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ABSTRACT Sporadic human infections of avian influenza virus (AIV) raise significant public health concerns . A critical factor limiting the transmission of AIVs is the shift in receptor-binding preference from Siaα2,3 to Siaα2,6. To reveal the adaptive selection dynamics during the host adaptation process of AIVs, this study generated a viral library with random mutations in the HA gene of the H9N2 strain . Upon passaging the viral library in chickens and mice , the predominantly selected variants exhibited a preference for Siaα2,3 receptors . Notably, the wild-type strain remained dominant in both inoculated and direct-contact chickens, while variants with the ΔL226/R229I substitutions were preferentially selected in mice. Ferrets have a predominance of Siaα2,6 in their respiratory tract. As expected, the variant harboring the N289D mutation, which prefers Siaα2,6 binding, was enriched during in vivo passaging in ferrets . The mice-adapted variant with the ΔL226/R229I mutations causes...

Abstract Low pathogenic H9N2 avian influenza viruses have become widespread in wild birds and poultry worldwide, raising concerns about their potential to spark pandemics or their role in enhancing the virulence and infectivity of H5Nx viruses through genetic reassortment . Therefore, influenza monitoring studies, including those of H9N2 viruses, are crucial for understanding, evaluating, and mitigating the risks associated with avian infections, and have broader implications for global public health. Although H9N2 viruses are not considered enzootic in Kazakhstan , they have been repeatedly detected in wild waterfowls and domestic poultry . In this study, all eight gene segments of influenza A/H9N2 viruses isolated in various regions of Kazakhstan between 2014 and 2020 were sequenced and analyzed. Molecular characterization revealed the presence of genetic markers associated with mammalian infectivity and disease potential . Furthermore, their predicted receptor binding site sequences...

Influenza at the human-animal interface Summary and risk assessment, from 20 March to 22 April 2025 {1}  • New human cases {2}:  From 20 March to 22 April 2025 , based on reporting date, the detection of influenza A( H5N1 ) in four humans and influenza A( H9N2 ) virus in three humans were reported officially.  • Circulation of influenza viruses with zoonotic potential in animals :  High pathogenicity avian influenza (HPAI) events in poultry and non-poultry continue to be reported to the World Organisation for Animal Health (WOAH).{3} The Food and Agriculture Organization of the United Nations (FAO) also provides a global update on avian influenza viruses with pandemic potential.{4}  • Risk assessment {5}:  Sustained human to human transmission has not been reported from these events. Based on information available at the time of the risk assessment, the overall public health risk from currently known influenza viruses circulating at the human-animal inter...

Abstract The 1889 Russian (also called ‘Asiatic’) Flu epidemic can be described as one of the first modern pandemics . The development of extensive railroad and shipping networks during and prior to this period facilitated the previously unprecedented movement of goods and people around the world. It additionally propagated the process of shrinking the barriers between the countryside and major metropolises. While the COVID-19 pandemic resulted in lockdown measures nearly worldwide and prompted widespread social, economic, and cultural disruptions, the Russian Flu was not accompanied by such drastic changes. In this article, it is argued that the blunted historical consciousness of this epidemic were a result of a combination of factors , including the nascent state of scientific research and understanding of infectious diseases, the circumscribed reach of media, implicit comparisons to other contemporary epidemics, temporal closeness to the Spanish Flu and suppression of memory , and ...

Abstract Seasonal influenza continues to be a global health problem . Current existing vaccines and antivirals against influenza have limited effectiveness, and typically do not stay ahead of the viral evolutionary curve. Broad-spectrum antiviral agents that are effective therapeutically and prophylactically are much needed. We have created a promising new broad-spectrum anti-influenza agent using molecular engineering of a lectin from bananas , H84T, which is well-tolerated and protective in small animal models . However, the potency and effect of H84T on human immune cells and influenza-specific immune responses are undetermined. We found that H84T efficiently inhibited influenza A virus (IAV) replication in primary human dendritic cells (DCs) isolated from blood and tonsil, preserved DC viability and allowed acquisition and presentation of viral antigen. Excitingly, H84T-treated DCs subsequently initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved t...

