after LNP formulation. In mouse models, CLsamRNA induced potent neutralizing antibody responses, cross-reactive activity against clade 2.3.4.4b H5N1 virus, Th1-skewed humoral immunity, and strong antigen-specific cellular immune responses. CLsamRNA also elicited platform-specific early inflammatory and lymph node immune gene signatures associated with antigen presentation, costimulation, and cellular immune priming. Notably, a minimal 0.01-μg dose of CLsamRNA conferred complete protection against lethal H5N8 influenza virus challenge in BALB/c mice. These findings support CLsamRNA as a distinct cap-independent RNA vaccine platform with dose-sparing protective efficacy against highly pathogenic avian influenza H5 viruses.
2026-07-17 | Characterization of bovine-derived H5N1 viruses expressing fluorescent and luminescent reporter proteins.
Highly pathogenic avian influenza H5N1 clade 2.3.4.4b viruses present a broad host range, with recent spillover and sustained transmission in dairy cattle reported in the USA. Replication-competent reporter viruses are critical tools that enable real-time monitoring of virus replication, facilitating high-throughput screens. In this study, we engineered three recombinant H5N1 clade 2.3.4.4b reporter viruses expressing nanoluciferase (NLuc) and two fluorescent reporter proteins, miniGFP2 and UnaG within the open reading frame of the nonstructural gene of the bovine A/Cattle/Texas/063224-24-1/2024 (TX2/24) virus. All reporter viruses replicated efficiently in vitro, presenting replication kinetics comparable to the parental rTX2/24 virus, but exhibited smaller plaque sizes, suggesting reduced cell-to-cell spread. In vivo infection studies in mice showed comparable pathogenicity among all four viruses, although rTX2/24-miniGFP2 and rTX2/24-UnaG exhibited decreased virus shedding relative to rTX2/24 and rTX2/24-NLuc. Virus titrations and in situ localization of virus replication sites demonstrated robust replication in respiratory tissues, with slightly attenuated systemic dissemination of all three reporter viruses. Fluorescent virus neutralization assays using miniGFP2 and UnaG reporter viruses accurately quantified neutralizing antibody titres in sera from naturally infected dairy cattle, consistent with wild-type virus assays. Additionally, the utility of the NLuc reporter virus for antiviral screening was validated against oseltamivir in vitro. Collectively, these results establish the H5N1 TX2/24-based reporter viruses as versatile and biologically relevant tools for investigating H5N1 pathogenesis and for use in serological and antiviral drug screens.
2026-07-09 | Characterization of oseltamivir-resistant A(H5N1) clade 2.3.4.4b, genotype D1.1 variants identified in poultry farms of British Columbia, Canada.
Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b, genotype D1.1, are responsible for widespread outbreaks in poultry and continue to cause sporadic, sometimes severe, human infections. Herein, we characterized a wild-type (WT) influenza A(H5N1) D1.1 isolate (BC-H5N1-WT) and its H275Y neuraminidase (NA) variant (BC-H5N1-H275Y), both of which emerged on farms in British Columbia, Canada, during the fall 2024 outbreak. In vitro analysis assessed replication kinetics in MDCK cells, with supernatants collected at different days post-infection (p.i.) and titrated by TCID50 and qRT-PCR. Neuraminidase inhibitor (NAI) susceptibility was determined by NA inhibition assays, whereas susceptibility to baloxavir acid (BXA) was evaluated by plaque reduction assay. In vivo virulence was evaluated in BALB/c mice infected with serial 10-fold dilutions of each virus to monitor weight loss and mortality. Viral titers in lungs, brain, nose, kidney, spleen, and heart were quantified at day 4 p.i. The BC-H5N1-WT virus was susceptible to the four antivirals tested, whereas BC-H5N1-H275Y displayed resistance to oseltamivir and peramivir but remained susceptible to zanamivir and BXA. The BC-H5N1-WT exhibited significantly higher viral replication titers than BC-H5N1-H275Y at all tested time points and showed larger plaque sizes. In mice, BC-H5N1-WT was more virulent with LD50 values of 1.78 × 103 PFUs compared to 8.71 × 104 PFUs for BC-H5N1-H275Y, and produced higher viral titers in lungs and other organs. Despite the reduced fitness of the resistant H5N1 D1.1 variant, its emergence in the absence of viral selection pressure underscores the need for continued surveillance.
2026-06-26 | Deciphering interferon functions in avian influenza using receptor knockout models in the natural host.
The rapid cross-species transmission of highly pathogenic avian influenza presents a significant zoonotic threat. Elucidating the avian interferon (IFN) system, the primary antiviral defense in chickens, is critical for controlling the virus at its source and preventing its spillover into humans and other species. We engineered type I (IFN-α/β) and type III (IFN-λ) IFN receptor knockout chickens to dissect the role of IFNs in viral infections. Results revealed that type I IFN predominantly modulates innate immune cell populations, T cell subsets, and their contribution to antibody production following immunization under physiological conditions. In ovo and in vivo challenge experiments utilizing diverse influenza A virus strains demonstrated strain-specific roles of both IFN-α/β and IFN-λ in orchestrating viral pathogenesis, immunological responses, and tissue-tropism effects. Notably, type I IFN was particularly crucial in the initial defense mechanisms against H3N1 avian influenza A virus infection. These novel models offer unprecedented insights into avian IFN biology within the context of avian influenza, which is essential for developing more effective strategies to prevent and control this public health challenge.
2026-06-25 | HA thermostability mutations S84F, G167N, and D168N potentiate H9N2 virus transmission in a warming environment.
