Mice immunized with #N1 NA in a single cycle infectious virus or in a recombinant nanoparticle #vaccine are protected against lethal challenge with HPAI #H5N1 influenza

 

Abstract

The recent spillover of highly pathogenic (HP) H5N1 clade 2.3.4.4b into dairy cattle and other mammalian species has been concerning. Vaccine candidates that can be rapidly synthesized and implemented are key countermeasures for protecting the human population against emerging pathogens. Here we examine the use of a pH1N1 virus lacking the genetic material for hemagglutinin (HA), limiting the infection to a single cycle (sciIAV) or Cobalt lipid-porphyrin nanoparticles decorated with neuraminidase (NA) of HPAI H5N1 (N1-CoPoP) as vaccine candidates. C57BL/6 mice that were inoculated intranasally with a single dose of pH1N1 sciIAV did not differ in serum NA antibody compared to uninoculated mice. However, mice that were inoculated intramuscularly with the N1-CoPoP alone or in combination with pH1N1 sciIAV had increased N1 IgG antibodies. Upon lethal challenge with HPAIV H5N1, all mice inoculated with either pH1N1 sciIAV or N1-CoPoP were protected from weight loss, unlike unvaccinated mice with substantial body weight losses that succumb to viral infection between 7 and 10 days post infection (dpi). Both pH1N1 sciIAV and N1-CoPoP immunization minimized viral infection such that only one mouse receiving pH1N1 sciIAV had detectable viral titer in the lungs at 4 dpi. By 6 dpi, no mouse inoculated with pH1N1 sciIAV and/or N1-CoPoP had detectable virus in nasal turbinates, lungs or the brain, unlike the high viral titers found in uninoculated mice. Both pH1N1 sciIAV and N1-CoPoP were protective and should be investigated further as alternative vaccine candidates.

Competing Interest Statement

J.F.L. holds interest in POP Biotechnologies. Other authors declare no competing interests.

Funder Information Declared

American Lung Association, https://ror.org/01p3rh655

Texas Biomedical Research Institute

Douglass Foundation

Source: 

Link:  https://doi.org/10.64898/2026.10.11.758125

____

Cross-reactive T-cell responses against #BDBV in #humans after rVSVΔG-ZEBOV-GP #vaccination

 

{Excerpts}

(...)

Our study shows that a single immunisation with the available, licensed EBOV vaccine induces T-cell cross-reactivity against BDBV and to a lesser extent against SUDV. Although it is not known whether these T cells contribute to improved clinical outcomes upon BDBV exposure in humans, preclinical studies show that T-cell responses are required for vaccine-mediated protection in non-human primates: CD4 T cell help to B cells is required for protection against disease caused by EBOV,10 and depletion studies have also shown a protective role of CD8 T cells.11

Our study has limitations. Due to the small sample size and single measured timepoint, dose–response differences and long-term persistence of the cross-reactive T-cell response could not be assessed. This study was performed in healthy adults in Germany, thus representativeness of populations in areas affected by the BDBV outbreak is limited.

Although a correlate of protection against disease caused by BDBV has not been defined, our findings provide first evidence that rVSVΔG-ZEBOV-GP vaccination against EBOV induces BDBV-cross-reactive T-cell responses. In the absence of a BDBV-specific vaccine, these data support the systematic evaluation of the available EBOV vaccine within clinical trials during the current outbreak.

Source: 

Link: https://doi.org/10.1016/S1473-3099(26)00529-3

____

Integrated in vivo and transcriptomic analyses of lethal #Oropouche virus #infection reveal suppression of pathogenic host responses by #antiviral therapy

 

Abstract

Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease in vivo. In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first in vivo, tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.

