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  ABSTRACT Current U.S. surveillance for highly pathogenic avian influenza A(H5N1) in humans prioritizes individuals with known animal exposures , potentially missing community-acquired infections . To address this gap, we implemented universal H5 subtyping of all influenza A-positive respiratory samples collected within our hospital system , regardless of patient exposure history. Between August 2024 and April 2025, we subtyped 4,488 influenza A-positive samples and identified two cases positive for H5 RNA in Alameda County, California, USA . The first case was a 14-month-old girl with mild respiratory symptoms and no H5N1 exposure risks ; sequencing of the sample revealed an H5 gene closely related to clade 2.3.4.4b, genotype B3.13 viruses circulating in U.S. dairies . The second case was a 79-year-old male, also with no known exposures , whose sample reproducibly tested positive with a high cycle threshold value but could not be confirmed by public health laboratories. Both pati...

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

  Summary Background Lassa virus (LASV) is a persistent threat to public health in west Africa and beyond . LASV is endemic in west Africa and each year it is responsible for an estimated 2·7 million infections, 23 700 hospitalisations, and 5000 deaths . With over 32 reported cases of Lassa fever imported into non-endemic countries—one-third of which were fatal—the importance of enhanced detection and management of Lassa fever extends beyond west Africa. Methods The prevalence, pathogenesis, and persistence (PREPARE) study was a prospective cohort study among patients admitted to two hospitals in a hyperendemic area of Liberia . Any patients aged 5 years or older with a febrile illness were eligible to enrol and be tested for Lassa fever. The study aimed to measure the prevalence of LASV infection and assess the signs and symptoms, LASV viral replication kinetics, and LASV-specific IgM and IgG responses longitudinally among adults and children with laboratory-confirmed Lassa fever....

  Abstract Highly pathogenic H5N1 avian influenza viruses of clade 2.3.4.4b cause sporadic human infections and currently raise concerns about a new influenza pandemic . Heterogeneities in disease severity have been observed in the past and are reported among infected farm workers in the United States . These may be attributed to differences in pre-existing H5N1 cross-reactive antibodies . In this study, we characterize H5N1 cross-reactive antibody landscapes in the current population (#NCT05794412 and #NCT01022905) and assess the effect of AS03-adjuvanted pandemic H1N1 and non-adjuvanted seasonal influenza vaccination on H5N1 cross-neutralizing and IgG antibody titers targeting a range of influenza virus-derived antigens. We detect H5N1 cross-neutralizing antibodies using a vesicular stomatitis virus-based pseudovirus system that correlate well with antibodies inhibiting the spread of authentic H5N1 viruses, anti-group 1 hemagglutinin stalk and anti-trimeric hemagglutinin antibodi...

  Abstract Since its emergence in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has posed a significant threat to human health . Recently, novel MERS-like coronaviruses with the potential for cross-species transmission have been identified. In this study, we focused on two newly isolated bat strains with putative health concern: BatCoV/Ii/GD/2014-422 (2014-422) and BtTp-BetaCoV/GX2012 (GX2012). We determined the cryo-EM structures of the spike glycoprotein trimer in the closed state for these two viruses. These structures display a more compact conformation compared to MERS-CoV spike . Biochemical characterization demonstrates that the spike receptor-binding domains (RBDs) of 2014-422 and GX2012 can bind to human dipeptidyl peptidase 4 (hDPP4). To investigate the structural determinants of pseudovirus infection, we solved the cryo-EM structures of 2014-422 RBD-hDPP4 and GX2012 RBD-hDPP4 complexes. The binding mode of the complex is conserved, but the angle of the RB...

  Abstract Ongoing transmission of influenza A virus (H5N1) in U.S. dairy cattle threatens both animal and human health , underscoring the need to understand the durability of host immunity against reinfection with evolving genotypes . We challenged naive and convalescent cows , infected one year prior with H5N1 genotype B3.13, with either homologous B3.13 or heterologous D1.1 genotype virus . Homologous rechallenge resulted in complete clinical protection with no infectious viral shedding . Conversely, heterologous rechallenge led to transient clinical disease and limited infectious viral shedding . Convalescent cows experienced significantly milder disease than naive cows, which developed severe illness with high viral shedding and required early euthanasia , regardless of the strain. These findings indicate that naturally acquired immunity offers strong protection against severe illness but may allow silent transmission of divergent strains . Therefore, natural herd immunity alo...

