Antiviral activity of an ACE2-Fc fusion protein against SARS-CoV-2 and its variants

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0312402 - e0312402

Published: Jan. 3, 2025

SARS-CoV-2 has continued spreading around the world in recent years since initial outbreak 2019, frequently developing into new variants with greater human infectious capacity. and its mutants use angiotensin-converting enzyme 2 (ACE2) as a cellular entry receptor, which triggered several therapeutic strategies against COVID-19 relying on of ACE2 recombinant proteins decoy receptors. In this work, we propose an silent Fc fusion protein (ACE2-hFcLALA) candidate therapy COVID-19. This was able to block binding RBD receptor measured by ELISA flow cytometry inhibition assays. Moreover, used classical neutralization assays progeny assay show that ACE2-hFcLALA is capable neutralizing authentic virus. Additionally, found more effective preventing vitro infection different interest ( alpha , beta delta omicron ) compared D614G strain. Our results suggest potential molecule be both preventive settings current emerging gateway cells.

Language: Английский

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Effect of Bacille Calmette–Guérin vaccination on immune responses to SARS‐CoV‐2 and COVID‐19 vaccination

Clinical & Translational Immunology, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 1, 2025

Abstract Objectives Bacille Calmette–Guérin (BCG) vaccination has off‐target effects on disease risk for unrelated infections and immune responses to vaccines. This study aimed determine the immunomodulatory of BCG vaccines against SARS‐CoV‐2. Methods Blood samples, from a subset 275 SARS‐CoV‐2‐naïve healthcare workers randomised (BCG group) or no (Control in BRACE trial, were collected before 28 days after primary course (two doses) ChAdOx1‐S (Oxford‐AstraZeneca) BNT162b2 (Pfizer‐BioNTech) vaccination. SARS‐CoV‐2‐specific antibodies measured using ELISA multiplex bead array, whole blood cytokine γ‐irradiated SARS‐CoV‐2 (iSARS) stimulation by T‐cell activation‐induced marker intracellular staining assays. Results After randomisation (mean 11 months) but prior COVID‐19 vaccination, group had lower iSARS than Control group. two doses ChAdOx1‐S, differences iSARS‐induced between found three cytokines (CTACK, TRAIL VEGF). No groups There also vaccine‐induced antigen‐specific antibody responses, activation production. Conclusion induced broad persistent reduction ex vivo Following this effect was abrogated, did not influence adaptive vaccine antigens.

Language: Английский

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Randomised controlled trial reveals no benefit to a 3-month delay in COVID-19 mRNA booster vaccine

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(17)

Published: July 11, 2024

BACKGROUNDThere is uncertainty about the timing of booster vaccination against COVID-19 in highly vaccinated populations during present endemic phase COVID-19. Studies focused on primary have previously suggested improved immunity with a longer interval between first and second vaccine doses.METHODSWe conducted randomized, controlled trial (November 2022-August 2023) assigned 52 fully adults to an immediate or 3-month delayed bivalent Spikevax mRNA vaccine. Follow-up visits were completed for 48 participants (n = 24 per arm), collection saliva plasma samples following each visit.RESULTSThe rise neutralizing antibody responses ancestral Omicron strains almost identical arms. Analyses salivary (IgG, IgA), antibody-dependent phagocytic activity, decay kinetics similar 2 Symptomatic asymptomatic SARS-CoV-2 infections occurred 49% (21 49) over median 11.5 months follow-up also arms.CONCLUSIONSOur data suggest that there was no benefit delaying preimmune COVID-19.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry number 12622000411741 (https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12622000411741).FUNDINGNational Health Medical Research Council, Australia (program grant App1149990) Future Fund (App2005544).

Language: Английский

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Increased SARS-CoV-2 IgG4 has variable consequences dependent upon Fc function, Fc receptor polymorphism, and viral variant

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 26, 2025

Repeated mRNA COVID-19 vaccination increases spike-specific immunoglobulin G4 (IgG4) titers. Here, we characterized the influence of increased IgG4 titers on a range Fc-mediated responses. Elevated reduced binding to FcγRIIIa and decreased antibody-dependent cellular cytotoxicity. However, in individuals with lower total IgG, acted synergy other IgG subclasses improve FcγRI FcγRIIa consequently phagocytosis. Furthermore, this trend was more pronounced recent SARS-CoV-2 variants where induced comparably These observations were further confirmed by silico modeling antibody subclass concentrations FcγR polymorphisms modulated. Collectively, illustrate that impact elevated upon Fc functions is dependent multiple interconnected antigen factors, which should be taken into consideration when dissecting mechanisms driving an effective response following vaccination.

Language: Английский

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Fc-effector functional antibody assays for SARS-CoV-2 variants of concern

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: May 20, 2025

Background The Fc regions of antibodies mediate important effector cell functions such as antibody-dependent cellular cytotoxicity (ADCC), phagocytosis (ADCP), neutrophil (ADNP), and complement-dependent (CDC). These enhance immune defense infected clearance. This study evaluated the effect COVID-19 XBB.1.5 booster vaccination on Fc-effector antibody responses to SARS-CoV-2. Methods We developed four assays evaluate SARS-CoV-2 antibodies. ADCC CDC utilized stably transfected luciferase-based target lines expressing spike variants (Ancestral, Wu-1 Omicron XBB.1.5, EG.5) measure antibody-mediated lysis by cells. ADCP ADNP were assessed flow cytometry fluorescently labeled virus-like particles that display variant proteins. Serum samples from 20 healthy adult volunteers pre- post-monovalent vaccine analyzed for pseudovirus neutralizing Results Prior administration vaccination, cross-neutralizing against EG.5 minimally detectable, while cross-functional present at higher baseline levels. significantly boosted both in magnitude breadth. greatest increase was strain, functional had similar fold-increases titers breadth tested. Neutralizing most highly correlated (prior vaccination) but less post-vaccination, consistent with differential boosting vs monovalent vaccine. Conclusion improved magnitude, breadth, quality Combining Fc-mediated provides a more comprehensive model understanding vaccine-induced immunity optimizing strategies.