Source: 

Link: https://doi.org/10.1371/journal.ppat.1014647

____

Cross-clade #protection against #human #H5N1 isolates by a clade 2.3.4.4b HA #mRNA #vaccine in mice

 

Abstract

The recent spread of clade 2.3.4.4b H5N1 high pathogenicity avian influenza (HPAI) viruses into mammals, despite limited human infections to date, has raised serious public health concerns and highlights the need for rapidly deployable vaccines, such as mRNA-based platforms, to strengthen pandemic preparedness. Here, we evaluated the effectiveness of an mRNA vaccine encoding the HA of NIID-002, a WHO-recommended H5 candidate vaccine virus (CVV) derived from A/Ezo red fox/Hokkaido/1/2022 (clade 2.3.4.4b) against A/Texas/37/2024 (TX37; clade 2.3.4.4b) and A/Cambodia/2311257/2023 (Cam23; clade 2.3.2.1e). The mRNA was formulated with ssPalmO, a low-inflammatory self-degradable ionizable lipid nanoparticle (LNP). BALB/c mice were immunized intramuscularly twice with the mRNA-LNP vaccine containing either 1 μg or 10 μg of H5 HA mRNA. After boosting, strong, dose-dependent serum IgG responses against NIID-002 HA were detected by ELISA. The mice were then challenged with a lethal dose of homologous TX37 or heterologous Cam23. All mice in the 10-μg group survived both challenges, demonstrating robust cross-clade protection. In the 1-μg group, complete protection without significant body weight loss was observed against TX37, whereas partial protection was observed following Cam23 challenge. Viral titers were significantly reduced in multiple tissues of the vaccinated mice compared to the unvaccinated controls. Our findings demonstrate that the NIID-002-HA mRNA vaccine confers protection against homologous and heterologous zoonotic H5N1 strains in a mouse model. This low-inflammatory ssPalmO-LNP platform thus supports safe, rapid vaccine development against emerging H5N1 viruses with pandemic potential.

Source: 

Link: https://doi.org/10.1016/j.vaccine.2026.129215

____

Comparison of #Baloxavir-Based Combinations and Monotherapies for Treating #Influenza #H5N1 Clade 2.3.4.4b Virus #Infection in Mice

 

Abstract

Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause animal outbreaks and sporadic zoonotic infections. In a mouse model of lethal influenza disease, we compared oseltamivir, baloxavir, and molnupiravir monotherapies with 2-drug combinations. Baloxavir-based combinations improved survival, reduced lung viral loads, and prevented extrapulmonary dissemination, supporting H5N1 preparedness strategies.

Source: 

Link: https://doi.org/10.3201/eid3210.260186

____

A single-cycle, recombinant VSV #platform #Nipah #vaccine cross-protects against #Hendra virus in nonhuman #primates

 

Abstract

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic paramyxoviruses that produce severe, often fatal disease in humans and animals. Zoonotic spillover of these henipaviruses from the Pteropid bat natural reservoir occurs near-annually in Southeast Asia and Oceania. Outbreaks of NiV disease frequently exceed case fatality rates of 75%, and person-to-person transmission makes controlling outbreaks in low-resource environments challenging. HeV is less transmissible between humans; however, the overall mortality rate is 57%. Approaches to human vaccine development have largely focused on NiV given the larger case burden, and immunogen selection has centered on display of the NiV attachment (G) or fusion (F) surface glycoproteins. However, experimental vaccines displaying these NiV antigens have failed to uniformly cross-protect against HeV disease in preclinical models. The HeV (G) antigen was shown to cross-protect against both HeV and NiV when delivered in a protein subunit form; however, attempts to utilize mRNA or canarypox vectors failed to achieve equivalent protection. We previously developed and evaluated a single-cycle recombinant vesicular stomatitis virus-vectored vaccine displaying the (G) glycoprotein of Nipah virus strain Bangladesh (NiV-B). This experimental vaccine (G*rVSV∆G-NiV-G) demonstrated ideal characteristics of rapid and durable protection against NiV-B challenge in nonhuman primates. In the present work, we show that the G*rVSV∆G-NiV-G vaccine cross-protects against lethal HeV challenge, with the protective response driven by a balance of both cell-mediated and humoral compartments.

