Showing posts with label immunology. Show all posts
Showing posts with label immunology. Show all posts

Friday, August 14, 2026

#Antibody #evasion and receptor binding of #SARS-CoV-2 variants #PQ.16.1.1 and RK.1

 


{Excerpt}

Since its rapid global spread beginning in late 2024, the SARS-CoV-2 variant NB.1.8.1 has progressively displaced older omicron variants, and has established near-total dominance in Asia. More recently, two NB.1.8.1-derived sublineages, PQ.16.1.1 and RK.1, have emerged and expanded substantially, particularly in China and Singapore (...). Specifically, the sublineage PQ.16.1.1 acquired the amino acid substitutions Asp253Gly (within the N-terminal domain), alongside Asn417Thr, Asp420Asn, and Ile478Thr (within the receptor-binding domain) relative to the parental NB.1.8.1 strain (...). Concurrently, the RK.1 sublineage (formally classified as a descendant of the PQ.17.7.2.1 branch) acquired Asp420Asn, His445Pro, and Ile478Thr (...). Furthermore, PQ.16.1.1 has continued to evolve into the SV series sublineages (predominantly SV.2 and SV.2.1), which have maintained all receptor-binding domain mutations, including Asp420Asn, and have subsequently come to dominate the circulating SARS-CoV-2 strains in Singapore (...).

(...)

In summary, the convergent acquisition of the Asp420Asn substitution in NB.1.8.1 sublineages again illustrates a classic SARS-CoV-2 receptor-binding domain evolution trade-off: a sacrifice in hACE2 receptor engagement in exchange for profound, targeted evasion of class 1 neutralising antibodies. (...) Given the increased evasion of class 1 antibodies by these Asp420Asn-carrying sublineages, these variants will likely spread from Asia and begin to prevail in countries where mRNA vaccination is common and populations are enriched with class 1 neutralising antibodies. 

Source: 


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#Vaccine #imprinting drives increased #SARS-CoV-2 #variant infection in #children

 


Abstract

Virus exposure history, particularly first exposure, is believed to shape vaccine efficacy and infection susceptibility; however, evidence for mechanistic links between immune responses in individuals and epidemiological outcome in populations is scarce. Recent co-circulation of SARS-CoV-2 variants XFG and BA.3.2 has revealed a striking enrichment in BA.3.2 cases among children. By combining epidemiological modeling, serology and monoclonal antibody analysis in children and adults, we show the dependence of effective variant-specific antibodies on vaccination history which may explain birth-year influence on differential susceptibility to these co-circulating variants. Ancestral cross-reactive site I antibodies frequently neutralize BA.3.2, but not XFG. By contrast, Omicron type-specific site I/III and III antibodies frequently neutralize XFG but not BA.3.2, revealing a tradeoff in the ability to neutralize these two co-circulating strains. These findings mechanistically link immune history, variant neutralization, antibody repertoire and variant infection risk, and suggest that vaccination regimens in children should prioritize neutralization breadth.


Competing Interest Statement

E.J.W. advises Arpelos Bioscience, Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics Related Sciences, Santa Ana Bio, and Synthekine. E.J.W. is a founder of and holds shares of Coherus, Danger Bio, and Arsenal Biosciences. All other authors declare no competing interests.


Funder Information Declared

National Institute of Allergy and Infectious Diseases, https://ror.org/043z4tv69, 75N93021C00015, U19AI082630, AI105343, AI108545, AI155577, AI149680

National Cancer Institute, 75N91019D00024, 75N91022F00005, 75N91023F00016

Source: 


Link: https://www.biorxiv.org/content/10.64898/2026.08.12.739589v1

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Wednesday, August 5, 2026

Virus #reactivation in acute and long #COVID19

 


