Prior #immunity to seasonal #influenza #H3N2 virus confers varying levels of cross - #protection against challenge with clade 2.3.4.4b #H5N1, #H7N9, or #H9N2 virus in a #ferret model

 

ABSTRACT

Evaluating how prior immunity to seasonal influenza viruses influences subsequent zoonotic influenza A virus (IAV) infection in animal models is critical for pandemic preparedness. In this study, we investigated the cross-protective effect of pre-existing A(H3N2) immunity in ferrets challenged with three distinct subtypes of zoonotic IAVs: low pathogenic A(H7N9) and A(H9N2) viruses, and highly pathogenic clade 2.3.4.4b A(H5N1) virus. Our results show that A(H3N2) preimmunity conferred some protection against A(H5N1) and A(H9N2) virus infection, as evidenced by more rapid viral clearance in the upper respiratory tract, reduced virus shedding in the nasal wash on select days post-inoculation, and a lowered frequency of viral detection in specific tissues compared with naive animals. In contrast, A(H3N2) preimmunity provided minimal cross-protection against A(H7N9) infection, as weight loss and viral dissemination in tissues were not significantly reduced in A(H3N2) preimmune ferrets relative to naive animals. These findings highlight the variable breadth and magnitude of cross-protection elicited by prior seasonal IAV immunity against zoonotic influenza virus challenges in the ferret model. Seasonal influenza A(H3N2) preimmunity provided differing levels of cross-protection against zoonotic influenza A virus infections in ferrets.

Source: 

Link: https://journals.asm.org/doi/10.1128/spectrum.03974-25

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Evaluation of Cross-Immunogenicity of #Ferret #Antisera Following Immunization with #H5N1 #Vaccine Strains

 

Abstract

Background: 

Highly pathogenic avian influenza H5N1 viruses of clade 2.3.4.4b have spread globally since 2021, causing extensive outbreaks in avian populations and repeated spillovers into diverse mammalian hosts, including humans. These cross-species transmission events highlight ongoing pandemic risks and underscore the need for vaccine strategies that reflect viral evolution at the human–animal interface. Despite the availability of licensed H5 vaccines and newly recommended World Health Organization (WHO) candidate vaccine viruses (CVVs), the extent to which these vaccines elicit cross-reactive antibody responses against contemporary clade 2.3.4.4b viruses, including mammalian spillover isolates of avian origin, remains incompletely characterized. 

Method: 

In this study, ferret antisera were generated using four WHO-recommended H5 CVVs, including a clade 1 strain (A/Vietnam/1194/2004) and three clade 2.3.4.4b strains (A/Astrakhan/3212/2020, A/American wigeon/South Carolina/22-000345-001/2021, and A/Ezo red fox/Hokkaido/1/2022), formulated with alum adjuvant to reflect licensed vaccine formulation used in national preparedness programs. Antibody responses and cross-reactive activity were evaluated using hemagglutination inhibition (HI) and microneutralization (MN) assays against homologous vaccine strains and a feline-origin clade 2.3.4.4b H5N1 field isolate from Korea, A/Feline/Korea/SNU-01/2023. 

Results: 

Antisera induced by clade 2.3.4.4b CVVs showed cross-reactive antibody responses against homologous and heterologous clade 2.3.4.4b viruses and demonstrated measurable HI and MN responses against the feline-origin field isolate. In contrast, antisera raised against the clade 1 Vietnam CVV exhibited limited cross-reactivity against clade 2.3.4.4b viruses. Overall, clade 2.3.4.4b CVVs generally showed higher antibody responses than the clade 1 vaccine strain across multiple panels. 

Conclusions: 

These findings provide descriptive insights into antigenic differences between clade 1 and clade 2.3.4.4b viruses and support the antigenic relevance of clade 2.3.4.4b CVVs for contemporary H5N1 strains. This study highlights the importance of ongoing antigenic evaluation to inform vaccine strain selection within a One Health framework.