Source: 

Link: https://doi.org/10.1371/journal.ppat.1014646

____

Limited added #benefit of seasonal #influenza #vaccination before #H5 vaccination in mice and #ferrets challenged with #H5N1

 

ABSTRACT

Limited A(H5)-specific vaccine supply is expected early in a potential A(H5N1) pandemic, raising the question of whether licensed seasonal influenza vaccines could enhance protection when administered before A(H5) vaccination. We evaluated this strategy in mouse and ferret models using clade 2.3.4.4b A(H5N1) viruses. Seasonal influenza vaccination induced antibodies to seasonal haemagglutinins but did not induce detectable antibodies against A(H5) and did not consistently enhance A(H5)-directed antibody responses after A(H5) vaccination. In lethal challenge studies, seasonal vaccine priming before A(H5) vaccination was associated with improved outcomes compared with A(H5) vaccination alone in one of three mouse experiments, but this effect was not observed in the other two mouse experiments or in ferrets. These findings suggest that seasonal influenza vaccine priming provides limited added benefit to A(H5) vaccine-mediated protection against A(H5N1) under the conditions tested.

Source: 

Link: https://doi.org/10.1080/22221751.2026.2731495

____

Pan - #Ebolavirus nanoparticle #vaccine provides protection in rodents from lethal #infection by #Zaire and #Sudan viruses

 

Abstract

Both Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) are members of the genus Ebolavirus and cause outbreaks marked by high fatality rates and repeated spillover from animal reservoirs. Filoviral glycoproteins (GPs) are the primary targets of neutralizing antibodies and form the basis of current vaccines. Here we describe the design, structural characterization, and evaluation of two-component self-assembling icosahedral I53-50 nanoparticles displaying prefusion EBOV or SUDV GP antigens, either individually or in cocktail and mosaic multivalent formats. EBOV-GP-I53-50 and SUDV-GP-I53-50 nanoparticles elicited strong homologous protection in mice and guinea pigs. In the mouse-adapted EBOV model (maEBOV), mosaic and cocktail formulations produced weak survival below that of the matched EBOV-GP-I53-50 GP immunogen. In contrast, in the gpaSUDV guinea pig model (gpSUDV), cocktail and mosaic nanoparticles elicited robust protection against gpSUDV, and detectable antibody responses to both SUDV and EBOV GPs. These findings demonstrate that multivalent GP-I53-50 nanoparticle immunogens can protect rodents from death, severe clinical signs of disease, and weight loss in relevant models. Together with the established clinical safety of the I53-50 platform, these results support continued efforts toward the development of a pan-ebolavirus vaccine.

Source: 

Link: https://www.nature.com/articles/s41467-026-76114-1

____

Elicitation of Potent #H5N1 - and #H7N9-Neutralizing #Antibody Responses in Rh. Macaques by Sequential Heterologous #Vaccination with #mRNA and Adenoviral Vectors Encoding Full-Length Hemagglutinins

 

Abstract

Highly pathogenic avian influenza (HPAI) represents an enormous pandemic risk amid the ongoing H5N1 panzootic. HPAI, defined by its high lethality in domestic poultry, includes the influenza A virus (IAV) H5N1 and H7N9 subtypes and has a 40–50% case fatality rate in humans. To facilitate the development of efficacious HPAI vaccination regimens and isolation of HPAI-neutralizing monoclonal antibodies (nmAbs) for prophylactic and therapeutic use, we performed a proof-of-concept pilot study wherein we developed an array of mRNA and adenovirus-vectored vaccines encoding HPAI hemagglutinins (HAs) and then assessed their immunogenicity in IAV-naïve Indian rhesus macaques (RMs). All RMs developed binding IgG recognizing both HPAI HAs. HPAI-nAbs were detected in RMs vaccinated with full-length HAs, but not in RMs vaccinated with HA stems alone. Potent HPAI neutralization activity was observed in two animals with serum ID50 titers of ~1:100,000 against H5N1 and ~1:50,000 against H7N9. Most RMs developed cross-reactive IgG recognizing the HAs of additional IAV subtypes, and HA-specific B cells were readily identifiable in vaccinee PBMCs by flow cytometric analysis. The results of our pilot study suggest that elicitation of potent HPAI-nAb responses is enhanced by vaccination with the HA head domain and that vaccination with the HA stem alone tends to elicit binding non-nAbs. Furthermore, use of our fluorophore-conjugated HA probes to identify HA-specific B cells could enable HPAI-nmAb isolation. Collectively, our findings could facilitate the development of novel vaccines and nmAb therapeutics leveraging the superior neutralization potency of HA head-specific Abs to prevent and treat HPAI infections in humans.