Abstract

Chronic viral infections are ubiquitous in humans, with individuals carrying multiple viruses that can reactivate during physiological stress, including severe illness1. Notably, SARS-CoV-2 infection has been shown to reactivate chronic viruses such as Epstein–Barr virus and cytomegalovirus, yet the full extent, temporal dynamics and immunological impact of viral reactivation in COVID-19 remain incompletely understood. Here, leveraging multi-omic longitudinal data from 1,154 hospitalized patients with COVID-19 from the Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study, we reveal significant reactivation of Herpesviridae and Anelloviridae during acute COVID-19, with distinct temporal dynamics for different viruses, and demonstrate that reactivation correlates with disease severity, host immune effects and clinical outcomes. Although our results do not establish causation between virus reactivation and clinical outcomes, we highlight the prevalence of chronic viral reactivation during acute COVID-19 and long COVID. Our findings challenge the prevailing view that chronic viral reactivation is primarily a consequence of immunosuppression, demonstrating that reactivations occur frequently in immunocompetent individuals during severe illness and in association with increased systemic inflammation. Additionally, we demonstrate persistence of viral reactivation in convalescence, and report an association of Anelloviridae with long COVID. This study provides immune, transcriptomic and metabolomic signatures of viral reactivation that could inform future strategies to prognosticate and treat acute COVID-19 and long COVID.

Source: 


Link: https://www.nature.com/articles/s41586-026-10740-z

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Monday, August 3, 2026

Structural and functional characterization of a conserved cryptic #epitope on #SARS-CoV-2 #spike S2 subunit

 


Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone extensive evolution since its emergence in 2019, underscoring the continuous need for vaccines and therapeutics effective against multiple variants of concern (VOCs). The S2 subunit of the viral spike (S) glycoprotein is highly conserved among sarbecoviruses, making it an attractive target for broadly protective countermeasures. To elucidate the S2 antigenic landscape, we employed yeast surface display to isolate S2-targeted antibodies from COVID-19 convalescent donors. Biophysical characterization revealed that these S2 apex-directed antibodies preferentially bind to open spike conformations and a stabilized S2 construct but not to the closed, trimeric prefusion spike. Cryo-electron microscopy structures defined a cryptic epitope encompassing the upper helix and fusion peptide proximal region on S2. This epitope is conserved among sarbecoviruses but remains largely occluded in the closed prefusion conformation of the spikes. As a result, the antibodies exhibited weak neutralization activity against SARS-CoV-2 pseudoviruses, failed to neutralize authentic viruses, and did not provide protection in a lethal mouse challenge model using a mouse-adapted SARS-CoV-2 strain. These findings highlight a non-neutralizing epitope on S2 capable of eliciting antibodies during SARS-CoV-2 infection in humans and provide valuable reagents for probing S2 conformational dynamics and optimizing S2-based vaccine antigens.

Source: 


Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014391

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Friday, July 31, 2026

Pre-existing and Cross-Reactive #Immunity to Avian #Influenza #H5N1 in #Humans: Implications for #Pandemic #Risk and Vaccine Strategies

 


Highlights

    ° Evidence of cross-reactive antibodies to H5N1 in humans.

    ° Seasonal influenza may induce partial H5N1 cross-protection.

    ° H5N1 clade 2.3.4.4b shows expanded host range and spread.

    ° Role of viral glycoproteins in immune cross-reactivity.

    ° Implications of baseline immunity for H5N1 pandemic risk.


Abstract

Due to the continuous evolution of Influenza A viruses (IAVs), novel strains with efficient human-to-human transmission may emerge and cause future pandemics. Among these, highly pathogenic avian influenza (HPAI) H5N1 remains a major concern because of its impact on wildlife, livestock, and human health. The widespread circulation of H5N1 clade 2.3.4.4b, detected in hundreds of bird species and numerous mammals worldwide, highlights important changes in viral ecology and transmission, increasing its zoonotic and pandemic potential. This review summarizes current evidence on cross-reactive and cross-protective immunity to H5N1 in humans, focusing primarily on humoral immune responses. We examine the presence of pre-existing H5N1-reactive antibodies in individuals without known exposure and discuss how previous seasonal influenza infection or vaccination may contribute to their development. Particular attention is given to antibodies targeting conserved regions of hemagglutinin (HA), especially the stalk domain, as well as neuraminidase (NA), which may provide heterosubtypic protection. We also evaluate the ability of seasonal influenza vaccines and infections to induce cross-reactive responses against H5N1 and their potential role in partial protection or immune priming. Finally, we review current and emerging H5N1 vaccination strategies, including adjuvanted and mRNA-based platforms, and identify priorities for surveillance, population immunity assessment, and the development of broadly protective influenza vaccines.