Source: 

Link: https://www.mdpi.com/2076-393X/14/4/301

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#SARS-CoV-2 #vaccination and #infection elicit cross-neutralizing responses against clade 3 and 4 #sarbecoviruses

 

Abstract

Two sarbecoviruses, SARS-CoV-1 and SARS-CoV-2 that engage ACE2 through their receptor-binding domains, have caused major human outbreaks. The pandemic potential of sarbecoviruses has prompted the discovery and classification of bat and other zoonotic sarbecoviruses that are also able to use human ACE2 or ACE2 ortholog receptors for infection. However, the current human immunological landscape reactive to these SARS-CoV-2-related viruses is not well profiled. Using a panel of pseudotyped lentiviruses expressing only spike proteins, we assess serum neutralization activity against clade 3 and 4 (also designated as clade 1c) receptor binding domain classified sarbecoviruses in a cohort who received a primary series of COVID-19 mRNA vaccines as well as individuals before and after infection with BA.5 or XBB.1.5 variants. Detectable neutralizing responses against clade 3 and 4 sarbecoviruses are observed in both vaccinees and convalescents and are comparable in magnitude to titers against SARS-CoV-2 variants. Infection with XBB.1.5 increases neutralization titers against SARS-CoV-2 variants as well as against clade 3 and 4 sarbecoviruses. Collectively, our findings suggest that the current immunologic landscape of vaccination and infection may confer some level of immunity against a variety of clade 3 and 4 sarbecoviruses, which should inform future pandemic response and pan-sarbecovirus countermeasure efforts.

Source: 

Link: https://www.nature.com/articles/s41467-026-71662-y

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#Birth #imprinting effects on the #antibody responses of #H7N9 patients from 2013-2018 in #China

 

Abstract

Background

There is an urgent need to understand the immune correlates of protection against avian influenza viruses (AIV), where pre-existing immunity may be limited.

Methods

Here, we characterized the antibody response in 12 severely ill A(H7N9) patients and examined its association with early-life imprinting and clinical outcome.

Results

We find that A(H7N9) patients imprinted with A(H2N2) during early life show minimal H7-IgM and a rapid IgG response across diverse hemagglutinin subtypes. They also have more high avidity H7-antibodies compared to older or younger patients. Early antibody titers against seasonal H1, H3, and conserved stalk domains trend negatively with clinical severity in A(H7N9) infection, while an inverse pattern is observed following severe A(H1N1) infection, potentially suggesting a different mechanism of immune regulation between seasonal and avian influenza virus infections.

Conclusions

These data provide direct serological evidence that birth imprinting profoundly shapes the humoral immune landscape during zoonotic influenza infection and may influence subsequent disease outcome.

Source: 

Link: https://www.nature.com/articles/s43856-026-01554-1

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High #risk of hypoxemic #COVID19 #pneumonia in #myasthenia gravis patients with type I IFN #autoantibodies

 

Abstract

Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-α2 and IFN-ω in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-α2 and IFN-ω in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng/mL of both IFN-α2 and IFN-ω (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-α2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.

Competing Interest Statement

J.-L. C. is an inventor on patent application PCT/US2021/042741, filed July 22, 2021, submitted by The Rockefeller University and covering the diagnosis of susceptibility to, and the treatment of, viral disease, and viral vaccines, including COVID-19 and vaccine-associated diseases. None of the other authors has any conflict of interest to declare.

Funding Statement

The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Fisher Center for Alzheimer s Research Foundation, the Meyer Foundation, the JPB Foundation, the Stavros Niarchos Foundation (SNF) as part of its grant to the SNF Institute for Global Infectious Disease Research at The Rockefeller University, the French Agence Nationale de la Recherche (ANR) under the France 2030 program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU202503020018), the ANR-RHU program ANR-21-RHUS-0008, ANR GENVIR (ANR-20-CE93-0003), ANR AABIFNCOV (ANR-20-CO11-0001) and ANR GenMISC (ANR-21-COVR-0039), AI2D (ANR-22-CE15-0046) projects, the European Union s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 101057100 (UNDINE), the Square Foundation, Grandir - Fonds de solidarite pour l enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea and Bowery Advisory Group; The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), William E. Ford, General Atlantic s Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic s Co-President, Managing Director and Head of Business in EMEA, and the General Atlantic Foundation, Institut National de la Sante et de la Recherche Medicale (INSERM), REACTing-INSERM and Paris Cite University. For the collection and biobanking of MG samples, RLP and FT acknowledge support provided by the FP6 program (MYASTAID, LSHM-CT-2006-037833), FIGHT-MG (HEALTH-2009-242-210). N.L. was supported by the Swedish Research Council (no 2021-03118) and the Goran Gustafsson Foundation (no 2141 and 2247). TLV was supported by a Poste CCA-INSERM-Bettencourt (with the support of the Fondation Bettencourt-Schueller). P.B. was supported by the French Foundation for Medical Research (FRM, EA20170638020), the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller), and a Poste CCA-INSERM-Bettencourt (with the support of the Fondation Bettencourt-Schueller).