Abstract Background .  Influenza A virus (IAV) is a major cause of morbidity and mortality globally , causing seasonal influenza in humans and infecting birds and some mammals. In 2024, IAV H5N1 highly pathogenic avian influenza (HPAI) in the United States moved into cattle. While the outbreak is currently of low risk to the general public, there is an urgent need to monitor the disease and prevent spread.  Methods .  We conducted a nationwide study evaluating the relationship between H5 hemagglutinin gene RNA concentrations in wastewater and reported outbreaks of IAV H5N1 in animals and humans . We utilized an H5-specific droplet digital RT-PCR test to quantify H5 RNA in wastewater in 40 states across the United States, and 1) examined the temporal association between outbreaks and wastewater detections and 2) utilized linear mixed models (LMM) to determine the relationship between measurements in wastewater and outbreak-related factors in the local area.  Results ....

Abstract The GreVac vaccine technology was created as a fast and flexible plug-and-play vaccine platform based on a 4th generation architecture of fully deleted (fd) helper virus independent (hi) adenoviral (Ad) vectors. For the initial proof-of-principle studies , we at Greffex had engineered an avian influenza vaccine , which delivered a transgene expression cassette for an avian influenza virus H5 hemagglutinin and N1 neuraminidase genes in a capsid of the common human Ad serotype 5 (Ad5). This vaccine proved highly immunogenic and protective in mice . These studies revealed that intramuscular (i.m.) delivery proved more efficient than subcutaneous (s.c.) or intranasal (i.n.) routes. In the human population, pre-exposure to the Ad5 virus is common. To minimize interference by pre-existing anti-Ad5 immunities, we created a new GreVac-based avian influenza vaccine, in which the fd Ad genome was packaged into a capsid of the rare human Ad serotype 6 (Ad6). We now report that at very lo...

Abstract Recently, Clade 2.3.4.4b H5N1 virus has been widely prevalent globally. Although no outbreaks of Avian Influenza have occurred in poultry in China recently, Clade 2.3.4.4b H5 virus can still be isolated from wild birds , live poultry markets and environment , indicating the ongoing co-circulation of H5N1 and H5N6 viruses. In this study, phylogenetic analysis of global Clade 2.3.4.4b viruses and 20 laboratory-isolated H5 strains revealed that Chinese H5N1 and H5N6 viruses since 2021 cluster into two distinct groups , G-I and G-II. Bayesian phylodynamic analysis reveals that G-I H5N6 virus has become an endemic virus in China . In contrast, G-II H5N1 virus, with South China as its main epicentre, has been disseminated in China and its surrounding countries, with its transmission more reliant on the connections of wild birds and waterfowl . Reassortment analysis indicates that since 2023, Clade 2.3.4.4b H5 viruses isolated in China have formed seven genotypes . The genome of H5 v...

Abstract The Sudan virus (SUDV) outbreaks in Uganda in 2022 and 2025 created public health concerns in-country and the entire East African region. There are currently no licensed countermeasures against SUDV . We developed a SUDV vaccine candidate based on a nanocarrier (LIONTM) complexed with an alphavirus-based replicon RNA . Here, we compare the protective efficacy of the LION-SUDV vaccine either encoding the SUDV glycoprotein (GP) alone or in combination with the Ebola virus (EBOV) GP (LION-Combination). A LION-EBOV vaccine which is protective against EBOV was also included to determine the potential for cross-protection against SUDV infection . Single-dose vaccinations were conducted three weeks before challenge with a lethal dose of guinea pig-adapted SUDV using a female guinea pig disease model. We demonstrate 100% survival and protection with the LION-SUDV and the LION-Combination vaccines, while the LION-EBOV vaccine achieved 50% protection. Antigen-specific humoral responses ...

