ETIDIOH - NEW

Abstract The continuous evolution and widespread dissemination of highly pathogenic avian influenza (HPAI) H5N1 viruses , particularly clade 2.3.4.4b, pose critical challenges to global pandemic preparedness . In this study, we assessed a low-dose inactivated split virus vaccine derived from clade 2.3.4.4b H5N1, formulated with an Alum/CpG adjuvant , using a preclinical mouse model . This vaccine induced potent humoral and cellular immune responses , generating high titers of cross-reactive antibodies targeting both hemagglutinin (HA) and neuraminidase (NA) glycoproteins across homologous and heterologous H5 clades. The Alum/CpG adjuvant enabled significant antigen dose-sparing while promoting a balanced Th1/Th2 immune profile . Functional analyses demonstrated strong virus neutralization , neuraminidase inhibition, and potent antibody-dependent cellular cytotoxicity activity . Additionally, the vaccine elicited robust antigen-specific CD4+ and CD8+ T cell responses and effectively con...

Significance An intranasal vaccine offers many unique advantages over traditional intramuscular-delivered vaccines . Here, we developed SARS-CoV-2 Omicron XBB.1.5 spike-based monovalent and trivalent vaccines using the live attenuated measles virus (MeV) and mumps viruses (MuV) as vectors . Intranasal immunization of hamsters and mice with monovalent and trivalent vaccines induces robust and broadly neutralizing antibodies , mucosal IgA antibodies , and lung-resident memory T cells , providing complete protection of the lung and nasal turbinate against challenges with SARS-CoV-2 WA1 and Omicron subvariants XBB.1.5, EG.5, and JN.1 . In addition, intranasal immunization efficiently blocks transmission of SARS-CoV-2 WA1 and Omicron XBB.1.5 among the hamsters by direct contact. Therefore, MeV- and MuV-based intranasal vaccines are highly promising next-generation COVID-19 vaccine candidates that can prevent virus infection and transmission. Abstract The emergence of immune-evasive SARS-CoV...

Abstract Monkeypox virus (MPXV) has re-emerged globally since May 2022, posing a significant public health threat . To address this, we develop two multivalent mRNA vaccine candidates —AAL, encoding three MPXV antigens, and AALI, which combines AAL with an immune-enhancing IFN-α protein. Both vaccines are delivered via mannose-modified lipid nanoparticles to target dendritic cells . Here we show that these vaccines elicit strong antibody responses against vaccinia virus and multiple MPXV clades , induce robust memory B-cell and T-cell responses, and promote dendritic cell maturation . In mouse challenge models , both vaccines provide protection against clade IIb MPXV and vaccinia virus , significantly reducing viral loads and preventing lung damage. Immune profiling reveals enhanced B- and T-cell receptor diversity and distinct CDR3 motifs post-vaccination. These findings demonstrate the potential of using mRNA-based multivalent vaccines as an effective strategy for preventing mpox and...

  Abstract Vaccine responses vary widely in human studies. Here we pooled data measuring 66 cytokines from 4 different inactivated influenza vaccine (IIV) cohorts over 5 seasons (N=581) and identified a significant correlation between baseline/day 0 serum IL-18 and IFN-β concentrations and the antibody response on day 28. We investigated this further in human tonsil and spleen organoids , and found that several cytokines, including multiple Type I IFNs (IFN-β and others), IL-21, IL-12, IL-10, but not IL-18 or its downstream Type II IFN (IFN-β), could adjuvant the IIV vaccine to enhance the antibody response . The live attenuated influenza vaccine (LAIV) induced a stronger antibody response than the inactivated one in organoids. Adding a single cytokine, IFN-β, recapitulated most of the live vaccine-specific cytokine activation program and increased the antibody response of the inactivated vaccine to that of the live vaccine. Thus, the human vaccinees and the organoid data showed th...