Source: 

Link: https://www.mdpi.com/1999-4915/18/9/981

____

#Safety, humoral and cellular immune responses to a pre-pandemic adjuvanted #influenza #H5N8 #vaccine

 

Abstract

Highly pathogenic avian influenza (HPAI) A(H5) viruses can be transmitted from infected birds to various mammalian species, including humans. Avian influenza viruses (AIVs), members of the Orthomyxoviridae family, possess segmented RNA genomes prone to reassortment, favoring the emergence of novel genetic traits that may alter transmissibility, pathogenicity, and antigenicity. Although no sustained human-to-human transmission has been reported, the potential adaptation of these viruses poses a significant pandemic threat. This study aimed to evaluate the non-clinical safety, toxicity, and humoral immune responses induced by an adjuvanted H5 influenza vaccine in rats and rabbits, to support future clinical safety trials in humans. Male and female Wistar rats and New Zealand rabbits were observed for 14, 28, and 90 days after receiving two intramuscular doses of the H5N8 vaccine (15 μg HA/dose) formulated with the IB160 oil-in-water emulsion adjuvant. No systemic comorbidities, central nervous system alterations, or relevant clinical signs were observed. Hematological parameters remained within normal ranges, with total and differential leukocyte counts showing only minor fluctuations (<1% of total leukocytes). Mild biochemical variations in urea and hepatic transaminase levels were not correlated with histopathological alterations. The vaccine elicited a robust humoral response soon after immunization, with all groups reaching protective HAI-antibody titers. Although antibody levels declined over time, particularly in males, they remained significantly above baseline, indicating durable immunological memory. Furthermore, the vaccine induced a specific cellular immune response, confirmed by IL-2 and TNF production by antigen-specific T lymphocytes in splenic cell cultures after the booster dose. In conclusion, the H5N8 vaccine with the IB160 adjuvant was well tolerated locally and systemically, without compromising vital organ function. The safety and immunogenicity findings are consistent with expectations for adjuvanted influenza vaccines, demonstrating strong and durable humoral and cellular immune responses.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S0264410X26008583?via%3Dihub

____

Sex differences in #vaccine-induced #neuraminidase cross-recognition impact #H5N1 #dissemination to the lower respiratory tract in mice

 