Source: 


Link: https://www.journalofinfection.com/article/S0163-4453(26)00148-9/fulltext

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Thursday, July 23, 2026

#SARS-CoV-2 BA.3.2.2 is more evasive of #neutralisation by #plasma from young #children

 


{Excerpt}

(...)

These findings suggest that susceptibility to emerging SARS-CoV-2 variants could diverge across age groups with different exposure histories. Adults in the USA and other countries have accumulated broader immunity through repeated infection and vaccination across antigenically distinct lineages, starting with the ancestral strain, whereas younger children and infants possess narrower exposure histories that are largely shaped by recent variants. The continued surveillance of SARS-CoV-2 variants should consider age-stratified differences in immunity, to anticipate or explain disproportionate burden of infections in some populations. Furthermore, studies of potential age-specific vaccine formulations targeting different variants are warranted, to investigate whether age-specific target selection could lead to broader protection across subpopulations with known differences in their exposure histories and susceptibility to co-circulating variants.

(...)

Source: 


Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00349-X/fulltext?rss=yes

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Wednesday, July 22, 2026

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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Saturday, July 18, 2026

Immune correlates of #risk for #SARS-CoV-2 #infection in #children: a prospective, community-based cohort study

 


Abstract

Few studies have characterized immune correlates of SARS-CoV-2 infection risk in children, particularly those with hybrid immunity from vaccination and prior infection. We conduct a prospective community-based cohort study of 1509 U.S. children (2022–2024), performing weekly SARS-CoV-2 PCR testing and measuring baseline binding and neutralizing antibody titers against multiple variants. Higher antibody levels, notably nucleocapsid-binding and Omicron-specific neutralizing antibodies, are significantly associated with reduced risk of SARS-CoV-2 infection after adjusting for age, recent infection, exposure settings, and temporal trends (adjusted hazard ratios ranging from 0.60 to 0.87 per positive unit difference in log10-fold antibody level (AU/mL)). Secondary analyses suggest these findings are robust to multiple stratifications of SARS-CoV-2 immune status, are relevant across different pediatric age groups, and appear to apply to both overall and symptomatic infection risk. Together, the results suggest that specific antibodies can predict relative infection risk in pediatric populations with diverse immune histories. Understanding these immune correlates may inform tailored vaccination strategies and risk assessments as SARS-CoV-2 continues to evolve.

Source: 


Link: https://www.nature.com/articles/s41467-026-74684-8

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Friday, July 17, 2026

#Autoantibodies against type I #interferons in patients with #zoonotic #H7N9 #influenza: an observational case–control study

 


Summary

Background

The determinants of the species barrier preventing human infections with avian influenza A viruses (IAV) are incompletely understood. We previously identified loss-of-function variants of the interferon-regulated antiviral factor MxA as a genetic factor for increased susceptibility to infections with the H7N9 subtype. Given the central role of type I IFNs (IFN-I) in antiviral defence, we hypothesised that IFN-I-neutralising autoantibodies may similarly predispose to zoonotic H7N9 infection.

Methods

In this observational case–control study, serum samples collected between 2013 and 2017 from 199 Chinese patients with laboratory-confirmed H7N9 infection and 531 healthy, uninfected controls (269 poultry workers, 262 close contacts) were screened for IgG autoantibodies binding IFNα2, IFNβ1b, or IFNω using a multiplex bead-based assay. Positive samples were tested for IFN-neutralising activity in a luciferase-based reporter assay. To confirm their ability to block IFNα2-mediated antiviral activity, selected samples (n = 19) were analysed in IAV infection experiments. Associations between age, sex, H7N9 case status, case fatality, and the presence of neutralising autoantibodies were evaluated by logistic regression. Available whole-genome sequencing data from 26 individuals with neutralising autoantibodies were screened for variants in genes linked to IFN-I autoimmunity.