Avian influenza A (H9N2) viruses are widespread in poultry and occasionally infect mammals, contributing genes to other emerging strains. The factors that allow these viruses to withstand higher temperatures are not well understood. In this study, we used high-temperature selection and deep mutational scanning of a saturated H9N2 hemagglutinin (HA) mutant library. We identified three HA mutations, S84F, G167N, and D168N, that increase viral thermostability. Viruses with these mutations survived better at elevated temperatures. In transmission experiments with chickens, the S84F mutation allowed waterborne spread at a temperature that blocked transmission of the wild-type virus. The combination of all three mutations was associated with evidence of airborne transmission in one of two experimental replicates. These results link HA thermostability to environmental persistence and transmission potential under thermal stress, which may affect the ecology of H9N2 viruses.
antibodies
2026-08-14 | Skuas as sentinels of high pathogenicity avian influenza H5N1 on the Antarctic Peninsula in the 2024/2025 austral summer.
Despite Antarctica's geographic isolation, the first incursion of high pathogenicity avian influenza (HPAI) H5N1 was detected in the 2023/2024 austral summer. Surveillance for HPAI H5N1 in Antarctica remains patchy due to logistical, financial and infrastructure challenges, with many suspected cases remaining unconfirmed and few viral genome sequences available to date. Through the 2024/2025 austral summer, we undertook five sampling expeditions to the South Shetland Islands and Antarctic Peninsula facilitated by cruise ships/operators. Across more than 500 faecal environmental samples collected from apparently healthy penguins and marine mammals, we found no detectable evidence of HPAI H5N1. However, HPAI H5N1 was detected in all but one of the skua carcasses sampled, which, in most cases, were found within metres of penguin sub-colonies. All HPAI H5N1 viral genome sequences from skuas on the Antarctic Peninsula fell within a single lineage, which included those genomes from skuas sampled in the 2024/2025 season from the South Shetland Islands. Genomes were in a different clade to those from the Antarctic Peninsula collected in the 2023/2024 austral summer. Our results confirm that although the prevalence may be low, HPAI H5N1 is recurring in Antarctica, emphasizing the need for ongoing surveillance to monitor and mitigate threats to wildlife, even in the planet's most isolated regions.
2026-08-12 | Epidemiological and clinical characterization of human infections with H9N2 avian influenza virus in Changsha city, China, 2015-2025.
H9N2 avian influenza virus poses a persistent public health concern due to its zoonotic potential. This study investigated the epidemiological and clinical characteristics of human H9N2 avian influenza infection in Changsha City, along with related environmental surveillance data, to provide a scientific basis for disease prevention and control. From January 2015 to December 2025, a total of 11 human H9N2 avian influenza cases were collected from historical surveillance data of the Changsha CDC in Changsha City. Cases occurred sporadically throughout the year; most (90.91%, 10/11) were mild, one severe case was co-infected with two types of respiratory pathogens, and the majority (72.73%, 8/11) were children under 5 years old. Among the 10 cases with available exposure history, 70.00% had been exposed to live poultry or LPMs, with the H9 and N2 subtypes detected in related environmental samples at rates of about 76%. Genetic analysis showed that the H9N2 viruses from human cases were highly homologous to H9N2 viruses found in the live poultry environment in Changsha City, while also exhibiting diverse mutations in key functional sites and domains. Environmental samples from large live poultry markets exhibited a significant year-on-year increase in positive rate (χ2=111.30, P<0.001), resulting in a substantially higher average rate in 2020-2024 versus 2014-2019 (77.11% vs. 47.43%; χ2=158.24, P<0.001). In conclusion, sporadic human H9N2 infections, predominantly affecting children, were mostly associated with live poultry exposure, with no evidence of human-to-human spread, while environmental data revealed a sharply increasing contamination trend in markets, pointing to a heightened risk.
2026-08-07 | Genetic characterization and zoonotic potential of G1-Lineage H9N2 avian influenza viruses isolated from poultry in Pakistan, 2023.
The H9N2 subtype of avian influenza A virus has been endemic in poultry populations across Asia and the Middle East, posing ongoing economic and public health concerns. Since their initial detection in Pakistan in the 1990s, H9N2 viruses have caused repeated outbreaks in commercial poultry, leading to substantial economic losses and raising concerns about zoonotic transmission. To characterize the recent genetic evolution and zoonotic potential of circulating strains, five H9N2 isolates were obtained from poultry in Pakistan between January and March 2023. Phylogenetic analysis of the haemagglutinin gene revealed that all five isolates belong to the G5.3.2, formerly known as B2, sub-lineage of the G1 Eurasian lineage, in accordance with the revised global classification system for H9 viruses. Comparative genomic analysis confirmed that all eight gene segments were closely related to previously reported Pakistani strains, with no evidence of recent reassortment, suggesting localized persistence and ongoing genetic drift. Notably, several mammalian-adaptive mutations were identified in internal gene segments of the isolates, suggesting a potential risk of cross-species transmission. In addition, all five isolates exhibited dual receptor-binding characteristics, recognizing both α2,3-linked (avian-type) and α2,6-linked (human-type) sialic acid glycans, with a stronger affinity for α2,6-linked glycans. These findings underscore the need for continuous surveillance and risk assessment of H9N2 viruses circulating in Pakistan.
2026-08-06 | Neutralizing and protective monoclonal antibodies identify antigenic sites in influenza H7 hemagglutinin and select for amino acid substitutions rarely observed at the global level.