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.03.27.26349525v1

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Monoclonal #antibodies from #COVID19 convalescent #patients target cryptic epitopes for broad #SARS-CoV-2 #neutralization

 

Significance

The rapid emergence of SARS-CoV-2 variants that efficiently spread and evade antibody-based treatments underscores the need for countermeasures that remain effective as the virus evolves. In this study, two human mAbs, TAU-1109 and TAU-2310, isolated from individuals who recovered from SARS-CoV-2 infection early in the pandemic, neutralize all tested variants of concern, including recent Omicron sublineages. Structural and functional analyses show that these antibodies recognize conserved, cryptic regions on the spike’s RBD and disable the virus by destabilizing the spike trimer and triggering premature loss of the S1 subunit, thereby preventing cell entry. These findings reveal a naturally occurring, broadly protective antibody mechanism and highlight conserved surfaces on the receptor-binding domain as promising blueprints for next-generation COVID-19 therapies and vaccines.

Abstract

The COVID-19 pandemic, which has resulted in over seven million global fatalities, poses a substantial threat to public health and precipitated a global economic crisis. Emerging variants of concern (VOCs) with enhanced transmissibility and improved immune evasion may compromise the efficacy of current antiviral and immunotherapies, necessitating comprehensive investigations into the immune response to SARS-CoV-2. The conformational dynamics of the receptor binding domain in SARS-CoV-2 spike and the presentation of neutralizing antibody epitopes influence viral transmission and infection rates. In this study, we have identified highly conserved non-receptor-binding motif epitopes for two potent monoclonal antibodies (mAbs), TAU-1109 and TAU-2310, isolated from convalescent human patients, which contribute to the broad neutralizing activity of these mAbs against all the circulating VOCs, including the recently emerged Omicron subvariants. We employed high-resolution structural data in conjunction with systematic biochemical investigation to elucidate the neutralization mechanism of TAU-1109 and TAU-2310. The mechanism involves antibody-mediated destabilization of the spike trimer, resulting in the premature shedding of the S1 subunit and rendering the spike incapable of mediating host cell entry. The identification of conserved cryptic epitopes in our study advances the mechanistic understanding of immune response against SARS-CoV-2, providing alternative avenues for the development of universal therapeutic antibodies and vaccines to combat COVID-19.

Source: 

Link: https://www.pnas.org/doi/abs/10.1073/pnas.2523864123?af=R

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Intravenous #immunoglobulin #treatment for #longCOVID: a case report of clinical and immunological findings

 

Summary

A previously healthy 39-year-old man developed highly symptomatic post-COVID-19 condition (also known as long COVID) marked by cognitive dysfunction, disabling fatigue, and autonomic symptoms unresponsive to multiple multidisciplinary interventions. Given the presence of markedly elevated serum autoantibodies against G protein-coupled receptors, high-dose intravenous immunoglobulin therapy was initiated at 400 mg/kg per day for 5 consecutive days. After 4 weeks, a maintenance dose of 500 mg/kg was administered for 1 day, followed by two further maintenance cycles consisting of 500 mg/kg per day for 3 consecutive days, each given at 4-week intervals. In parallel, the patient underwent a cognitive stimulation intervention. Neurological symptoms were assessed with the Fatigue Assessment Scale and the WHO Disability Assessment Schedule 2.0, and the immunological profile was longitudinally analysed during intravenous immunoglobulin treatment. Fatigue scores normalised, neurocognitive performance returned to normal value, and quality of life improved after the first infusion and fully recovered within 1 year. Immunological profiling revealed the presence of an inverted CD4 to CD8 T-cell ratio that persisted during the whole follow-up. We also identified a CD8+ T cell–monocyte complex and spontaneous IFNγ release. Intravenous immunoglobulin therapy was associated with a significant reduction of these complexes, spontaneous IFNγ and TNF production, markers of endothelial inflammation, and circulating autoantibody titres. This patient provides exploratory evidence that high-dose intravenous immunoglobulin was associated with sustained clinical recovery from long COVID over 1 year of follow-up, accompanied by immunological changes consistent with modulation of post-viral immune dysregulation, including a reduction in pathogenic T cell–monocyte synapses. Although causal inference cannot be established from a single patient, these findings suggest that this cellular interaction can contribute to long COVID and that immunomodulation could represent a rational therapeutic approach to be evaluated in selected patients.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00063-0/abstract?rss=yes