Abstract Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults ; however, older adults remain significantly at risk for severe influenza-related illness . Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response. In this study, we combined in vitro and ex vivo assays with human samples to investigate B, CD4+ T, and myeloid cell responses to influenza vaccine antigens . We found that older adults mounted equivalent antibody titers to younger adults but had fewer influenza-specific CD4+ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets . These data suggest that with aging, transcriptional programming alterations in myeloid cells contribute to reduced antiviral T cell responses, and formulating vaccines tai...

Highlights •  Reconstituted human airway epithelia (HAE) are more effective than cell lines or mouse models for generating and predicting resistance-conferring mutations. •  The resistance barrier of oseltamivir is superior to baloxavir or HA targeting compounds in HAE or mouse model. •  HA-targeting therapeutics quickly led to resistant HA mutations without compromising viral fitness. •  A baloxavir-resistant virus with PA mutations E23G and C241Y was isolated in HAE. •  Combined therapy using clinical antiviral compounsd and HA-targeting compounds did not prevent the emergence of HA mutations. Abstract Influenza viruses pose a significant threat due to annual epidemics and pandemic potential . Resistance to current antivirals underscores the need for new drugs and strategies to prevent its emergence. We previously developed two novel HA-targeting compounds (CD-6’SLN and CD-SA) with demonstrated efficacy against influenza A and B strains . Here, we compared the...

Abstract Enterovirus D68 (EV-D68) caused large biennial cyclical outbreaks of respiratory disease and cases of acute flaccid myelitis from 2014 to 2018 in the USA . An anticipated outbreak did not occur in 2020, likely due to non-pharmaceutical interventions targeting the COVID-19 pandemic. A large respiratory disease outbreak occurred again in 2022 , but uncertainty remained regarding if circulation of EV-D68 would return to the pre-pandemic patterns. We conducted prospective active surveillance of clinical respiratory specimens from Colorado children for EV-D68 in 2023 and 2024. A subset of residual specimens positive for rhinovirus/enterovirus (RV/EV) were tested for EV-D68 via a validated in-house EV-D68 reverse transcription–PCR assay. During epi weeks 18–44 in 2023, 525 residual specimens positive for RV/EV all tested negative for EV-D68. In 2024, during epi weeks 18–44 , 10 ( 1.8% ) of the 546 RV/EV-positive specimens were EV-D68-positive . The EV-D68-positive cases were predomi...

Abstract In Europe, highly pathogenic avian influenza (HPAI) virus circulates in avian wildlife, undergoing frequent reassortment , sporadic introductions in domestic birds , and spillover to mammals . An H5N1 clade 2.3.4.4b reassortant, EA-2023-DG, affecting wild and domestic birds was detected in western Europe in November 2023. Six of its RNA segments came from the EA-2021-AB genotype, but the polymerase basic 2 and polymerase acidic segments originated from low pathogenicity avian influenza viruses . Discrete phylogeographic analyses of concatenated genomes and single polymerase basic 2 and polymerase acidic segments suggested reassortment in summer 2023 near the southwestern Baltic Sea . Subsequent continuous phylogeographic analysis of all concatenated EA-2023-DG genomes highlighted circulation in northwestern Europe until June 2024 and long-distance dispersal toward France, Norway, England, Slovakia, Switzerland, and Austria . Those results illustrate the value of phylodynamic a...

Abstract The global spread, frequent antigenic changes, and pandemic potential of clade 2.3.4.4b highly pathogenic avian influenza H5N1 underscore the urgent need for robust cross-protective vaccines . Here, we developed a clade 2.3.4.4b H5N1 whole inactivated virus (WIV) vaccine strain with improved structural stability, productivity, and safety. By analyzing the evolutionary trends of clade 2.3.4.4b H5N1 viruses, we identified a key mutation (R90K) that increases heat stability while preserving antigenicity. Additionally, the PB2 gene of PR8 was replaced with a prototypical avian PB2 gene to increase replication efficiency in embryonated chicken eggs and reduce replication efficiency in mammalian cells, thereby improving productivity and biosafety. We found that our optimized clade 2.3.4.4b H5N1 vaccine strain (22W_KY), inactivated with binary ethylenimine (BEI), had superior antigen internalization into respiratory epithelial cells compared to those inactivated with formaldehyde or ...