Avian influenza viruses of the H7 subtype infect a variety of avian as well as mammalian species, and a better understanding of H7 virus antigenicity and immunogenicity is vital to the development of effective countermeasures for a potential H7 pandemic threat. We have developed a diverse panel of murine monoclonal antibodies (mAbs) to the H7 hemagglutinin (HA) and characterized these mAbs for the HA epitope(s) that they bind, their neutralizing activity in vitro against several strains of H7, and their ability to provide protection against virus challenge in vivo. The majority of the isolated mAbs recognized antigenic sites A and B on the globular head of the influenza HA, but mAbs were also isolated to non-canonical sites on HA. Escape viruses generated against the mAbs were used to further define the antigenic sites on the H7 HA, and notably, we find that most amino acid substitutions identified in these escape viruses are rare at the global level. Finally, we used a polyclonal antibody generated by virus infection to assess whether antibody binding and neutralization were impacted by individual amino acid substitutions in the HA of escape viruses generated by the mAbs. The results showed that all of the escape viruses, each of which carried a single amino acid substitution, were still effectively neutralized by polyclonal antibodies, suggesting that the antibody response to H7 infection was broad and redundant.IMPORTANCEInfluenza H7 viruses infect a variety of avian and mammalian species, and present a potential threat to human health. We used a panel of murine monoclonal antibodies (mAbs) to facilitate the identification of important protective epitopes on the H7 hemagglutinin (HA). While most of the antibodies bind to antigenic sites A and B on the H7 HA that correspond to well-characterized cognate sites on influenza H3, some antibodies appear to recognize new epitopes in HA distinct from those known antigenic sites. We also identified amino acid substitutions in escape viruses selected by these mAbs and evaluated their impact in the context of polyclonal responses and natural H7 virus evolution over a >60-year period. Taken together, the results add to our understanding of influenza H7 virus antigenicity and immunogenicity, and may have positive implications for successful H7 vaccine development.
2026-08-04 | Subclass switching enhances protective efficacy of a non-neutralizing H7N9 avian influenza antibody.
Non-neutralizing antibodies contribute to protection against the H7N9 subtype avian influenza virus through Fc effector functions. Antibody subclass plays a critical role in determining binding affinity to Fc receptors (FcR) and downstream Fc effector functions. In this study, to assess whether antibody subclass switching can enhance antibody protective efficacy, subclass of a non-neutralizing monoclonal antibody (mAb) against the hemagglutinin of H7N9 virus was switched from IgG1 to IgG2a, and their activity and protective efficacy were assessed. Subclass switching caused no significant changes in antigen binding, hemagglutination-inhibition and virus neutralizing activities of the antibody. The hybridoma-derived mAb conferred no protection against H7N9 virus infection. Interestingly, both IgG2a and IgG1 antibodies produced in CHO cells provided full protection against mortality caused by a sublethal H7N9 virus challenge. Upon lethal challenge, IgG2a antibody conferred 70% protection, whereas its IgG1 counterpart only provided 30% protection. However, both antibodies did not decrease virus loads in mouse lungs. Moreover, compared to the IgG1 antibody, affinity of the subclass-switched IgG2a antibody to FcR was significantly increased, as evidenced by enhanced binding of the antibody to recombinant murine FcγRI and to FcRs on murine macrophages. Our findings highlighted a benefit of subclass-engineering to antibody modification and development of therapeutic antibodies.
small molecules
2026-07-26 | Synergistic control of viral persistence via wettability and ion release on antiviral coatings.
Antiviral coating design remains largely empirical due to the lack of quantitative principles linking interfacial properties to viral persistence under realistic conditions. Here, we establish a survival time-based evaluation framework that captures the drying dynamics of 2-μL virus-containing microdroplets and enables quantitative assessment of antiviral coating performance using viral survival time (duration of infectivity) and survival time reduction rate. Using this framework, we identify surface virus density, defined as infectious virus per unit distribution area, as a physical determinant governing viral persistence. When surface virus density was matched, viral survival times converged irrespective of inoculum level or droplet geometry. Accordingly, viral survival time decreased with decreasing surface virus density, and hydrophilic surface design alone reduced viral survival time by approximately 70-80%. Furthermore, we demonstrate that the initial release rate of antiviral metal ions constitutes a complementary chemical control parameter under rapid-drying conditions. Antiviral coatings incorporating amorphous vanadate glass particles enabled rapid release of copper or silver ions within the first 1-5 min following droplet deposition. By integrating wettability-mediated viral redistribution with rapid ion release, synergistic suppression of viral persistence was achieved, reducing viral survival time relative to uncoated surfaces by up to 97.6% for influenza virus, 98.2% for feline calicivirus, and 94.9% for highly pathogenic avian influenza virus. These findings demonstrate that viral persistence can be predictively controlled through the combined physical regulation of surface virus density and chemical inactivation by rapidly released antiviral agents. This antiviral coating strategy may contribute to reducing contact transmission risks in healthcare, agricultural, and community environments.
2026-07-23 | Antiviral and immunomodulatory effects of Siji antiviral mixture against H9N2 avian influenza virus infection in chickens.
The H9N2 subtype avian influenza virus (AIV) is common in poultry and poses significant risks to both the poultry industry and public health. Current control strategies for H9N2 AIV predominantly rely on vaccination; however, these approaches are often undermined by the continuous antigenic drift of hemagglutinin under the pressure of antibodies. This study evaluated the antiviral efficacy of Siji Antiviral Mixture (SAM) against H9N2 infection in specific pathogen-free chickens. Compared with the infected control group, SAM significantly reduced viral loads in multiple tissues, including liver, spleen, lung, kidney, brain, and trachea, demonstrating its direct antiviral activity. Further analysis revealed that SAM modulated H9N2-induced inflammation by downregulating excessive innate immune responses. Specifically, SAM significantly enhanced the expression of antiviral effectors (OASL and MX-1) in the lungs during the early stages of viral infection, while attenuating the production of inflammatory cytokines (IL-6, IL-10) in the later stages. Additionally, SAM regulated the expression levels of pattern recognition receptors (MDA5, TLR3, and TLR7), thereby preventing excessive immune responses. These findings indicate that SAM possesses both antiviral and immunoregulatory effects, highlighting its potential as an effective anti-AIV agent for the management of H9N2 AIV infection.