Abstract

H5N1 vaccines have been poorly immunogenic in humans, creating a challenge for vaccine development. Seasonal influenza vaccines offer some cross-protection against H5N1, but there has been no consideration of whether protection differs between the sexes. We investigated sex differences in antibody responses following receipt of either beta-propiolactone inactivated whole virus H1N1 or H5N1 (LAIV backbone) vaccines in C57BL/6 mice. Using systems serology assays, vaccination induced strong homologous and heterologous antibody responses, with females generating greater IgG titers than males against whole virus H1N1 and H5N1, which was primarily mediated by greater IgG responses to neuraminidase (NA) than hemagglutinin (HA) protein. Cross-reactive H5N1 IgG titers were greater among H1N1-vaccinated females, and primarily mediated by greater N1-specific IgG titers. IgG2b and IgG2c were the primary antibody isotypes generated in response to these vaccines, with females having greater IgG2b titers and enhanced binding to FcγRIV for avian and human NA than males following either homologous or heterologous vaccination. Antibody-dependent complement deposition was measured as an FcR-mediated non-neutralizing response against HA and NA and was more robust among H1N1 and H5N1 vaccinated females than their male counterparts in response to homologous HA only. Vaccinated females tended to have greater neutralizing antibody titers than males against the homologous vaccine strain, with limited cross-neutralizing antibodies detected in either sexes. Neuraminidase inhibition titers were greater in vaccinated females than males against the heterologous virus following H1N1 vaccination and against both the vaccine and heterologous viruses following H5N1 vaccination. When H1N1 and H5N1 vaccinated mice were challenged with a lethal dose of A/Texas/37/2024 H5N1, all H5N1 vaccinated mice were protected, regardless of sex. Among H1N1 vaccinated mice, while both sexes were protected against disease, H1N1 vaccinated females restricted virus to the upper respiratory tract and had lower pulmonary virus titers than males at 3 days post challenge. These findings highlight that sex differences in vaccine-induced NA-specific antibody responses are associated with differential respiratory dissemination of H5N1 and that sex should be considered in studies of vaccine-induced cross-reactive influenza immunity.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

NIH/NIAID Johns Hopkins Center of Excellence for Influenza Research and Response, 75N93021C00045

Richard Eliasberg Family Foundation

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.05.26.728011v3

____

Isolation and characterisation of #Nipah virus neutralising candidate therapeutic monoclonal #antibodies from an #mRNA-immunised pig

 

Abstract

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus with epidemic potential. Despite the threat NiV poses, no therapeutics are licensed to treat infection. Studies have shown that monoclonal antibodies (mAb) can protect animals against NiV and the related Hendra virus (HeV). The best studied mAb, m102.4, has been used to treat infected patients on a compassionate basis, and has entered clinical trials. However, there is a need to define additional mAbs with therapeutic potential, which could be combined with m102.4 to improve neutralising potency and breadth. Here, we isolated five high affinity mAbs from an mRNA immunised pig, which bound the G glycoprotein derived from NiV Malaysia strain (NiV-M), and one of which (mAb A2) also bound HeV G. Aligned with this, all mAbs neutralised NiV-M pseudovirus but only mAb A2 neutralised pseudovirus representing the NiV Bangladesh (NiV-B) strain. mAb A2 and the most potent NiV-M neutralising mAb, C1, showed minimal competition with each other and m102.4, suggesting recognition of non-overlapping epitopes. Single-particle cryogenic electron microscopy of the NiV-M G receptor binding domain complexed to A1 and C2 Fab fragments revealed distinct epitopes that did not overlap with the receptor-binding site, targeted by m102.4, suggesting action through steric impedance of receptor binding or interference downstream of receptor engagement. Inoculation of mAb A2 to hamsters did not provide complete protection against NiV-B challenge (60% survival), however, a split dose of mAb A2 and m102.4 provided the same protection as m102.4 alone (100% survival). Collectively, these data demonstrate the potential of the porcine model for isolation of therapeutic candidate mAbs, which contribute both to our understanding of the NiV G antigenic landscape, and the development of mAb combinations, that exert complementary mechanisms of neutralisation, for therapeutic intervention.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

European Commission, https://ror.org/00k4n6c32, VetBioNet, EMJMD LIVE

Innovate UK, 971555

UK Research and Innovation, BBS/E/I/00007031, BBS/E/I/00007037, BBS/E/I/00007038, BBS/E/I/00007039, MR/S007555/1, BB/T008784/1

Wellcome Trust, 203141/Z/16/Z

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.08.28.745669v1?rss=1

____

#Maraviroc Inhibits #SARS-CoV-2 Through Variant-Dependent Effects on Viral Entry and #Mpro Activity Using Single-Round Infectious Particle and Virus-like Particle Models