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Porcine #influenza #mAbs to #H3, #H5, and #H7 hemagglutinins recognize H3 egg adapted site and target the HA stem

 

Abstract

Introduction

Monoclonal antibodies (mAbs) are critical tools for elucidating viral evolution, informing vaccine design, and developing antiviral therapeutics. Large-animal models, such as the pig, that closely mirror human immune responses are essential for understanding influenza immunity.

Methods

Pigs were either infected or sequentially immunized with influenza viruses and monoclonal antibodies directed against H3, H5, and H7 influenza virus haemagglutinins were isolated. Antibody specificity, breadth, epitope targeting (head versus stem), neutralizing capacity, and Fc-mediated activity were assessed across influenza subtypes.

Results

Pigs generated both strain-specific and broadly reactive mAbs targeting haemagglutinin head and stem epitopes. An H3-specific mAb (H3–57) selectively recognized the egg-adapted L194P mutation associated with reduced human vaccine effectiveness. H5 and H7 immunization induced neutralizing antibodies, including cross-group stem mAbs reactive with H1, H3, and H5 haemagglutinins. Fc-mediated activity correlated with antibody binding strength rather than epitope location.

Conclusions

These findings demonstrate that pigs mount antibody responses closely resembling those observed in humans, including recognition of conserved stem epitopes and adaptive head mutations. Porcine mAbs represent powerful new tools for dissecting influenza immunity, guiding vaccine design, and enhancing pandemic preparedness using a physiologically relevant large-animal model.

Source: 

Link: https://academic.oup.com/discovimmunology/article/5/1/kyag006/8503709

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Defining #influenza-specific B cells in #vaccine #responders, non-responders and influenza breakthrough #infections

 

Abstract

Although seasonal influenza vaccination programs are effective at a population level, our data from inactivated influenza vaccine (IIV) cohorts in years 2015-2022 reveal that 50-60% of individuals do not seroconvert following immunization. The underlying mechanisms of vaccine non-responsiveness are far from understood. In this study, we sought to define key determinants of optimal B cell immune responses elicited by seasonal influenza vaccination, and to explore why some individuals fail to elicit humoral immunity following immunization. Immune responses associated with seroconversion and vaccine failure from individuals immunized with IIVs were compared at cellular and molecular levels using single-cell transcriptomics. We analyzed HA-specific B cell immunity across vaccine-responders, breakthrough infections and patients hospitalized with acute influenza. Droplet-based single-cell RNA sequencing and VDJ-sequencing of influenza-specific B cells from stored PBMCs was performed using 10x Genomics. Our results show that atypical B cells are the major subset of B cell responses in vaccine non-responders on day 28 post-vaccination. Conversely, individuals who seroconvert had diverse B cell phenotypes. The use of recombinant influenza-specific HA probes allowed us to dissect expression patterns on influenza HA-specific B cells. We found that HA-specific B cells of vaccine non-responders for A/H1N1 and A/H3N2 components displayed elevated atypical-like markers (CD11c, FcRL-5) at baseline, compared to responders. Analysis of differentially expressed genes (DEGs) between responders and non-responders identified differential expression of HLA-DR, CD74, CD83, and CXCR3 genes. We subsequently demonstrated reduced frequencies of HLA-DR-, CD74- and CD83-expressing B cells in patients hospitalized with influenza, compared to healthy participants. Hospitalized influenza patients also had significantly higher proportions of atypical CD21-CD27- B cells. Overall, our data demonstrate an association between elevated frequencies of atypical-like B cells with both lack of seroconversion following immunization and severe influenza infection. These findings broaden our understanding of humoral immunity in influenza vaccination and infection, providing novel insights for vaccination strategies and design.