Findings

Neutralising autoantibodies against at least one IFN-I were detected in 19.1% (38/199) of patients but in only 1.1% (6/531) of controls, consistent with published general population data. Most patient sera targeted IFNα2 and/or IFNω (35/199), and 18.1% (36/199) neutralised even high IFN-I concentrations of 1–10 ng/ml. The presence of neutralising autoantibodies was associated with 8.2- to 25.3-fold higher odds of H7N9 infection (p < 0.0001), depending on antibody specificity and reference group. Autoantibody prevalence increased significantly with age in patients (44.8% ≥70 years; OR = 1.05; 95% CI 1.02–1.07; p = 0.0001), but was not associated with sex (OR for males vs. females = 0.52; 95% CI 0.23–1.14; p = 0.106). All selected sera containing neutralising autoantibodies blocked IFNα2-induced antiviral activity in cell culture. No known genetic predisposition for IFN-I autoimmunity was identified.

Interpretation

Our findings suggest that IFN-I-targeting autoimmunity is associated with susceptibility to zoonotic IAV infection with the H7N9 subtype, and possibly also other subtypes, including panzootic H5N1. Given the ease of implementation, screening for anti-IFN-I autoantibodies could be readily integrated into surveillance or targeted testing. This could be relevant in environments with increased exposure to zoonotic IAVs.

Funding

Shenzhen Medical Research Fund, National Natural Science Foundation of China, Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, Guangdong Provincial Science and Technology Program, Program for Youzuzhikeyan of Shenzhen University, German Research Foundation, Swiss National Science Foundation.

Source: 


Link: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(26)00271-9/fulltext

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Thursday, July 9, 2026

#Cattle and #human #organoids reveal 2.3.4.4b #H5N1 cross-species #transmission potential and #neuraminidase-specific neutralizing #antibodies in humans

 


Abstract

The unexpected circulation of clade 2.3.4.4b H5N1 influenza viruses in dairy cattle and the transmission to diverse mammalian species poses a pandemic risk. We sought to explore cattle and human respiratory susceptibility to the 2.3.4.4b H5N1 virus. We establish long-term expandable cattle airway and mammary organoids. The 2.3.4.4b H5N1 virus exhibits high replicative fitness in cattle mammary organoids, recapitulating its remarkable mammary tropism. The virus also replicates robustly in cattle airway organoids, suggesting an underrecognized respiratory component in ongoing outbreaks. Interestingly, human airway and nasal organoids are highly susceptible to the 2.3.4.4b H5N1 virus. Yet, a novel organoid-based neutralization assay reveals that N1 antibodies in human sera had cross-neutralizing activity against the 2.3.4.4b H5N1 and ancestral H5N1-VN1194 viruses. The cross-neutralization, exclusively manifested in the organoid-based assay, is enhanced after seasonal influenza vaccination and diminished after depleting N1-specific antibodies. Therefore, cross-neutralizing N1 antibodies are likely limiting zoonotic infection by H5N1 viruses in humans.

Source: 


Link: https://www.nature.com/articles/s41467-026-74345-w

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Friday, July 3, 2026

Mapping #SARS-CoV-2 #immunity after an #XBB.1.5 #booster by antigenic cartography of merged #human and hamster sera

 