 

Abstract

Maraviroc (MVC), a CCR5 antagonist, has been proposed as a potential antiviral agent against SARS-CoV-2; however, its mechanism of action across viral variants remains unclear. Here, we evaluated the antiviral activity of MVC against SARS-CoV-2 wild-type (WT) and Omicron BA.1 variants using single-round infectious particles (SRIPs), virus-like particles (VLPs), and cell-based assays, with a focus on its impact on viral entry and Mpro function. MVC potently inhibited infection of both WT and BA.1 SRIPs in Vero E6 cells, exhibiting EC50 values of 0.0065 μM and 0.016 μM, respectively. Time-of-addition assays revealed that MVC primarily targets the early phase of infection, with the strongest inhibition observed at the viral entry stage, while moderate effects were detected during attachment and post-entry stages. Fluorescence-labeled VLP imaging demonstrated distinct entry pathways, with WT predominantly entering via plasma membrane fusion and BA.1 via endocytosis, independent of cell type. MVC altered WT-VLP trafficking by promoting internalization and lysosomal localization, whereas it had minimal impact on BA.1 internalization. In spike-mediated cell–cell fusion assays, MVC preferentially inhibited WT spike-driven syncytium formation but showed limited effects on BA.1 or BA.4 fusion, while more effectively reducing Omicron spike-mediated binding. At the post-entry stage, MVC inhibited SARS-CoV-2 main protease (Mpro) activity, with BA.1 Mpro (P132H) exhibiting greater sensitivity (IC50 = 0.496 µM) than WT (1.869 µM). Collectively, these findings demonstrate that MVC exerts variant-dependent antiviral effects by targeting viral entry, modulating trafficking pathways, and inhibiting Mpro activity. This study highlights MVC as a multi-stage inhibitor with differential efficacy against SARS-CoV-2 variants, providing insights into its potential therapeutic application.

Source: 

Link: https://www.mdpi.com/1999-4915/18/8/911

____

A novel candidate #vaccine virus derived from #Japan's first #mammalian case of clade 2.3.4.4b #H5N1 highly pathogenic avian #influenza virus

 

Abstract

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.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S0264410X26008571?via%3Dihub

____

#Lassa fever and Argentine hemorrhagic fever #treatment in guinea pigs using broad-spectrum cap-dependent #endonuclease #inhibitors

 

ABSTRACT

The class Bunyaviricetes encompasses several highly pathogenic viruses that cause lethal hemorrhagic fevers. Due to their limited prevention and treatment options and high pathogenicity, these viruses require handling in biosafety level-4 facilities. Within the bunyaviruses, arenaviruses are particularly notable for their pathogenicity and ability to cause severe hemorrhagic disease in humans. The cap-dependent endonuclease (CEN) is a unique and crucial enzyme involved in the replication cycle of these viruses. As humans do not possess a similar enzyme, CEN represents an ideal target for antiviral drug development with reduced risk of side effects. Recently, we identified a promising CEN inhibitor (CENi) demonstrating potent inhibition of virus replication. In this manuscript, we demonstrate the successful therapeutic efficacy of CENis against Lassa fever and Argentine hemorrhagic fever virus infections in guinea pig models of lethal hemorrhagic fever. In addition, we identified several CENis with antiviral activity against other highly pathogenic arenaviruses. These findings further support the potential of CENis as therapeutic agents for arenavirus infections that cause severe and often lethal hemorrhagic fever. Collectively, our results suggest that CENis are promising candidates for pan-arenavirus therapy and may also have broader utility against other CEN-containing viruses for which no approved antiviral treatments currently exist.

Source: 

Link: https://journals.asm.org/doi/10.1128/mbio.00880-26

____

Protective effect of #H5N8 stockpiled #vaccine against a virus genetically identical to a #human isolate of #bovine #H5N1 #influenza virus

 

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

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.