Competing Interest Statement

Katherine Kedzierska has received paid honoraria from Pfizer. Hayley McQuilten has a consultancy role for Ena Therapeutics

Funder Information Declared

NHMRC

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.03.19.710321v1

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#RSV #infection induces heterologous #protection against #SARS-CoV-2 through γδ T cell-mediated trained #immunity and activation of SARS-CoV-2–reactive mucosal T cells

 

ABSTRACT

Respiratory viruses can infect hosts concurrently or sequentially, potentially influencing each other’s pathogenic trajectory. However, the underlying immune mechanisms governing these interactions remain poorly understood. In this study, we examined whether respiratory syncytial virus (RSV) infection modulates host susceptibility to subsequent SARS-CoV-2 infection using two murine models. We found that prior RSV infection conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Transcriptomic and immunological analyses revealed that RSV activated lung antigen-presenting cells (APCs) and SARS-CoV-2–reactive mucosal T cells by day 9 post-infection, with responses waning by 1 month. RSV also promoted expansion of pulmonary γδ T cells and upregulation of their metabolic pathways. Notably, RSV-infected TCRδ⁻/⁻ mice, which lack γδ T cells, exhibited diminished SARS-CoV-2–reactive mucosal T cell responses, elevated viral loads, and exacerbated lung inflammation following SARS-CoV-2 challenge compared to wild-type controls. These findings suggest that RSV infection induces γδ T cell-mediated trained immunity and primes mucosal T cell responses, thereby providing heterologous protection against SARS-CoV-2.

Source: 

Link: https://journals.asm.org/doi/full/10.1128/jvi.01658-25?af=R

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#Immunity to #hemagglutinin and #neuraminidase results in additive reductions in #airborne #transmission of #influenza #H1N1 virus in #ferrets

 

Abstract

Currently, there is limited knowledge on the impact of immunity to hemagglutinin (HA) and/or neuraminidase (NA) on the transmission of influenza viruses. Therefore, using intramuscular vaccination, intranasal vaccination, or infection with reassortant viruses, we induced immunity to each antigen alone or both antigens combined in ferrets. We then assessed transmission of the 2009 pandemic H1N1 virus from these ferrets to naïve respiratory contacts. For all strategies used to induce immunity, combined immunity to HA and NA resulted in the largest reductions in transmission. Moreover, immunity to HA and NA conferred additive rather than synergistic reductions in transmission. No escape variants emerged in our transmission studies, and logistical regression showed that the probability of transmission was less than 50% when viral titers in donors were reduced to 101.5 and 102 median tissue culture infectious dose per ml on days 1 and 3 postinfection, respectively. These studies define the relationship between immunity to HA and NA on transmission and identify a threshold titer indicative of decreased transmission in ferrets.

Source: 

Link: https://www.science.org/doi/10.1126/sciadv.aea8719

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#Glycoprotein-specific transcriptional response contributes to differential #vaccine #protection against lethal #Ebola virus #infection

 

Abstract

Since the West African Ebola virus (EBOV) epidemic in 2014-2016, recurrent outbreaks of the EBOV-Makona variant have been driven by recrudescence and human-to-human transmission emphasizing the need for effective vaccination strategies. A live-attenuated recombinant vesicular stomatitis virus (VSV)-based vaccine expressing the EBOV-Kikwit variant glycoprotein (VSV-Kik) received FDA approval in December 2019 and provides complete, rapid protection against EBOV-Makona as early as 7 days post-vaccination (DPV). During the 2018-2020 Ebola outbreak, the VSV-Kik vaccine, known as ERVEBO, was administered to lower-risk individuals at a 5-fold dose reduction of the standard 2 × 107 PFU to provide broader population protection. Identification of a protective lower dose providing rapid protection would ease supply burdens during future outbreaks and enhance vaccine coverage. We previously generated a VSV-based vaccine expressing the glycoprotein of the Makona variant (VSV-Mak) which provided complete protection against homologous challenge 28 DPV at as low as 1 × 101 PFU. However, the transcriptional responses engendered by VSV-Mak and VSV-Kik vaccines in the context of early EBOV-Makona challenge have not yet been evaluated. In the current study, we compared transcriptional responses following a low dose (1 × 104 PFU) of lab-grade VSV-Mak or GMP-grade VSV-Kik and subsequent EBOV-Makona challenge 10 DPV. VSV-Kik provided complete protection against heterologous challenge and elicited rapid antiviral transcriptional changes followed by the activation of adaptive immunity. On the other hand, VSV-Mak only provided partial protection and induced minimal transcriptional response. These results highlight a glycoprotein-specific transcriptional response after vaccination despite the high EBOV variant homology.