Abstract

The ongoing evolution of SARS-CoV-2, particularly the emergence and rapid spread of new immune-evasive variants, continues to challenge the durability of vaccine-induced protection. Understanding how repeated variant exposures shape neutralizing antibody breadth is therefore essential for optimizing booster design. Here, we investigated polyclonal neutralizing antibody responses in individuals who received a bivalent (ancestral + BA.4/5) boost followed by an additional monovalent XBB.1.5 boost, with and without breakthrough infection, against a diverse panel of SARS-CoV-2 variants. To visualize human multi-exposure immunity in antigenic space via antibody landscapes, we extended our existing human sera-based antigenic map with hamster sera infected with more recent variants. The hamster sera allowed us to map BA.2.86 and JN.1 variants, which largely escape human single exposure sera. Our analysis of human multi-exposure sera revealed that the number and type of exposures significantly shaped antibody landscapes. The XBB.1.5 booster immunization notably increased neutralizing antibody titers across variants, elevating the height of the antibody landscape. However, titers against more recent Omicron variants, such as JN.1, were low despite booster administration. These findings highlight the dynamic nature of SARS-CoV-2 immunity and emphasize the need for continuous monitoring and adaptation of vaccine strategies to maintain effective protection against emerging variants.

Source: npj Vaccine, https://www.nature.com/npjvaccines/

Link: https://www.nature.com/articles/s41541-026-01516-7

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Thursday, July 2, 2026

#COVID19 #vaccination induces cross-neutralisation of #sarbecoviruses related to #SARS-CoV-2

 


Abstract

The combined threats of future sarbecovirus zoonosis and continually emerging SARS-CoV-2 VOCs highlight the need to assess the breadth of existing SARS-CoV-2 vaccine-mediated protection. Here, we investigate a cohort of older individuals who received four COVID-19 vaccine doses, for potential cross-neutralisation against lentiviral particles bearing spikes from either Omicron VOCs or other sarbecoviruses. Despite recent fourth bivalent mRNA vaccine doses (encoding SARS-CoV-2 Wu-1 and Omicron spikes), neutralisation of Omicron lineage VOCs was reduced compared to Wu-1, consistent with an imprinted immune response. Similarly, particles bearing either SARS-CoV-1 or a SARS-CoV-1-related bat sarbecovirus spike were neutralised less efficiently than Wu-1. Unexpectedly, however, we observed that particles with spikes from two animal SARS-CoV-2-related viruses, BANAL-20-52 from bats and a pangolin CoV, were significantly more sensitive to serum neutralising antibodies than SARS-CoV-2 Wu-1 itself. These surprising findings suggest that vaccine-mediated adaptive immunity may provide efficient cross-neutralisation and potential protection against certain animal sarbecoviruses.

Source: npj Vaccines, https://www.nature.com/npjvaccines/

Link: https://www.nature.com/articles/s41541-026-01469-x

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Thursday, June 25, 2026

Cross-clade #vaccination to overcome #sarbecovirus or #merbecovirus #neutralization gaps

 


Highlights

    • Multiplex sVNT profiles neutralizing antibodies across two zoonotic viral families

    • Pre-pandemic serosurveillance identifies human exposure to ACE2-using MERS-like viruses

    • Pathogen-specific vaccination leaves major neutralization gaps against related viral clades

    • Cross-clade prime-and-boost vaccination elicits broad-spectrum neutralizing antibodies


Summary

The coronavirus disease 2019 (COVID-19) pandemic highlights the importance of identifying high risk pathogens, defining the immunity gaps and developing preemptive vaccination strategies. Here, we establish a high-resolution surrogate virus neutralization test detecting neutralizing antibodies against multiple virus families simultaneously, demonstrating good concordance with traditional assays. Extensive serosurveillance of pre-pandemic sera from different continents reveals low prevalence human exposures to different beta-coronaviruses, and identifies individuals with prior exposure to ACE2-binding MERS-like viruses. Furthermore, COVID-19 vaccination induces significant cross-neutralizing antibodies against clade 1b, 1c, and 3 but not clade 1a sarbecoviruses. Similarly, MERS and Nipah convalescent sera neutralize cognate viruses but have limited cross-neutralization against other related merbecoviruses and henipaviruses that utilize DPP4 and ephrin B2 receptors. Finally, a cross-clade prime-and-boost vaccination strategy using antigenically distinct antigens could induce broadly neutralizing antibodies against related viruses beyond vaccine antigens, supporting broad-spectrum beta coronavirus vaccine development.