Source: 

Link: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(26)00314-2/fulltext

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A One-Shot Multivalent Live-Attenuated Candidate #Influenza #Vaccine against Divergent #Zoonotic #H5N1 Clades

 

Abstract

The continued emergence of genetically diverse high pathogenicity avian influenza (HPAI) H5N1 viruses with zoonotic potential highlights the urgent need for developing vaccines capable of providing broad protection against multiple circulating clades. Here, we developed a one-shot, multivalent, live-attenuated influenza vaccine (LAIV) based on the temperature-sensitive (ts), cold-adapted (ca), and attenuated (att) influenza A/Ann Arbor/6/1960 master donor virus (MDV) that incorporates the hemagglutinin (HA) and neuraminidase (NA) glycoproteins from representative clades 2.3.4.4b (A/Louisiana/12/2024), 2.3.2.1a (A/Victoria/149/2024), and 2.3.2.1e (A/Cambodia/2302009/2023) H5N1 viruses. A single intranasal (IN) immunization of C57BL/6 mice with the multivalent LAIV elicited robust humoral immune responses, with immune sera exhibiting broad cross-reactivity against antigens from all three H5N1 clades included in the vaccine. Following homologous viral challenge, vaccinated C57BL/6 mice were completely protected from disease, demonstrating the immunogenicity and protective efficacy of the multivalent LAIV. By simultaneously targeting antigenically distinct H5N1 lineages with pandemic potential, this strategy expands antigenic coverage within a single LAIV to confirm pan-H5N1 protection. Together, these findings support the development and implementation of this multivalent LAIV as a broadly protective pan-H5N1 LAIV for pandemic preparedness.

Competing Interest Statement

The A.G.-S. laboratory has received research support from Avimex, Dynavax, Pharmamar, and Accurius, outside of the reported work within the last three years. A.G.-S. has consulting agreements for the following companies involving cash and/or stock within the last three years: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, Avimex, Pagoda, Accurius, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Virofend, Prosetta and A.A.C.T., outside of the reported work. A.G.-S. has been an invited speaker in meeting events within the last three years organized by Seqirus, Novavax and Hipra. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. The Icahn School of Medicine at Mount Sinai has licensed some of these inventions to Medimmune, Avimex, Leinco Technologies, Castlevax, Virofend, Kerafast, Cell Signaling, EMD Millipore, Genentech, Paratus and Nura Bio, and as a result receives financial compensation. Subject to Mount Sinai receiving such financial consideration, AG-S will receive a portion of that consideration pursuant to the terms of the Mount Sinai Intellectual Property Policy. All other authors declare no commercial or financial conflict of interest.

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.08.02.742385v1

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Synergistic #antiviral effect of #Asunaprevir and #Ribavirin in combination against Murray Valley #Encephalitis Virus replication

 

Highlights

    • Renilla luciferase-based MVEV sub-genomic replicon was constructed and applied in antiviral drug evaluation.

    • Removal of Stem Loop I from 3’UTR impairs viral genome replication.

    • Asunaprevir and ribavirin exhibit synergistic antiviral activity against MVEV.

    • A single-round MVEV infectious particle platform was developed.

Abstract

Murray Valley encephalitis virus (MVEV) is a mosquito-borne flavivirus known for causing severe neurological diseases in humans. Despite the rising number of reported infections and high mortality rate among hospitalized patients, no antiviral therapies or licensed vaccines are available. To strengthen preparedness against this reemerging virus, we establish a subgenomic replicon (SGR) platform and a complementary single-round infectious particles (SRIPs) production system, using widely circulating genotype 1 (G1) MVEV as backbone. Stem-loop I(SLI) from 3’UTR stands for the major difference among 4 MVEV genotypes and removal of SLI resulted in mild decrease of genome replication. Through screening a mini anti-flavivirus drug library, we identified that asunaprevir (ASV) and ribavirin (RBV) inhibit MVEV infection independently. Combination of ASV and RBV also showed synergistic activity against MVEV. These results underscore the value of the MVEV replicon system as a versatile tool for evaluating antiviral compounds, supporting the potential of ASV and RBV as a combinatorial therapeutic approach.