Source: Vaccine, https://www.sciencedirect.com/journal/vaccine/vol/79/suppl/C

Link: https://www.sciencedirect.com/science/article/abs/pii/S0264410X26002185?via%3Dihub

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Structural #insights into #antibody responses against #influenza A virus in its natural reservoir

 

Abstract

While influenza A virus undergoes rapid antigenic drift in humans, at least some subtypes, such as H3, have relatively stable antigenicity in natural waterfowl reservoirs, despite the presence of immune pressure. However, the underlying mechanisms remain poorly understood. This study identified and characterized 187 antibodies to H3 hemagglutinin from experimentally infected mallard ducks, 18 of which were further analyzed by cryo-EM. Compared with human H3 antibodies, duck H3 antibodies exhibited higher glycan-binding propensity, more balanced immunodominance hierarchy, and targeted distinct epitopes. Other unique features of duck H3 antibodies included a convergent CDR H3-independent heavy chain-only binding mode and an N-glycosylated CDR H3 as decoy receptor. By annotating duck immunoglobulin germline genes, we also demonstrated the importance of gene conversion in duck H3 antibodies. Overall, our findings provide insights into how millennia of coevolution have shaped the interplay between influenza A virus antigenic drift and antibody responses in the natural reservoir.

Competing Interest Statement

N.C.W. consults for HeliXon. The authors declare no other competing interests.

Funder Information Declared

National Institutes of Health, https://ror.org/01cwqze88, R01 AI165692

Carl R. Woese Institute for Genomic Biology, Carl R. Woese Institute for Genomic Biology Postdoctoral Fellowship

Vallee Foundation, https://ror.org/05nmp3276, Vallee Scholars Program

Foundation for Partnership Initiatives in the Niger Delta, https://ror.org/041nz5a71, Searle Scholars Program

Howard Hughes Medical Institute, https://ror.org/006w34k90, Emerging Pathogens Initiative

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

Link: https://www.biorxiv.org/content/10.64898/2026.03.11.711171v1

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Identification of a Key #Hemagglutinin #Mutation Mediating #Antibody Escape in #Influenza #H1N1pdm09 Viruses

 

Abstract

Background: 

The H1N1 influenza A virus evades host immunity through continuous antigenic drift, posing a significant challenge to broad-spectrum neutralizing antibody therapies. This study aims to systematically evaluate the neutralizing capacity of the broad-spectrum antibody C12H5 against H1N1 strains from different eras and identify key immune escape mutation sites. 

Methods: 

Three representative H1N1 virus strains from 2009, 2018, and 2023 were selected. An antigen–antibody binding prediction model based on the ESM-2 large language model was constructed by integrating 48,762 GISAID sequence data and deep mutation scanning data from the Bloom laboratory. Candidate escape sites were screened using SHAP (SHapley Additive exPlanations) value analysis. Mutant viruses were constructed via reverse genetics, and their neutralizing capacity and replication fitness were validated through hemagglutination inhibition assays, microneutralization assays, and viral growth kinetics analysis. 

Results: 

Machine learning scoring identified five potential escape sites, with K147 exhibiting the highest overall score (0.92). SHAP analysis revealed that the K147 site within the HA protein’s 130-loop region received the highest importance score (0.28), significantly surpassing other candidate sites. Experimental validation revealed that the K147N mutation reduced neutralizing potency against C12H5 by 8-fold (from 1:1024 to 1:128) and approximately 6-fold in microneutralization assays (from 8.3 log2 to 5.7 log2), while exhibiting a replication advantage in MDCK cells. Microneutralization assays further confirmed an approximately 6-fold reduction in neutralization sensitivity. Structural analysis indicated that K147 is located at the periphery of the HA receptor-binding domain, immediately adjacent to the receptor-binding site. 

Conclusions: 

K147N is identified as the critical mutation mediating C12H5 immune escape, and this mutation has emerged in 2023 circulating strains. This study provides important molecular targets and early warning mechanisms for broad-spectrum antibody optimization and influenza vaccine updates.

Source: 

Link: https://www.mdpi.com/1999-4915/18/3/349

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Compartmentalized #cytokine #networks and systemic immune remodeling in #bovine mammary #H5N1 #infection.