2026-07-23 | Oseltamivir Resistance in Human Influenza A(H5N1) and A(H7N9) Infections: A Mini Review.
Avian influenza viruses (AIVs) have been reported to cause infections in humans following avian-to-human transmission, resulting in a range of clinical outcomes. A(H5N1) and A(H7N9) infections, which constitute the majority of human AIV cases, are responsible for severe infections leading to high mortality. The neuraminidase inhibitor oseltamivir is expected to play a major role for the control of AIV infections in humans. However, the emergence of resistance may compromise the impact of antiviral therapy. The objective of this article is to review human cases of A(H5N1) and A(H7N9) infections for which mutations of oseltamivir resistance were detected. Neuraminidase mutations rapidly occurred in a subtype-specific manner, with H274Y and N294S substitutions predominating in A(H5N1) cases and the R292K substitution in A(H7N9) cases. Serious clinical outcomes and mortality were seen in most A(H5N1) and A(H7N9) cases despite oseltamivir therapy, thus highlighting the need for improving antiviral strategies against these AIVs.
2026-07-10 | Preclinical characterization of HEC116094, an oral inhibitor of the influenza A virus polymerase PB2 subunit.
Influenza A virus remains a global health threat due to its high mutation rate and its resistance to existing neuraminidase and polymerase inhibitors. The polymerase basic protein 2 (PB2) subunit is a promising target for novel therapeutics due to its critical role in inhibiting viral transcription and replication. Here, we reported the preclinical characterization of HEC116094, a novel PB2 inhibitor, against influenza A virus. HEC116094 exhibited potent in vitro activities against multiple laboratory strains (IC50: 0.012-0.069 nM) and the highly pathogenic avian influenza strains H5N1 and H7N9 (IC50: 0.071-0.122 nM). These activities are more potent than VX-787 (Pimodivir) and oseltamivir. Our studies demonstrated that HEC116094 treatment could reduce the extent of weight loss and maintain a 100% survival rate in BALB/c mice, even when initiated 72 h post-infection. In addition, HEC116094 exerted potent in vitro synergy and in vivo therapeutic benefits when combined with oseltamivir. Furthermore, HEC116094 displayed minimal kinase inhibition and excellent PK characteristics. Superior preclinical activity demonstrated that HEC116094 was a more potent PB2 inhibitor against influenza A virus than VX-787 in this study. Currently, HEC116094 is under evaluation in Phase I clinical studies.
2026-07-10 | Optimizing an avian influenza vaccine using a novel Bacterial Enzymatic Combinatorial Chemistry (BECC) TLR4 adjuvant.
The development of broadly protective and dose-sparing influenza vaccines remains a critical challenge, particularly for zoonotic H5N1 strains with pandemic potential. This study evaluates BECC470s, a synthetic TLR4 adjuvant, for its ability to enhance the immunogenicity and protective efficacy of recombinant H5 hemagglutinin (rHA) vaccination in murine models. BECC470s-adjuvanted rHA elicited robust IgG1/IgG2a antibody responses and complete survival following homologous 2004 H5N1 challenge in a prime-boost model. Although BECC470s broadened antibody binding to both variable HA head and conserved stalk domains by ELISA, functional neutralizing antibody responses were restricted to the matched 2004 H5N1 isolate, with no detectable neutralization of H5N1 viruses isolated in 2022 or 2024. These data indicate that BECC470s enhances the magnitude and apparent cross-reactivity of binding antibody responses while maintaining strain-specific neutralizing activity, supporting its potential as an adjuvant for next-generation influenza vaccines while underscoring the need for further optimization to achieve true cross-neutralizing protection.IMPORTANCEBECC470s is a synthetic TLR4 agonist adjuvant that enhances the breadth and potency of recombinant H5 hemagglutinin vaccination in mice. By driving balanced antibody responses, complete protection against homologous challenge, and neutralizing activity targeting both HA head and stalk, BECC470s outperforms the comparator TLR4 adjuvant. These preliminary findings indicate that BECC470s enables antigen sparing while increasing antigen immunogenicity, supporting its potential translational application to current H5N1 vaccines.
vaccines
2026-08-17 | A novel candidate vaccine virus derived from Japan's first mammalian case of clade 2.3.4.4b A/H5N1 highly pathogenic avian influenza virus.
The development of candidate vaccine viruses (CVVs) for pre-pandemic preparedness requires attenuation of pathogenicity while maintaining immunogenicity. In this study, we developed and characterized NIID-002, a reassortant virus derived from A/Ezo red fox/Hokkaido/1/2022 (H5N1; clade 2.3.4.4b), to evaluate its suitability as a candidate vaccine. NIID-002 exhibited markedly reduced pathogenicity compared with its parental strain, while retaining broad antigenic reactivity and protein yield comparable to other clade 2.3.4.4b CVVs. In mammalian models, NIID-002 demonstrated strong attenuation, causing no lethal infection in mice and only minimal weight loss with limited viral replication in ferrets. Antisera raised against NIID-002 reacted broadly with recent wild-type H5N1 isolates, suggesting potential broad protection. Protein yield analysis confirmed a production efficiency comparable to that of other CVVs within the same clade, supporting its feasibility for large-scale vaccine manufacturing. Overall, NIID-002 fulfills the key requirements for the pandemic preparedness of CVV, combining reduced pathogenicity, broad antigenic reactivity, and adequate production efficiency. These findings highlight its potential as a candidate H5N1 vaccine and underscore the continued need for surveillance and refinement of influenza vaccine strategies to address evolving viral threats.