Source: 


Link: https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00522-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112472600522X%3Fshowall%3Dtrue

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Wednesday, June 24, 2026

Identification of HLA-A33-restricted #CD8+ T cell epitopes from avian #influenza #H5N1

 


Abstract

The rapid evolution of avian influenza A/H5N1, including the recent U.S. clade 2.3.4.4b outbreak, highlights its pandemic potential and the urgent need for durable, broadly protective vaccines. Given the capacity of CD8+ T cells to mediate cross-strain immunity, we investigated whether geographically distinct HLA-A33 allotypes, HLA-A*33:01 in East/Southeast Asia and HLA-A*33:03 in South Asia, differentially shape the influenza immunopeptidome and influence antiviral immunity. Antigen-presenting cells overexpressing HLA-A*33:01 or HLA-A*33:03 were transfected with single A/H5N1 antigens or infected with A/X-31 (H3N2) as a control comparison representing current seasonal influenza virus. We identified novel ligands restricted to HLA-A*33:01 (57 from A/H5N1; 55 from A/X-31) and HLA-A*33:03 (29 from A/H5N1; 45 from A/X-31). Although fewer peptides were recovered for HLA-A*33:03, a larger proportion of A/X-31-derived peptides were predicted as high-affinity binders (74%) compared with HLA-A*33:01 (61%), indicating qualitative differences in antigen presentation. To determine immunogenicity, peripheral blood lymphocytes from HLA-A*33:03-positive, A/H5N1-naĂ¯ve donors were stimulated with four conserved peptides: PB2GTF, PB2KTY, NPSVQ and PB1MTK. All elicited robust CD8+ T cell activation despite the absence of prior A/H5N1 exposure, demonstrating cross-recognition by memory T cells primed against seasonal influenza. These findings define HLA-A33-restricted influenza epitopes and reveal allotype-specific presentation features that shape CD8+ T cell immunity. Conserved, immunogenic peptides identified here represent promising candidates for rational design of broadly cross-reactive vaccines to protect HLA-A33-expressing populations against severe A/H5N1 disease. Data are available via ProteomeXchange with identifier PXD078870.


Competing Interest Statement

AWP is a scientific advisor for Bioinformatics Solutions Inc (Canada), a shareholder and scientific advisor for Evaxion Biotech (Denmark), and a co-founder of Resseptor Therapeutics (Australia). These organisations had no role in the design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript or in the decision to publish the results. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Funder Information Declared

NHMRC, 1122099, 2016596

Source: BioRxIV, https://www.biorxiv.org/

Link: https://www.biorxiv.org/content/10.64898/2026.06.21.733083v1

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Tuesday, June 16, 2026

#Antibodies to #influenza A virus #hemagglutinin and #neuraminidase limit egress and alter the physical properties of released virus particles

 


Abstract

Influenza A virus (IAV)-specific antibodies neutralize mature virions by inhibiting functional sites or, in some cases, by promoting virion aggregation. Many antibodies also act on infected cells to reduce virion yields, but the underlying mechanisms and effects on the physical properties and function of released virus particles remain incompletely characterized. Here we use flow virometry to acquire high-sensitivity yield and size measurements of virus particles released in the presence of antibodies. Combined with digital-droplet PCR and electron microscopy, this approach enables comprehensive characterization of antibody-induced changes in particle genome-content and morphology. We show that antibodies rapidly and dynamically alter released particle distributions, reducing yields and inducing the production of larger particles. Both effects result in part from aggregation induced by crosslinking of viral antigen on the infected-cell surface and inhibition of viral NA. However, yield reduction is not fully explained by aggregation, and a subset of induced larger particles are elongated virions. Finally, particles formed in the presence of HA stem-binding antibody, which does not inhibit attachment of mature virions, show reduced attachment in subsequent rounds of infection. Altogether, we uncover an unappreciated mechanism by which antibodies interfere with viral infection that occurs only during budding and release. Our work highlights the necessity of studying how the immune response shapes virus populations in the context of active infection processes.