  ABSTRACT Monoclonal antibodies represent potent biological countermeasures against a wide range of human diseases ; however, their clinical application and widespread use are limited by the high cost and complexity of antibody production and manufacturing. The mRNA-lipid nanoparticle (mRNA-LNP) platform offers a versatile strategy for vaccine development and protein-replacement therapies. Since the COVID-19 pandemic, a number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)- neutralizing antibodies have been identified, with several granted emergency use authorization for patients. Here, we report the design and generation of mRNA-LNPs encoding two SARS-CoV-2-neutralizing antibodies , 76E1 and LY1404, which, respectively, target the spike protein’s fusion peptide (FP) and receptor-binding domain (RBD). We demonstrated that a single intramuscular administration of these mRNA-LNPs in mice resulted in robust antibody production that sustained in circulation for 7–14 d...

  ABSTRACT Accurate antigenic characterization of influenza viruses is critical for vaccine strain selection but is often confounded by intrahost genetic diversity and culture-induced adaptations . We analyzed 60 A(H3N2)-positive nasopharyngeal specimens collected during the 2017–2018 influenza season to determine how virus propagation in MDCK cells affects viral genetic and antigenic properties . Deep sequencing revealed frequent genome-wide intrahost polymorphisms , including amino acid variants within major hemagglutinin (HA) antibody-binding sites . Virus propagation imposed rapid purifying selection, markedly reducing intrahost genetic diversity . Serological analyses demonstrated that these selective events altered antigenic properties, indicating that culture adaptation can alter antigenic profiles . To assess the functional impact of HA polymorphisms, we generated mixed viral populations containing defined ratios of HA-160K, HA-160T, and HA-160I variants identified in clini...

  Abstract Hemagglutinins (HA) from different influenza A virus subtypes share as little as ~40% amino acid identity , yet their protein structure and cell entry function are highly conserved . Here we examine the extent that sequence constraints on HA differ across three subtypes . To do this, we first use pseudovirus deep mutational scanning to measure how all amino-acid mutations to an H7 HA affect its cell entry function. We then compare these new measurements to previously described measurements of how all mutations to H3 and H5 HAs affect cell entry function . We find that ~50% of HA sites display substantially diverged preferences for different amino acids across the HA subtypes. The sites with the most divergent amino-acid preferences tend to be buried and have biochemically distinct wildtype amino acids in the different HA subtypes. We provide an example of how rewiring the interactions among contacting residues has dramatically shifted which amino acids are tolerated at s...

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

  Abstract Introduction Prion diseases are mortal neurodegenerative disorders , which include Creutzfeldt-Jakob disease (CJD). Due to its heterogenous clinical presentation diagnosis uncertainties are common. In this paper we explore CJD diagnostic challenges focusing on differential diagnosis and diagnostic delays. Methods We report a case of a patient who was misclassified and evaluated by several medical specialties before the CJD suspicion . A systematic review of the literature of the CJD case reports focused on the timely and differential diagnosis was carried out in Medline and Embase until May 2023. Results Patient with diagnosis was made due to the form of presentation and clinical evolution , neuroimaging and the presence of protein 14-3-3 . In systematic review, fifteen articles were selected, who reported 31 cases of CJD with problems in the timely diagnosis and incorrect initial diagnosis , the main initial differential diagnoses were psychiatry exacerbation, myelopath...

  Abstract The highly pathogenic avian influenza viruses (HPAIV) of subtype H5N1 represent a major threat to animal and public health . The current panzootic with H5 clade 2.3.4.4b has caused numerous, widespread outbreaks in various domestic and wild avian species with high mortalities, massive losses and a high frequency of spillover events to unexpected novel mammalian hosts such as dairy cows . The global H5N1 situation raises serious concerns about zoonotic risks due to effective mammal-to-mammal transmission . Therefore, it is critical to increase surveillance intensity of a broadened species range, particularly at the human-animal interface . For this purpose, reliable and cost-effective serological tools that are easy to perform and suitable for high-throughput screenings are critically needed. The newly developed double antigen ELISA format employing a luminescence-based detection technology has demonstrated to comply with such prerequisites. The assay allowed the detectio...