2026-08-14 | Impact of prior low-pathogenicity avian influenza H7N7 exposure on susceptibility and protection against homologous high-pathogenicity avian influenza H7N7 challenge in chickens.
Circumstances driving the transition from low-pathogenicity to high-pathogenicity avian influenza viruses (LPAIVs to HPAIVs) remain poorly understood. In July 2015, a UK layer outbreak revealed circulation of an H7N7 LPAIV (H7N7-LP), which subsequently mutated into a high-pathogenicity H7N7 virus (H7N7-HP) at the same farm. The emergent H7N7-HP caused high mortality, though prior H7N7-LP exposure provided partial protection in some chickens. We experimentally assessed the protective effect of prior H7N7-LP exposure upon subsequent H7N7-HP challenge. In the absence of an isolated H7N7-LP direct-precursor to this H7N7-HP outbreak strain, eight chickens were directly-inoculated with an H7N7-LP which was closely genetically related to the outbreak H7N7-HP. At 1-day post-infection (dpi), eight naïve contact chickens were introduced to assess H7N7-LP transmission. All (100%) directly inoculated chickens became H7N7-LP infected, whereas only 3/8 contacts (37.5%) acquired infection. At 14 dpi, these 16 chickens, together with eight immunologically naïve controls, were challenged with H7N7-HP. Among the naïve controls and the previously H7N7-LP contact-exposed chickens, all 16 (100%) shed H7N7-HP, with 62.5% and 50% mortality, respectively. In contrast, none of the chickens previously directly-inoculated with H7N7-LP subsequently shed H7N7-HP, where all remained healthy and survived. Therefore, direct H7N7-LP inoculation induced effective immunity against antigenically related H7N7-HP. However, the more limited H7N7-LP infection acquired via contact exposure resulted in all shedding H7N7-HP, with reduced clinical protection. This sequential infection model highlighted how the route and timing of initial LPAIV exposure, along with acquired immunity, differed in influencing susceptibility to an emergent HPAIV, reflecting outcomes observed during layer outbreaks.
2026-08-11 | Protective effect of A(H5N8) stockpiled vaccine against a virus genetically identical to a human isolate of bovine A(H5N1) influenza virus.
Since early 2024, highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b have caused extensive outbreaks in dairy cattle in the United States, with spillover into mammalian species, including humans. A bovine-derived A(H5N1) virus isolated from a human case retains high pathogenicity and transmissibility in mammalian models, highlighting its pandemic potential. Stockpiled pre-pandemic influenza vaccines are intended to provide early protection before strain-matched vaccines are available; however, their protective efficacy against bovine A(H5N1) viruses has not been directly evaluated in vivo. In this study, we assessed the protective efficacy of an AS03-adjuvanted A/Astrakhan/3212/2020 (H5N8) clade 2.3.4.4b-based influenza vaccine stockpiled in Japan using mouse and ferret models. Vaccinated and unvaccinated animals were challenged with a virus genetically identical to a human isolate of bovine A(H5N1) virus. Neutralising antibody responses, viral replication in organs, and survival were evaluated. Vaccination with the AS03-adjuvanted A(H5N8)-based stockpiled vaccine induced robust neutralising antibody responses in both animal models, significantly suppressed viral replication, and conferred complete protection against lethal challenge. In contrast, all unvaccinated mice and ferrets succumbed to infection. These findings demonstrate that the AS03-adjuvanted A(H5N8)-based stockpiled vaccine provides strong cross-protective efficacy against bovine A(H5N1) viruses. An AS03-adjuvanted A(H5N8)-based vaccine stockpiled in Japan could serve as an immediate countermeasure against bovine A(H5N1) viruses during the early phase of a pandemic. This work was supported by grants from the Japan Program for Infectious Diseases Research and Infrastructure (JP20wm0125002) and the Japan Initiative for World-leading Vaccine Research and Development Centers (JP223fa627001) from the Japan Agency for Medical Research and Development.
2026-08-05 | Heterologous prime-boost vaccination against H5 avian influenza: Safety and immunogenicity of a MF59-adjuvanted, cell-culture derived H5N6 vaccine.
With increasing H5 avian influenza cases reported globally and the potential for pandemic emergence, induction of cross-reactive antibody responses may represent an important attribute of an effective vaccine. This phase 2 extension study evaluated immunogenicity and safety of MF59-adjuvanted, cell culture-derived H5N6 vaccine (aH5N6c) in adults primed with MF59-adjuvanted, cell culture-derived H5N1 vaccine (aH5N1c) and in unprimed adults. Adults previously primed with two doses of aH5N1c in the parent study V89_18 were randomized to receive two aH5N6c doses (Group 1) or one aH5N6c and one placebo (Group 2) 3 weeks apart. Unprimed adults received two aH5N6c doses (Group 3). Immunogenicity was assessed by hemagglutination inhibition (HI) and microneutralization (MN) assays against the priming (H5N1) and booster (H5N6) strains on Days 1, 8, 22, 43, and 202. Among 258 exposed participants, primed subjects (Groups 1 and 2) showed higher HI geometric mean titers against both strains than unprimed (Group 3) subjects, with MN responses similarly enhanced. Heterologous H5N1 responses were robust in primed subjects (Day 43 HI GMTs: 333-343; seroconversion rates >89%) but minimal in unprimed subjects, with responses persisting to Day 202. Solicited adverse events were mild or moderate, comparable between groups, and consistent with other MF59-adjuvanted pandemic vaccines; no vaccine-related serious adverse events occurred. Heterologous H5N6 booster vaccination in H5N1-primed adults elicited strong cross-reactive immunity against the priming strain, demonstrating long-lasting immune memory for at least 6 y and supporting heterologous prime-boost strategies for pandemic preparedness against emerging H5 outbreaks.