Competing Interest Statement

T.I. is involved on a patent related to the flow virometry methodology: PCT/US2022/042125, status pending. The authors declare no other competing interests.


Funder Information Declared

Intramural Research Program of the National Institutes of Health (NIH), ZIAAI001385

G. Harold & Leila Y. Mathers Foundation, https://ror.org/02a7hjv13

Source: 


Link: https://www.biorxiv.org/content/10.64898/2026.06.15.729605v1

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Wednesday, June 10, 2026

#Antigenic mapping of #H2 #influenza viruses recognized by #ferret and #human sera and predicting antigenically significant sites

 


ABSTRACT

Influenza viruses cause hundreds of thousands of infections globally every year. In the past century, seasonal influenza viruses have included H1N1, H2N2, and H3N2 strains. H2N2 influenza viruses circulated in the human population between 1957 and 1968. Previously, our group demonstrated a lack of H2N2 influenza virus immunity in individuals born after 1968, as well as the effectiveness of hemagglutinin (HA)-based vaccines for multiple influenza virus subtypes. In this study, H2 antigenic maps and radial graphs were generated using previously published data from H2 HA vaccinations of ferrets and seasonal influenza vaccinations of humans. The antigenic maps revealed a stark difference in the clustering of HA antigens between ferrets and humans, and the radial graphs showed that specific antigen recognition varies greatly among different influenza preimmune ferrets. These maps also revealed the significant impact that different pre-existing immunities have on antigenic recognition and clustering of antigens after vaccine boost. From these data, we predicted two possible antigenically significant sites containing various mutations that have not been previously reported, and showed that one of these sites is relevant using mouse antisera.

Source: 


Link: https://journals.asm.org/doi/10.1128/msphere.00022-26

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Tuesday, June 9, 2026

Egyptian rousette #bat humoral #immunity to #H9 #influenza hemagglutinin

 


Abstract

In mammals, antibodies are central to antiviral defense, but they can also impose selective pressure that drives viral evolution. The interplay between viral antigenic variation and host antibody diversification constitutes a molecular arms race that influences pathogenicity, transmission, and spillover risk. Bats are reservoirs for zoonotic viruses with pandemic potential yet they appear to tolerate infection without overt disease. Although distinctive features of bat innate immunity have been described, the role of adaptive immunity, particularly antibody-mediated responses, remains largely undefined. Moreover, how antibody evolutionary pressure operates in bats is unknown, in part because tools to interrogate bat B cell responses at the monoclonal level are limited. Here, we developed a yeast surface display library of bat antibodies derived from splenic RNA of wild-caught Egyptian rousette bats to interrogate humoral responses to the bat-derived H9 influenza hemagglutinin. We isolated monoclonal antibodies recognizing the hemagglutinin (HA) antigen and defined their gene usage, somatic hypermutation frequency, binding affinities, and breadth. We then used cryo-EM to structurally characterize three bat antibodies in complex with HA engaging distinct antigenic sites. Together, these data enable direct comparison with human anti-influenza antibodies highlighting similarities in humoral immunity across mammals and provides a tool to examine bat antibody responses to other potential zoonotic viruses.


Competing Interest Statement

The authors have declared no competing interest.

Source: 


Link: https://www.biorxiv.org/content/10.64898/2026.06.04.730146v1

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Saturday, May 30, 2026

Sex differences in #vaccine-induced #neuraminidase cross-recognition and #protection against #H5N1 in mice

 