  ABSTRACT The H5N1 strain of influenza A virus (IAV) continues to cause severe infections in a range of avian and mammalian species , including sporadic but concerning cases in humans. There is growing concern that circulating H5N1 strains could lead to widespread human outbreaks . Research with highly pathogenic H5N1 viruses is restricted to Biosafety Level 3 (BSL-3) laboratories. Vesicular stomatitis virus (VSV)-based vaccine vectors expressing heterologous viral proteins from Ebola, SARS-CoV-2, Lassa virus, etc., have previously been shown to be safe and effective in animal models and human clinical trials . Here, we report the development of a recombinant VSV expressing the hemagglutinin (HA) and neuraminidase (NA) genes of H5N1 IAV (H5N1-VSV), which serves as a versatile platform to study various aspects of H5N1 IAV biology. H5N1-VSV replicated robustly to titers comparable to those of the full H5N1 virus in multiple cell lines. In mice , H5N1-VSV vaccination was safe, elicit...

Highlights •  Conserved T cell epitope regions elicit strong CD4+ and CD8+ T cell responses in SARS2-exposed •  CTERs enhance cross-reactivity across multiple Betacoronaviruses •  Targeting non-spike proteins expands immune breadth and HLA coverage •  Removing low population coverage regions preserves cross-reactivity Summary The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats . Betacoronaviruses, including severe acute respiratory syndrome coronavirus ( SARS-CoV ), Middle East respiratory syndrome ( MERS ), and SARS-CoV-2 , present significant pandemic risks due to their zoonotic potential and genetic diversity . T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell ...

Abstract The global burden of Guillain-Barré syndrome (GBS), an immune-mediated neuropathy, remains poorly characterized during the COVID-19 pandemic . We analyzed age-standardized years lived with disability (YLD) for GBS from 1990 to 2021 using GBD 2021 data and COVID-19 vaccination coverage from Our World in Data, focusing on 2020–2021. During the pandemic, GBS YLD rates rose dramatically , with greater increases seen in low-SDI regions, females and individuals aged 15–29 years. Higher vaccination coverage was inversely associated with GBS disability burden , exhibiting a non-linear protective effect at moderate to high coverage levels. Causal mediation analysis indicated that 44.6% of this association was mediated by reductions in COVID-19 incidence, highlighting both direct and indirect neuroprotective benefits of vaccination programs . These results underscore the importance of sustaining and expanding the vaccine rollout to mitigate the secondary neurological burden associated w...

Abstract Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals , heightening the risk of a human pandemic . Influenza viruses adapted to transmission in birds and some other animals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses , enabling membrane fusion at comparatively high pH levels. Here, we combine five mutations within H5 HA that dramatically increase its melting temperature and promote stable closure of the HA trimer . Structural analysis by cryo-electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions , while maintaining local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than non-stabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative stain electron mic...

Summary Background Little epidemiological evidence exists on the protective effects of the JN.1 -adapted mRNA vaccines against COVD-19 hospitalisation and death. In this study, we estimated vaccine effectiveness against COVID-19 hospitalisation and death. Methods This nationwide, register-based, cohort study included all Danish residents older than 65 years on Oct 1, 2024 . We used Denmark's national COVID-19 surveillance system and comprehensive population-based registers, which are updated daily and linked via the unique civil registration number assigned to all residents. To minimise differences between the comparison groups with regard to vaccination history, participants were required to have completed a primary vaccination course in 2021 and have received the 2023–24 XBB.1.5-adapted vaccine between Oct 1, 2023, and Jan 15, 2024. Participants with a recent recorded infection, or a vaccine dose since the previous season and prior to study start, were excluded. COVID-19 hospital...

Abstract Outbreaks of H5 highly pathogenic avian influenza A viruses (HPAIVs) in animals pose a threat to humans immunologically naïve to avian influenza viruses. However, annual vaccination, such as for seasonal influenza is not planned because the number of human patients infected with H5 HPAIVs is small, and the possibility of human-to-human transmission of H5 HPAIVs is low at present. However, various clades of H5 HPAIVs have emerged continuously . Therefore, a vaccine that confers long-term and cross-clade immunity is required. To examine the long-term effectiveness and cross-clade reactivity of an H5 influenza virus vaccine, cynomolgus macaques were infected with an H5N1 HPAIV 5 years after two subcutaneous vaccinations with inactivated H5N1 whole-virus particles (H5 clade classical/outlier), which showed higher immunogenicity than did split vaccines in our previous studies. Neutralization titers against the vaccine strain were maintained for 5 years , and a recall immune respons...