2026-08-03 | A bivalent inactivated influenza vaccine incorporating epitope-optimized surface proteins confers cross-protective immunity against H9N2 influenza virus.
AbstractThe H9N2 avian influenza virus (AIV) has caused substantial economic losses to the global poultry industry and poses a zoonotic threat to humans. Vaccination constitutes a pivotal strategy for the prevention and control of H9N2 AIVs. However, the ongoing antigenic evolution of the virus poses a persistent challenge to the protective efficacy of existing vaccines. Therefore, the development of a broadly protective H9N2 influenza vaccine capable of eliciting cross-reactive immune responses is crucial for mitigating both the disease burden and the risk of pandemics. Here, we developed a bivalent chimeric inactivated vaccine, designated cHANA, by combining two individually rescued chimeric inactivated viruses, cHANA1 and cHANA2. Each recombinant virus carries one set of Epigraph-designed HA and NA immunogens, and the two sets were computationally optimized from global H9N2 HA and NA sequence datasets to complement each other in epitope coverage across the H9N2 viral population. Compared to the WHO-recommended candidate vaccine virus (CVV), AL/39, cHANA elicited more potent cross-reactive antibody responses and T cell immunity in mice. Furthermore, it elicited effective cross-protection against lethal challenge with heterologous H9N2 virus and significantly reduced pulmonary viral loads of mice. By conferring broad protective immunity, this vaccine represents a promising universal candidate for controlling H9N2 outbreaks.
proteins
2026-08-13 | Identification and characterization of PB2 mutations associated with mammalian adaptation of highly pathogenic H5N1 avian influenza viruses.
The highly pathogenic avian influenza virus (HPAIV) subtype H5N1 has been continuously circulating among wild bird populations and domestic poultry. It's ongoing circulation has led to outbreaks in poultry and U.S. dairy cattle populations, as well as sporadic severe infections in individuals engaged in poultry and dairy farming. These occurrences have raised concerns about the potential evolution of this virus into a pandemic strain. To elucidate the molecular determinants facilitating H5N1 cross-species adaptation and to evaluate its implications for public health, we conducted serials of sequence analysis and specific-site mutations on the viral polymerase subunit PB2 to determine its effect on polymerase activity and viral infectivity. The results showed that three mutations in the PB2 protein (E362G, D441N and M631L) were presented cooperative effects associated with enhanced viral replication in mammalian cells. Compared to the original isolated strain of the 2.3.4.4b clade, A/chicken/NL/FAV-0033/2021, these three mutations were predominantly identified in isolates obtained from cattle and other mammalian hosts between 2021 and 2024. The M631L mutation, identified as the primary determinant of increased polymerase activity in mammalian cells, significantly enhanced the binding affinity of PB2 to ANP32A. The mutation E362G and D441N did not increased polymerase activity and viral replication significantly but enhanced binding affinity of PB2 to ANP32A. The combined mutations with E362G, D441N and M631L resulted in a significantly increased polymerase activity and viral replication in H5N1 virus, and significantly elevated viral loads and aggravated pulmonary pathology in lungs of mice with H5N1 infection. These findings indicate that the PB2-M631L mutation constitutes a crucial molecular marker for the adaptation of H5N1 to mammalian hosts, whereas the E362G and D441N mutations likely function as supportive modulatory factors that optimize this host-adaptation process.
2026-08-11 | Identification and functional characterization of a novel antiviral chicken interferon-υ.
Interferons are critical mediators of antiviral immunity in vertebrates. While type IV interferon (IFN-υ) has been identified in fish and amphibians, its existence and function in chickens remained unknown. Through systematic genomic screening, we identified and cloned a novel chicken interferon gene, designated ChIFN-υ. Phylogenetic analysis placed ChIFN-υ within a distinct clade alongside zebrafish and clawed frog IFN-υ, confirming its identity as a type IV interferon, with minimal homology to classical type I, II, or III IFNs. Expression profiling revealed constitutive ChIFN-υ expression in mucosal and immune tissues of healthy chickens, exhibiting a distinct developmental shift: highest in trachea and small intestine in 1-day-old chicks, shifting to spleen and lung in 4-week-old chickens. ChIFN-υ expression was strongly upregulated following H9N2 AIV infection. Functionally, recombinant ChIFN-υ protein activated the interferon-stimulated response element (ISRE) and Mx promoter in a dose-dependent manner and significantly inhibited the replication of both vesicular stomatitis virus (VSV) and H9N2 AIV in DF-1 cells. In vivo, early treatment with exogenous ChIFN-υ significantly reduced pulmonary and tracheal viral loads and decreased oropharyngeal and cloacal virus shedding in H9N2-infected chickens. In conclusion, this study identifies and functionally characterizes the type IV interferon in chickens, elucidating the evolutionary status, regulated expression, and antiviral efficacy of ChIFN-υ. These findings highlight its potential as a candidate for developing interferon-based therapies against avian viral diseases.
2026-06-26 | Avian Foxp3 acts as a switch for IL-10 by directly binding the T3G motif: revealing a novel epigenetic modulation paradigm.