 

Abstract

Highly pathogenic avian influenza A H5N1 has recently expanded its mammalian host range; in 2024, genotype B3.13 emerged in U.S. dairy cattle with pronounced mammary tropism. In the past, Influenza A virus immunology has been characterized primarily in respiratory infection models, whereas this study delineates immune responses after intramammary infection. An intramammary H5N1 challenge in Jersey cows in the early dry-off period enabled integration of dose- and compartment-resolved (alveoli versus teat cistern) cytokine and chemokine profiles with peripheral leukocyte dynamics and H5/N1-specific antibody responses. Infection-induced quarter-restricted, monophasic inflammatory networks peaking at 3 to 7 days post-infection, coordinated peripheral myeloid expansion and IFN gamma competent lymphocyte activation, and rising antibody titers across quarters.

Competing Interest Statement

The J.A.R. laboratory received support from Tonix Pharmaceuticals, Xing Technologies, Genus plc and Zoetis, outside of the reported work. J.A.R. is an inventor of patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by Kansas State University.

Funder Information Declared

Funding for this study was partially provided through grants from the Howard Hughes Medical Institute Emerging Pathogens Initiative (NCW), the National Bio and Agro-Defense Facility (NBAF) Transition Fund from the State of Kansas, the BRI Endowed Professorship in Animal Infectious Diseases (JAR), the AMP Core of the Center of Emerging and Zoonotic Infectious Diseases (CEZID) from the National Institute of General Medical Sciences (NIGMS) under award number P20GM130448 (JAR, IM), and the NIAID supported Centers of Excellence for Influenza Research and Response (CEIRR, contract number 75N93021C00016 to JAR).

Source: 

Link: https://www.biorxiv.org/content/10.64898/2026.03.06.710145v1

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#Panzootic #H5 #influenza viruses acquired #resistance to human head interface #antibodies

 

Abstract

Antibodies to the influenza hemagglutinin protein (HA) confer the strongest protection against infection. Immunity elicited by endemic, seasonal, human viruses is correlated with diminished disease severity and death caused by antigenically novel viruses. Antibodies to the HA head interface are broadly protective and abundant in human serologic and memory repertoires. Notably, few head interface antibodies from H5 naive donors are reported to bind H5 HAs. We find head interface antibodies engage a wide range of H5 isolates but fail to engage most isolates from the goose Guangdong (GsGd) lineage. We identify a single substitution, P221S, largely dictates antibody binding. Phylogenetic analysis indicates that P221S arose in a Chinese avian reservoir by the year 2000. Descendants of these viruses have caused the current global panzootic and have achieved sustained mammal-mammal transmission in farmed and wild mammals. Our findings demonstrate that viral evolution in non-mammalian species can, by chance, produce viruses that resist broadly protective human antibody responses.

Source: 

Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014005

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Unveiling the #epitope #repertoires and protective roles of #MERS-CoV-specific T cells in mice

 

Highlights

• MERS-CoV structural proteins and ORFs potently induce T cell responses in mice

• MERS-CoV-specific T cell epitope repertoires are identified in C57BL/6 and BALB/c mice

• Airway ORF4b208-CD4+ and ORF5167-CD8+ T cells are optimal effector T cells

• ORF4b208 and ORF5167-specific T cells protect mice against MERS-CoV infection

Summary

Since its initial emergence in 2012, MERS-CoV has remained endemic and a global health threat. While accessory proteins (ORFs) are known for immune evasion, their role in adaptive immunity is unexplored. This study systematically investigated T cell responses against MERS-CoV ORFs. We mapped epitope repertoires targeting structural proteins and ORFs in C57BL/6 and BALB/c mice, revealing that ORFs potently induced virus-specific T cells. Notably, ORF5 induced the dominant CD8+ T cell responses in BALB/c mice. Further analysis revealed that ORF4b208-specific CD4+ and ORF5167-specific CD8+ T cells in the respiratory tract exhibited polyfunctional cytokine profiles, high antigen sensitivity, and potent in vivo cytotoxicity. These specific T cells played protective roles during MERS-CoV infection by promoting viral clearance. Collectively, this study identified MERS-CoV-specific T cell epitopes and elucidated the roles of ORF4b- and ORF5-specific T cells, enhancing our understanding of anti-MERS-CoV T cell responses and advancing vaccine design strategies against MERS-CoV.