Abstract Nipah virus (NiV) causes a severe neurological disease in humans . The first NiV outbreak, in Malaysia , involved pig-to-human transmission , that resulted in significant economic losses to the local pig industry. Despite the risk NiV poses to pig-dense regions, no licensed vaccines exist . This study therefore assessed three NiV vaccine candidates in pigs: (1) adjuvanted soluble NiV (s)G protein, (2) adjuvanted pre-fusion stabilised NiV (mcs)F protein, and (3) adenoviral vectored NiV G (ChAdOx1 NiV G). NiV sG induced the strongest neutralising antibody response , NiV mcsF induced antibodies best able to neutralise cell-cell fusion, whereas ChAdOx1 NiV G elicited CD8+ T-cell responses. Despite differences in immunogenicity, prime-boost immunisation with all candidates conferred a high degree of protection against NiV infection. Follow-up studies demonstrated longevity of immune responses and broadly comparable immune responses in Bangladeshi pigs under field conditions. These ...

Abstract With the recent rise in cases of highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b infection in humans and animals , there is an associated increase in the risk of human-to-human transmission . In this study, we characterize a recombinant A(H5N1) A/American Wigeon/South Carolina/22/000345-001/2021 (A/AW/SC/2021) clade 2.3.4.4b vaccine . Purified recombinant A/AW/SC/2021 HA trimers formulated with Matrix-M® adjuvant, saponin-cholesterol-phospholipid combination arranged in cage-like particles, are found to non-covalently anchor to the vertices of the Matrix-M and form A(H5N1) HA–Matrix-M nanoparticles (H5-MNPs). In naïve female mice , two intranasal (IN) or intramuscular (IM) doses of A/AW/SC/2021 H5-MNP vaccine induces robust antibody- and cell-mediated immune responses , including neutralizing antibodies against A(H5N1). In non-human primates (NHPs) primed with seasonal influenza vaccine , a single IM or IN dose of the A/AW/SC/2021 H5-MNP vaccine induces geometr...

Abstract Seasonal influenza vaccines are most frequently delivered as intramuscular inactivated vaccines which elicit systemic responses against the immunodominant hemagglutinin (HA) head domain . An intranasally administered, live-attenuated influenza vaccine designed to stimulate mucosal immunity , FluMist, is the sole intranasal vaccine approved in the United States. However, FluMist has lower systemic immunogenicity and efficacy in adults compared to intramuscular formulations. In this study, human mucosal and systemic immunity were examined following seasonal intramuscular or intranasal vaccination. Nasopharyngeal swabs of adenoid tissue were used to longitudinally sample the upper airway. Notably, FluMist induced substantial increases in upper respiratory tract IgG+ and IgA+ HA-specific memory B cells , which displayed an activated CD27+CD21- phenotype. H1, H3, and influenza B virus HA-specific memory B cells were all detected in the upper airway after intranasal immunization and...

ABSTRACT Effective vaccines are an important public health tool which may be needed to combat the emerging, highly pathogenic H5N1 avian influenza viruses currently circulating in cattle and poultry in the United States . While nucleic acid-based vaccines such as mRNA -lipid nanoparticles (LNPs) have several potential advantages during a viral epidemic compared to traditional seasonal influenza vaccines , their utility and efficacy against H5N1 viruses remain incompletely defined. Here, we developed novel DNA- and mRNA-LNP-based vaccines encoding both hemagglutinin (HA) and neuraminidase (NA) proteins from the human-isolated highly pathogenic avian influenza H5N1 strain, A/Texas/37/2024, in a single open reading frame. This dual-antigen expression approach elicited strong protective immune responses targeting both the HA and NA proteins and provided complete protection against lethal viral challenges in a murine model . The pre-clinical data described in this work suggest that these mu...

Abstract An increase in the number of human cases of influenza A/H5N1 infection in the US has raised concerns about the pandemic potential of the virus . Preexisting population immunity is a key determinant for risk assessment and pandemic potential for any virus. Antibody responses against the bovine A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins were measured among a population of influenza-vaccinated or influenza-infected individuals . Modest titers of bovine A/H5N1 HA-binding antibodies and low to undetectable neutralizing antibody responses were detected in a cohort of 73 individuals . Conversely, bovine A/H5N1 NA binding and neuraminidase-inhibiting antibody responses were comparable to those against a human A/ H1N1 NA at baseline. Seasonal influenza vaccination failed to significantly increase antibody titers against both HA and NA glycoproteins of bovine A/H5N1. Recent infection with human A/H1N1 but not A/H3N2 viruses induced significant increases in bovine A/H5N1 n...