Foxp3 is the master transcription factor for regulatory T (Treg) cell differentiation and function, essential for immune homeostasis and tolerance. While its role is well-characterized in mammals, its functional mechanisms in avian species remain poorly understood. We conducted comparative genomic and functional analyses of chicken Foxp3 (chFoxp3). DNA-binding specificity was determined using motif analysis and genome-wide scanning. An H9N2 avian influenza challenge model was used to assess Foxp3 expression dynamics and CD4⁺CD25⁺ T cell frequency in vivo. The transcriptional regulation of IL-10 by chFoxp3 was investigated through promoter binding and transactivation assays, with key domains mapped via mutagenesis. Avian Foxp3 has evolved independently from its mammalian ortholog. Unlike human Foxp3, which binds the FKHM motif, chFoxp3 specifically recognizes a T3G microsatellite motif. Genome-wide scanning identified potential targets enriched in the FoxO signaling pathway, including IL-10. In an H9N2 infection model, Foxp3 expression and CD4⁺CD25⁺ T cell frequency exhibited biphasic dynamics. Mechanistically, chFoxp3, but not human FoxP3, directly binds the T3G motif in the IL-10 promoter to activate transcription. This transactivation function critically depends on the HNT linker within its Fork-head domain. Our study reveals a novel mode of transcriptional regulation by chFoxp3 via T3G motif recognition, underscoring its functional diversification during evolution. These findings provide a foundation for understanding immune regulation in birds under both physiological and pathological conditions, such as avian influenza infection.
2026-06-17 | The N-terminal region of pdm09/H1N1 PA synergizes with its cognate NP to enhance mammalian adaptation of avian-origin H9N2 canine influenza virus.
The PA gene of the 2009 pandemic H1N1 (pdm09/H1N1) lineage is derived from avian influenza virus (AIV). Together with other polymerase subunits, it enhances the adaptation of avian-origin influenza virus to mammals. However, the functional region of the PA protein remains unclear. Using reverse genetics, we mapped functional domains of pdm09/H1N1 PA in an avian-origin H9N2 canine influenza virus (CIV) background. The N-terminal 169-252 region conferred high intrinsic polymerase activity yet failed to support efficient viral replication alone, revealing a dissociation between catalytic potential and replicative fitness. In contrast, the 85-168 region enabled robust replication despite lower activity. Importantly, synergy between the 169-252 region and its cognate pdm09/H1N1 NP drove high polymerase activity and replication. This pairing also enhanced viral growth in vitro, increased viral titers in mouse lungs and nasal turbinate, and induced pulmonary damage. Mechanistically, the 169-252 region interacts with NP, accelerating nuclear import and cRNA synthesis, thereby optimizing viral RNA replication timing. Thus, PA-NP co-evolution is a key driver of mammalian adaptation, moving beyond single mutations and highlighting internal gene compatibility as a determinant of viral fitness and pandemic potential.
2026-06-17 | Molecular cloning and antiviral function analysis of pigeon interferon lambda(piIFN-λ).
Type III interferons (IFN-λ) are critical components of the interferon system, serving as key antiviral cytokines in the innate immune response of epithelial cells. However, the biological role of pigeon IFN-λ (piIFN-λ) remains poorly understood. In this study, we cloned and characterized the biological effects of piIFN-λ. Our results reveal that the open reading frame (ORF) of piIFN-λ is 561 base pairs long, encoding a protein consisting of 186 amino acids. The amino acid sequence of piIFN-λ shares 76.3%, 65.1%, 64%, 60.2%, and 31.2% identity with those of shearwater, chicken, duck, goose, and human IFN-λ, respectively. Notably, recombinant piIFN-λ, expressed in a prokaryotic system, exhibited dose‑dependent antiviral activity against both vesicular stomatitis virus (VSV) and H9N2 avian influenza virus (AIV). Mechanistically, luciferase reporter assays indicated that recombinant piIFN-λ activated the Mx and ISRE promoters and enhanced Mx, OAS and PKR mRNA expression in a dose‑dependent manner in DF-1 cells. These findings suggest that piIFN-λ may hold potential as a therapeutic agent for avian viral diseases.
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2026-07-30 | Capless self-amplifying mRNA vaccine induces dose-sparing protective immunity against HPAI clade 2.3.4.4 H5 virus in mice.
Self-amplifying mRNA (samRNA) vaccines can induce potent immune responses at lower doses than conventional non-replicating mRNA vaccines; however, large RNA size and manufacturing considerations associated with 5' capping remain important challenges. Here, we developed a capless samRNA (CLsamRNA) vaccine platform derived from a Coxsackievirus B5 replicon that uses internal ribosome entry site-mediated cap-independent translation. Systematic optimization of key genetic elements enhanced antigen expression from the CLsamRNA backbone. Using reporter RNAs, LNP-formulated CLsamRNA showed rapid early expression and RNA amplification, with expression kinetics distinct from VEEV-based saRNA and nucleoside-modified mRNA comparators. When encoding the hemagglutinin antigen of highly pathogenic avian influenza clade 2.3.4.4 H5 viruses, CLsamRNA induced potent immune responses after LNP formulation. In mouse models, CLsamRNA induced potent neutralizing antibody responses, cross-reactive activity against clade 2.3.4.4b H5N1 virus, Th1-skewed humoral immunity, and strong antigen-specific cellular immune responses. CLsamRNA also elicited platform-specific early inflammatory and lymph node immune gene signatures associated with antigen presentation, costimulation, and cellular immune priming. Notably, a minimal 0.01-μg dose of CLsamRNA conferred complete protection against lethal H5N8 influenza virus challenge in BALB/c mice. These findings support CLsamRNA as a distinct cap-independent RNA vaccine platform with dose-sparing protective efficacy against highly pathogenic avian influenza H5 viruses.
2026-07-17 | Characterization of bovine-derived H5N1 viruses expressing fluorescent and luminescent reporter proteins.