Source: 

Link: https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00121-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112472600121X%3Fshowall%3Dtrue

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Longitudinal #assessment of functional #antibodies to a novel #influenza virus strain across age groups

 

Abstract

Newly emerging influenza virus strains pose a constant threat as they encounter a population lacking neutralizing antibodies against the new strain. However, cross-reactive non-neutralizing antibodies (nnABs) may be present and assist in mitigating disease symptoms via various effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Although nnABs to influenza virus have received more attention lately, little information is available on their age-related prevalence, steady-state levels, functional properties, and changes in these parameters over time. Using longitudinal samples from adolescents, adults, and older adults, collected before and after the 2009 swine flu pandemic, we comprehensively characterized the specificity and functionality of nnAB responses against H1N1 pandemic 2009 (H1N1pdm09) virus. Remarkably, all participants exhibited cross-reactive antibodies to this virus before having encountered it through infection or vaccination, with the highest baseline levels observed in older adults. The levels of these IgG antibodies showed a strong correlation with engagement of fragment crystallizable γ receptor IIIa (FcγRIIIa) and ADCC activity, both of which were notably lower in adolescents compared to adults and older adults. Without infection or vaccination, average amounts of H1N1pdm09-reactive antibodies remained relatively stable on population level over the 5-year study period. However, on an individual level, substantial increases and decreases occurred. H1N1pdm09 infection or vaccination significantly enhanced specific antibody levels and the FcγRIIIa-engaging capacity of these antibodies in all age groups. ADCC-mediating antibodies increased however only in adolescents, reaching the same level as observed in the adult groups. Taken together, our results demonstrate the presence of cross-reactive, non-neutralizing, functional, and boostable antibodies against a never-encountered influenza virus strain across all age groups. These antibodies can potentially contribute to protection from severe disease. Accordingly, in case of a newly emerging virus, their further enhancement by vaccination could be beneficial as an immediate protective measure before a strain-specific vaccine becomes available.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study did not receive any funding

Source: 

Link: https://www.medrxiv.org/content/10.64898/2026.02.21.26346781v1

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Overcoming immune #imprinting with the #COVID19 #LP81 #mRNA #boosters

 

{Summary}

In summer 2025, the SARS-CoV-2 JN.1 sublineage became dominant with more resistant variants, such as XFG, LP.8.1, and NB.1.8.1. COVID-19 mRNA boosters were therefore updated for the 2025–2026 season to target the LP.8.1 spike.1 Previous boosters, particularly the WA1/2020+BA.5 bivalent booster, were characterised by substantial boosting of the ancestral strain, a phenomenon known as immune imprinting.2,3 We therefore evaluated whether the phylogenetically more distant LP.8.1 mRNA booster would preferentially boost currently circulating strains. Recent data from European and Asian populations have reported the immunogenicity of the LP.8.1 mRNA booster.4,5 Herein, we report the immunogenicity of the LP.8.1 mRNA booster in a US population with a different exposure history and high population immunity. We show that the LP.8.1 mRNA booster induced neutralising antibody (NAb) and binding antibody responses, primarily to the vaccine-matched L.P.8.1 variant and other currently circulating variants and lower responses to the ancestral WA1/2020 strain.

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Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00050-2/fulltext?rss=yes

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Immune history confers #antibody - and T cell-dependent cross-protection against highly pathogenic avian #influenza #H5N1 viruses

 

ABSTRACT

The outbreak of highly pathogenic avian H5 influenza (HPAI) clade 2.3.4.4b in cattle has spread across the United States. Mice with pre-existing immunity to H1N1 virus or with a live-attenuated influenza vaccine showed protection against a lethal bovine-derived HPAI H5N1 viral challenge. Notably, ferrets with mixed immunity also demonstrated protection against a feline-derived H5N1 virus, independent of cross-reactive neutralization titers, but antibodies to whole virus were observed. To investigate protective factors, we conducted T cell epitope mapping using published H1N1 viral sequences and found high conservation of key T cell epitopes in the bovine HPAI H5N1 strain. Depletion of T cells in mice prior to and during primary H1N1 infection impacted cross-protective antibodies to H5N1 virus, with CD4 depletion increasing mortality and CD8 depletion mildly impacting morbidity upon H5N1 viral challenge. This underscores the need to investigate memory T cell responses alongside antibodies in assessing preexisting cross-protection to HPAI H5N1 viruses.

Source: 

Link: https://journals.asm.org/doi/full/10.1128/jvi.02088-25?af=R

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