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

  Abstract Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b has expanded rapidly across the Southern Ocean since 2023 , causing extensive mortality in sub-Antarctic wildlife . Yet its penetration into Antarctica and impacts on ice-dependent species remain poorly resolved primarily due to surveillance constraints . We report the first confirmed H5N1 infection in an Antarctic ice-dependent seal (crabeater seal; Lobodon carcinophaga) and document mortality of crabeater seals across the northern Weddell Sea during November-December 2024 . Combining genomic, serological and observational data across nine species, we detected H5N1 RNA in a crabeater seal and a kelp gull (Larus dominicanus), and recovered complete HA, NA and M2 gene sequences from both. Phylogenetic analyses allowed us to identify at least two independent introductions of HPAI H5N1 clade 2.3.4.4b into the northern Antarctic Peninsula region. Serology provided strong evidence of prior exposure in scavenging bir...

Abstract Enterovirus D68 (EV-D68), a neurotropic respiratory pathogen, poses a considerable clinical threat through its link to pediatric acute flaccid myelitis (AFM) and severe respiratory illness . The possibility of recurrent epidemics , evidenced since the 2014 outbreak, remains a major concern . Genomic determinants of virulence are central to this threat. Sequence variations that affect host–receptor interactions , immune evasion, and replication efficiency serve as critical modifiers of pathogenicity. This article systematically reviews the evidence for specific genomic sites that enhance EV-D68 virulence , focusing on three critical regions: the VP1 receptor-binding site , the 2Apro/TRAF3 cleavage site, and the 3Cpro immunoregulatory region . Mutations in the VP1 receptor-binding site can alter affinity for host receptors such as sialic acid, heparan sulfate, and MFSD6 , thereby shaping viral entry and tissue tropism . Alterations in the 2Apro/TRAF3 cleavage site may impair pro...

  Antiviral Res RODRIGUEZ L, Hu Y, Li J, Han D, et al SARS-CoV-2 Resistance Analyses From the Phase 3 OAKTREE Study of Obeldesivir in Low-Risk Nonhospitalized Participants With COVID-19. Antiviral Res. 2025 Dec 29:106339. doi: 10.1016/j.antiviral.2025.106339. PubMed           Abstract available Eur J Radiol YAO J, Zhang L, Huang S, Cao S, et al Changes in the cerebral glymphatic system after rehabilitation of COVID-19 patients: A five-year follow-up study. Eur J Radiol. 2025;195:112615. PubMed           Abstract available Int J Infect Dis DAVIDO B, Mamona C, Gault E, Annane D, et al "Three of a Kind?" Unmasking the Clinical Burden of Human Metapneumovirus and Parainfluenza Virus Compared to Respiratory Syncytial Virus in Hospitalized Adults: A Pre-COVID-19 Multicenter Cohort Study. Int J Infect Dis. 2025 Dec 26:108353. doi: 10.1016/j.ijid.2025.108353. PubMed         ...

  BMC Pediatr CHEN Y, Wang Y, Tao X, Zhou M, et al Pediatric necrotizing pneumonia caused by mixed infection with influenza A virus and Panton-Valentine Leucocidin-producing Staphylococcus aureus: case report and literature review. BMC Pediatr. 2025 Dec 24. doi: 10.1186/s12887-025-06410. PubMed           Abstract available Eur J Epidemiol OSTERGREN OM, Counil E, Karimi A, Fall T, et al Who got tested and who got sick? Sociodemographic inequalities in COVID-19 testing and hospitalization among 1.48 million individuals in Sweden. Eur J Epidemiol. 2025;40:1431-1439. PubMed           Abstract available J Immunol ABE K, Holmes TH, Nguyen TT, Kim-Schulze S, et al Evaluating COVID-19 severity prediction and immune dynamics with NULISAseq: Insights from the IMPACC study. J Immunol. 2025;214:3310-3320. PubMed           Abstract available OSUAGWU AE, Payne M, Bosch J, Mbony...

Abstract Monkeypox (MPOX) is an emerging zoonotic disease caused by monkeypox virus (MPXV), an orthopoxvirus closely related to smallpox . Initially confined to endemic regions in Central and West Africa , MPOX has recently gained global significance with outbreaks reported across multiple continents . MPXV is maintained in animal reservoirs but is increasingly transmitted from person to person , facilitated by close contact, respiratory droplets , and, in some cases, sexual transmission . Clinically, MPOX presents with fever, lymphadenopathy, and a characteristic vesiculopustular rash , though atypical manifestations have been observed in recent outbreaks, complicating diagnosis. Laboratory confirmation relies on molecular testing , while differential diagnosis must consider varicella, herpes, and other vesicular illnesses. Therapeutic options remain limited ; supportive care is the cornerstone of management, but antivirals such as tecovirimat and brincidofovir, as well as smallpox va...