Highly pathogenic avian influenza H5N1 clade 2.3.4.4b viruses present a broad host range, with recent spillover and sustained transmission in dairy cattle reported in the USA. Replication-competent reporter viruses are critical tools that enable real-time monitoring of virus replication, facilitating high-throughput screens. In this study, we engineered three recombinant H5N1 clade 2.3.4.4b reporter viruses expressing nanoluciferase (NLuc) and two fluorescent reporter proteins, miniGFP2 and UnaG within the open reading frame of the nonstructural gene of the bovine A/Cattle/Texas/063224-24-1/2024 (TX2/24) virus. All reporter viruses replicated efficiently in vitro, presenting replication kinetics comparable to the parental rTX2/24 virus, but exhibited smaller plaque sizes, suggesting reduced cell-to-cell spread. In vivo infection studies in mice showed comparable pathogenicity among all four viruses, although rTX2/24-miniGFP2 and rTX2/24-UnaG exhibited decreased virus shedding relative to rTX2/24 and rTX2/24-NLuc. Virus titrations and in situ localization of virus replication sites demonstrated robust replication in respiratory tissues, with slightly attenuated systemic dissemination of all three reporter viruses. Fluorescent virus neutralization assays using miniGFP2 and UnaG reporter viruses accurately quantified neutralizing antibody titres in sera from naturally infected dairy cattle, consistent with wild-type virus assays. Additionally, the utility of the NLuc reporter virus for antiviral screening was validated against oseltamivir in vitro. Collectively, these results establish the H5N1 TX2/24-based reporter viruses as versatile and biologically relevant tools for investigating H5N1 pathogenesis and for use in serological and antiviral drug screens.
2026-07-09 | Characterization of oseltamivir-resistant A(H5N1) clade 2.3.4.4b, genotype D1.1 variants identified in poultry farms of British Columbia, Canada.
Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b, genotype D1.1, are responsible for widespread outbreaks in poultry and continue to cause sporadic, sometimes severe, human infections. Herein, we characterized a wild-type (WT) influenza A(H5N1) D1.1 isolate (BC-H5N1-WT) and its H275Y neuraminidase (NA) variant (BC-H5N1-H275Y), both of which emerged on farms in British Columbia, Canada, during the fall 2024 outbreak. In vitro analysis assessed replication kinetics in MDCK cells, with supernatants collected at different days post-infection (p.i.) and titrated by TCID50 and qRT-PCR. Neuraminidase inhibitor (NAI) susceptibility was determined by NA inhibition assays, whereas susceptibility to baloxavir acid (BXA) was evaluated by plaque reduction assay. In vivo virulence was evaluated in BALB/c mice infected with serial 10-fold dilutions of each virus to monitor weight loss and mortality. Viral titers in lungs, brain, nose, kidney, spleen, and heart were quantified at day 4 p.i. The BC-H5N1-WT virus was susceptible to the four antivirals tested, whereas BC-H5N1-H275Y displayed resistance to oseltamivir and peramivir but remained susceptible to zanamivir and BXA. The BC-H5N1-WT exhibited significantly higher viral replication titers than BC-H5N1-H275Y at all tested time points and showed larger plaque sizes. In mice, BC-H5N1-WT was more virulent with LD50 values of 1.78 × 103 PFUs compared to 8.71 × 104 PFUs for BC-H5N1-H275Y, and produced higher viral titers in lungs and other organs. Despite the reduced fitness of the resistant H5N1 D1.1 variant, its emergence in the absence of viral selection pressure underscores the need for continued surveillance.
2026-06-26 | Deciphering interferon functions in avian influenza using receptor knockout models in the natural host.
The rapid cross-species transmission of highly pathogenic avian influenza presents a significant zoonotic threat. Elucidating the avian interferon (IFN) system, the primary antiviral defense in chickens, is critical for controlling the virus at its source and preventing its spillover into humans and other species. We engineered type I (IFN-α/β) and type III (IFN-λ) IFN receptor knockout chickens to dissect the role of IFNs in viral infections. Results revealed that type I IFN predominantly modulates innate immune cell populations, T cell subsets, and their contribution to antibody production following immunization under physiological conditions. In ovo and in vivo challenge experiments utilizing diverse influenza A virus strains demonstrated strain-specific roles of both IFN-α/β and IFN-λ in orchestrating viral pathogenesis, immunological responses, and tissue-tropism effects. Notably, type I IFN was particularly crucial in the initial defense mechanisms against H3N1 avian influenza A virus infection. These novel models offer unprecedented insights into avian IFN biology within the context of avian influenza, which is essential for developing more effective strategies to prevent and control this public health challenge.
2026-06-25 | HA thermostability mutations S84F, G167N, and D168N potentiate H9N2 virus transmission in a warming environment.
Avian influenza A (H9N2) viruses are widespread in poultry and occasionally infect mammals, contributing genes to other emerging strains. The factors that allow these viruses to withstand higher temperatures are not well understood. In this study, we used high-temperature selection and deep mutational scanning of a saturated H9N2 hemagglutinin (HA) mutant library. We identified three HA mutations, S84F, G167N, and D168N, that increase viral thermostability. Viruses with these mutations survived better at elevated temperatures. In transmission experiments with chickens, the S84F mutation allowed waterborne spread at a temperature that blocked transmission of the wild-type virus. The combination of all three mutations was associated with evidence of airborne transmission in one of two experimental replicates. These results link HA thermostability to environmental persistence and transmission potential under thermal stress, which may affect the ecology of H9N2 viruses.
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Drug Discovery Landscape
1 orphan drug designation for Avian influenza.
1 orphan drug designation for Avian influenza.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Anti-H5N1 equine immunoglobulin F(ab')2 fragments | antibodies | EMA | 2015-07-28 | — | Fab'entech |
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