Source: 

Link: https://www.sciencedirect.com/science/article/abs/pii/S0166354226001567?via%3Dihub

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Elicitation of #stem-directed #antibodies in rhesus #macaques by a conventional #hemagglutinin immunogen

 

Abstract

Because they can bind many strains of influenza, antibodies targeting the hemagglutinin (HA) stem have been attractive targets for vaccine development. Many monoclonal antibodies (mAbs) directed at the HA stem have been isolated from humans, and these mAbs have mediated broad protection in animal models. We describe here HA stem-directed mAbs isolated from rhesus macaques immunized with an "ordinary" H1 HA trimer. All immunized rhesus macaques developed high serum titers with broad reactivity to diverse H1N1 and H5N1 viruses, and 7 isolated mAbs strongly blocked canonical stem antibody CR6261 binding to H1. MAb DH726.1 robustly protected mice from lethal challenge with H1N1 and H5N1 viruses, and cryo-EM showed the binding footprint overlapped that of some human mAbs. These findings suggest that vaccination with the standard, trimeric HA immunogens may be sufficient to elicit stem antibodies at titers adequate to protect against zoonotic H5N1 influenza.

Competing Interest Statement

The authors have declared no competing interest.

Funder Information Declared

NIH NIAID, Division of Microbiology and Infectious Diseases, P01-AI089618

NIH NIAID Division of AIDS, Center for HIV/AIDS Vaccine Immunology, U19-AI067854

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.07.16.738984v1

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Immunoinformatics-Guided Design and In Silico Evaluation of a Multi-Epitope #Vaccine Against #Influenza A #H10N5 and #H3N2 Strains Based on HA and NA Proteins

 

Abstract

Influenza A viruses H3N2 and H10N5 represent, respectively, a persistently dominant seasonal pathogen and a newly documented zoonotic threat with the latter strain variants responsible for the first confirmed human fatality in January 2024, yet no vaccine platform currently addresses co-protection against both subtypes within a unified immunogen. We report here the immunoinformatics based vaccine design and multi-layered computational validation of a 419-amino-acid multi-epitope subunit vaccine construct targeting conserved hemagglutinin (HA) and neuraminidase (NA) antigens identified through multiple sequence alignment of the avian H10N5 (A/swine/Hubei/10/2008) and H3N2 human reference strain sequences to identify viral agents undergoing mammalian adaptations. Linear B-cell, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) epitopes were predicted using ABCpred, BCEpred, BepiPred 2.0, NetMHCpan 2.1, and NetMHCpan 4.0, then filtered through VaxiJen 3.0, AllerTOP v2.1, and ToxinPred to retain only antigenic, non-allergenic, non-toxic candidates. The final construct, incorporating an avian β-defensin N-terminal adjuvant with GPGPG, AAY, and EAAAK linkers, exhibited a molecular weight of 43.9 kDa, instability index of 31.15, and SOLPro solubility probability of 0.763. Tertiary structure modeling via I-TASSER and GalaxyRefine achieved 84.4% Ramachandran-favored residues. Molecular docking against TLR3 and TLR7 yielded binding free energies of −16.1 and −16.8 kcal/mol with picomolar dissociation constants. Molecular dynamics simulations confirmed complex stability over extended trajectories. Furthermore, codon optimization produced a Codon Adaptation Index of 1.0 for E. coli K12 expression. In silico immune simulation demonstrated robust activation of humoral and cellular immunity including elevated IgG1, IgM, IFN-γ, IL-2, rapid NK cell expansion, and broad B-cell clonal diversity. These findings establish a computationally validated candidate capable of providing protection against influenza in multiple host organisms, warranting experimental advancement.

Competing Interest Statement

The authors have declared no competing interest.

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.07.03.736294v1

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