Abstract

Despite concerns about the spread and pandemic potential of H5N1, there is no commercial H5N1 vaccine. Seasonal influenza vaccines offer some cross-protection against H5N1, but to date there has been no consideration of whether protection differs between the sexes. We investigated immune responses and protection in adult male and female C57BL/6 mice following vaccination with either inactivated H1N1 or H5N1 (LAIV backbone) virus vaccines. Vaccination induced strong homologous antibody responses, with females generating greater total IgG than males against both H1N1 and H5N1 vaccine, which was primarily mediated by greater IgG responses to neuraminidase (NA) than hemagglutinin (HA) protein. IgG cross-recognition of H1N1 also was greater among H5N1 vaccinated females and was primarily caused by greater IgG responses to N1. IgG2b and IgG2c were the primary isotypes generated in response to these vaccines, with females having greater IgG2b responses and greater binding to FcγRIV for avian and human NA than males in response to both homologous and heterologous vaccination. Antibody-dependent complement deposition was measured as an FcR-mediated non-neutralizing response against HA and NA and was robust in both sexes. Vaccinated females had greater neutralizing antibody titers than males against the homologous vaccine virus, 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 cleared virus faster than their male counterparts. These findings highlight that female-biased NA-specific antibodies result in greater cross-protection and should be considered in studies of influenza vaccines.


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

Source: 


Link: https://www.biorxiv.org/content/10.64898/2026.05.26.728011v1

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Saturday, May 16, 2026

Membrane-anchored #influenza #neuraminidase vaccine drives #human-like broadly protective B cell responses

 



Abstract

Influenza neuraminidase (NA) is a promising target for universal flu vaccines, yet eliciting potent B-cell responses against its conserved epitopes remains challenging. Here, we developed a membrane-anchored, folding-domain-free NA (mNA) that elicited superior head-specific germinal center B cell and antibody responses compared to soluble tetrameric NA. In non-human primates, mNA immunization induced cross-reactive memory B cell (MBC) responses, expanding clones with the conserved DR motif in HCDR3, a hallmark of human broadly reactive NA antibodies. These MBCs conferred cross-inhibitory activity against diverse NA variants and in vivo cross-protection. Cryo-EM analysis revealed that the 554-C2 clone targets the conserved enzymatic pocket via the DR motif, while the 554-C1 clone recognizes previously uncharacterized epitopes at the interface between two adjacent N2 monomers, effectively reducing plaque formation by contemporary H3N2 strains. Our findings highlight the immunological advantages of membrane-anchoring, providing a robust strategy for designing next-generation vaccines against influenza and other pathogens.


Competing Interest Statement

Westlake University has filed for patent protection for mNA used as an influenza vaccine.


Funder Information Declared

State Key Laboratory of Gene Expression, SKLGE-ZX-2025007

Zhejiang Provincial Key Laboratory Construction Project, 2024ZY01026, 2024E10060, 2024E10052

Natural Science Foundation of Zhejiang province, LR26H190001

National Natural Science Foundation of China, 82471855, 825B2062, 82330054, 82502209, 32471303

Source: 


Link: https://www.biorxiv.org/content/10.64898/2026.05.13.724804v1

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Wednesday, May 13, 2026

Pre-existing systemic and #nasal #antibodies against avian #H5 #influenza A viruses vary according to #childhood imprinting

 


Abstract

Avian influenza A viruses (IAV) pose a constant pandemic threat, with the recent 2.3.4.4b clade of the H5 subtype causing high pathogenicity and spreading across animal species and geographic locations. Understanding human pre-existing immunity to avian H5 IAV can inform on population susceptibility, a critical aspect of pandemic preparedness. To that end, we analysed the IAV HA-specific antibodies across individuals born between 1928-1999 with different early life exposures to IAV subtypes. Individuals born prior to 1957 had the highest pre-existing serum antibodies to group 1 HA antigens, including the 2.3.4.4b H5 and a group 1 HA stem antigen. These birth-year-specific patterns were not reflected in the limited pre-existing serum neutralising antibodies detectable against a 2.3.4.4b H5 IAV or in H5-specific memory B cell populations. They were however evident in pre-existing nasal IgG and IgA titres to H5, which were greater in individuals born prior to 1957. Our findings demonstrate that the immunological biases afforded by early life exposure extend to antibodies detected in the nasal mucosa, the site of IAV replication.

Source: 


Link: https://www.biorxiv.org/content/10.64898/2026.05.08.723737v1

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