Abstract Clinical progression and medium-long term morbidity from myocarditis following mRNA COVID-19 vaccinations remains an important but undefined public health concern . We conducted prospective follow-up of individuals with either confirmed or probable myocarditis following monovalent Pfizer-BioNTech BNT162b2 or Moderna mRNA-1273 vaccination between 21 April 2021 and 5 July 2022 in Australia . Of 256 individuals who consented to follow up, mostly males following a second dose, 60% (133/221) had ongoing symptoms at 3-6 months and 35% (81/231) at 12-18 months. Self-reported ongoing exercise restrictions, medication requirements, and hospital re-presentations were associated with ongoing symptoms, as was a lower self-reported health status and quality of life. Clinical severity remained mild , with low hospitalisation rates and no deaths in the follow-up period and health-related quality of life improved over time. These findings support ongoing use of mRNA COVID-19 vaccines in at-ri...

Abstract Avian Influenza viruses (AIVs) present a public health risk, especially with seasonal vaccines offering limited protection. AIV H5N1 clade 2.3.4.4b has caused a multi-state outbreaks in the United States (US) poultry and cattle since March 2024, raising pandemic concerns . We developed a nonstructural protein 1 (NS1)-deficient mutant of a low pathogenic version of the cattle-origin human influenza A/Texas/37/2024 H5N1 , namely LPhTXdNS1, and assessed its safety, immunogenicity, and protection efficacy . LPhTXdNS1 is attenuated in vitro , showing reduced replication efficiency in Vero cells and inability to control IFNβ promoter activation. The LPhTXdNS1-immunized C57BL/6 J mice exhibit significantly reduced viral replication and pathogenicity compared to those infected with the low pathogenic version expressing NS1, namely LPhTX. Notably, a single intranasal dose of LPhTXdNS1 elicited protective immune responses, providing robust protection against lethal wild-type H5N1 challe...

Report of a WHO virtual scientific consultation, September 2024 © World Health Organization 2025 Some rights reserved. This work is available under the Creative Commons AttributionNonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo ).   Executive summary   Avian influenza viruses – particularly A(H5) – pose a significant risk for potential pandemics as they can infect humans and other mammals .  The high mutation rate of influenza viruses raises concerns about their potential to adapt for efficient human-to-human transmission .  Influenza vaccines are crucial tools in mitigating the impact of influenza epidemics and pandemics.  Given the global circulation of A(H5) viruses – especially the spillover to dairy cattle since early 2024 – and the rapidly evolving vaccine landscape, the World Health Organization (WHO) held a virtual scientific consultation on 12–13 September 2024 to review:  --...

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 and outcome have been observed in the past and are currently reported among infected farm workers in the US. 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 and assess the effect of pH1N1/AS03 and non-adjuvanted seasonal influenza vaccination on H5N1 cross-neutralizing and IgG antibody titers targeting a range of influenza virus-derived antigens. We were able to detect H5N1 cross-neutralizing antibodies using a VSV-based pseudovirus system that correlated well with antibodies inhibiting the spread of authentic H5N1 viruses. Additionally, we found that pH1N1/AS03 vaccination increases H5N1 cross-reactive antibodies significantly, while non-adjuvanted i...

Summary Background mRNA-1283 is an investigational, next-generation COVID-19 vaccine that encodes only the immunodominant regions of the SARS-CoV-2 spike protein —the receptor-binding domain (RBD) and the N-terminal domain rather than the full-length spike used in currently authorised mRNA vaccines. We evaluated the relative vaccine efficacy (rVE), immunogenicity, and safety of mRNA-1283 compared to the first-generation vaccine (mRNA-1273). Methods This randomised, observer-masked, active-controlled, phase 3 trial (NextCOVE) was conducted in individuals (aged ≥12 years) with no evidence of SARS-CoV-2 infection within 90 days of screening in the USA, the UK, and Canada. Participants were randomly assigned in a 1:1 ratio to receive one 10 μg dose of the bivalent formulation of mRNA-1283 (original plus omicron BA.4/BA.5) or 50 μg of the bivalent mRNA-1273, encoding the same variants. Randomisation was stratified by age (12–17 years, 18–64 years, and ≥65 years). Primary objectives comparin...