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Abstract Influenza A(H5N1) viruses have been detected in US dairy cow herds since 2024 . We assessed the pathogenesis, transmission, and airborne release of A/Michigan/90/2024, an H5N1 isolate from a dairy farm worker in Michigan , in the ferret model. Results show this virus caused airborne transmission with moderate pathogenicity , including limited extrapulmonary spread , without lethality. Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b viruses have displayed unprecedented global spread among wild birds leading to numerous spillover infections in mammalian species. Of note, outbreaks in dairy cattle and gallinaceous birds have resulted in human infections in the United States during 2024–2025 (1). Increased frequency of H5N1 viruses crossing species barriers has caused concern that the avian influenza viruses are adapting to mammals . A critical component of influenza pandemic preparedness is early identification of emerging novel influenza viruses that cause disease and t...

Abstract Avian influenza A(H5N1) poses a public health risk due to its pandemic potential should the virus mutate to become human-to-human transmissible. To date, reported influenza A(H5N1) human cases have typically occurred in the lower respiratory tract with a high case fatality rate . There is prior evidence of some influenza A(H5N1) strains being a small number of amino acid mutations away from achieving droplet transmissibility , possibly allowing them to be spread between humans. We present a mechanistic within-host influenza A(H5N1) infection model, novel for its explicit consideration of the biological differences between the upper and lower respiratory tracts. We then estimate a distribution of viral lifespans and effective replication rates in human H5N1 influenza cases. By combining our within-host model with a viral mutation model, we determine the probability of an infected individual generating a droplet transmissible strain of influenza A(H5N1) through mutation. For thr...

  Ann Intern Med BILINSKI A, Emanuel N, Ciaranello A Sins of Omission: Model-Based Estimates of the Health Effects of Excluding Pregnant Participants From Randomized Controlled Trials. Ann Intern Med. 2025 Apr 29. doi: 10.7326/ANNALS-24-00689. PubMed           Abstract available YEK C, Mancera AG, Diao G, Walker M, et al Impact of the COVID-19 Pandemic on Antibiotic Resistant Infection Burden in U.S. Hospitals : Retrospective Cohort Study of Trends and Risk Factors. Ann Intern Med. 2025 Apr 29. doi: 10.7326/ANNALS-24-03078. PubMed           Abstract available RIDDLER SA, Moodie Z, Clark J, Yen C, et al High Frequency of Chronic Urticaria Following an Investigational HIV-1 BG505 MD39.3 Trimer mRNA Vaccine in a Phase 1, Randomized, Open-Label Clinical Trial (HVTN 302). Ann Intern Med. 2025 Apr 29. doi: 10.7326/ANNALS-24-02701. PubMed           Abstract available KIM...

  Arch Virol SVYATCHENKO SV, Boldyrev ND, Panova AS, Kolosova NP, et al Seroprevalence of anti-influenza antibodies in humans and characterization of seasonal influenza viruses isolated in Russia during the 2023-2024 flu season. Arch Virol. 2025;170:118. PubMed           Abstract available Biochem Biophys Res Commun CHU X, Yang Y, Guo H, Ji X, et al SARS-CoV-2 NSP2 specifically interacts with cellular protein SmgGDS. Biochem Biophys Res Commun. 2025;764:151828. PubMed           Abstract available ZHANG YH, Su AM, Hou XM Structural and functional insights into the SARS-CoV-2 SUD domain and its interaction with RNA G-Quadruplexes. Biochem Biophys Res Commun. 2025;764:151817. PubMed           Abstract available Epidemiol Infect STERIAN M, Naganathan T, Corrin T, Waddell L, et al Evidence on the associations and safety of COVID-19 vaccination and post COVID-19 conditi...