Language: Английский

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Navigating the Landscape of B Cell Mediated Immunity and Antibody Monitoring in SARS-CoV-2 Vaccine Efficacy: Tools, Strategies and Clinical Trial Insights

Vaccines, Journal Year: 2024, Volume and Issue: 12(10), P. 1089 - 1089

Published: Sept. 24, 2024

Correlates of Protection (CoP) are biomarkers above a defined threshold that can replace clinical outcomes as primary endpoints, predicting vaccine effectiveness to support the approval new vaccines or follow up studies. In context COVID-19 vaccination, CoPs help address challenges such demonstrating in special populations, against emerging SARS-CoV-2 variants determining durability vaccine-elicited immunity. While anti-spike IgG titres and viral neutralising capacity have been characterised for contribution other components humoral immune response immediate long-term protective immunity is less well characterised. This review examines evidence supporting use trials, how they be used define It also highlights alternative biomarkers, including Fc effector function, mucosal immunity, generation long-lived plasma memory B cells discuss these applied studies tools available study them.

Language: Английский

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Binding behavior of receptor binding domain of the SARS-CoV-2 virus and ivermectin

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 2, 2024

Abstract The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), sparked an international debate on effective ways to prevent and treat the virus. Specifically, there were many varying opinions use of ivermectin (IVM) throughout world, with minimal research support either side. IVM is FDA-approved antiparasitic drug that was discovered in 1970s found show antiviral activity. objective this study examine binding behavior rates association dissociation between SARS-CoV-2 receptor domain (RBD), IVM, their combination using aminopropylsilane (APS) biosensors as surrogates for hydrophobic interaction viral protein human angiotensin-converting enzyme (ACE2) receptors determine potential a repurposed prevention treatment. RBD, kinetics analyzed biolayer interferometry (BLI) validated multiple silico techniques including protein–ligand docking, molecular dynamics simulation, mechanics-generalized Born surface area (MM-GBSA), principal component analysis (PCA). Our results suggest increasing concentrations rate biosensor increases simultaneous decrease dissociation. Significant kinetic changes when combined only at concentration thousand times approved dosage over 35-min time period. suggests not preventative or treatment method currently dosage.

Language: Английский

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Immunoglobulin G genetic variation can confound assessment of antibody levels via altered binding to detection reagents

Clinical & Translational Immunology, Journal Year: 2024, Volume and Issue: 13(3)

Published: Jan. 1, 2024

Abstract Objectives Amino acid variations across more than 30 immunoglobulin (Ig) allotypes may introduce structural changes that influence recognition by anti‐Ig detection reagents, consequently confounding interpretation of antibody responses, particularly in genetically diverse cohorts. Here, we assessed a panel commercial monoclonal anti‐IgG1 clones for capacity to universally recognise two dominant IgG1 haplotypes (G1m‐1,3 and G1m1,17). Methods Four anti‐human were via ELISAs multiplex bead‐based assays their ability bind G1m‐1,3 G1m1,17 variants. Detection antibodies validated against allotype standards tested antigen‐specific plasma from homozygous heterozygous SARS‐CoV‐2 BNT162b2 vaccinated ( n = 28) COVID‐19 convalescent 44) individuals. An Fc‐specific pan ‐IgG corroborated differences between hinge‐ responses. Results Hinge‐specific clone 4E3 preferentially bound compared IgG1. Consequently, Spike‐specific levels detected G1m1,17/G1m1,17 vaccinees appeared 9‐ 17‐fold higher G1m‐1,3/G1m‐1,3 vaccinees. equivalently variants, comparable haplotypes. responses other human coronaviruses influenza similarly poorly subjects. Conclusion Anti‐IgG1 confounds assessment clinical cohorts owing bias towards Validation should include evaluation binding relevant as the role immunogenetics upon humoral immunity is increasingly explored populations.

Language: Английский

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Antibody glycosylation correlates with disease progression in SIV‐Mycobacterium tuberculosis coinfected cynomolgus macaques

Clinical & Translational Immunology, Journal Year: 2023, Volume and Issue: 12(11)

Published: Jan. 1, 2023

Abstract Objectives Tuberculosis (TB) remains a substantial cause of morbidity and mortality among people living with human immunodeficiency virus (HIV) worldwide. However, the immunological mechanisms associated enhanced susceptibility HIV‐positive individuals remain largely unknown. Methods Here, we used simian (SIV)/TB‐coinfection Mauritian cynomolgus macaque (MCM) model to examine humoral responses from plasma SIV‐negative ( n = 8) SIV‐positive 7) MCM 8‐week postinfection Mycobacterium tuberculosis Mtb ). Results Antibody were impaired during SIV coinfection. Elevated inflammatory bulk IgG antibody glycosylation patterns observed in coinfected macaques early at post‐ infection, including increased agalactosylation (G0) reduced di‐galactosylation (G2), which correlated endpoint bacterial burden gross pathology scores, as well time‐to‐necropsy. Conclusion These studies suggest that immunity may contribute control TB disease support growing literature highlights Fc biomarker progression.

Language: Английский

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Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Dec. 9, 2023

The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we describe the development employment new functional assay measures antibodies present longitudinal data illustrating impact age, sex comorbidities on kinetics strength vaccine-induced key in an Asian volunteer cohort. We also accurate quantitation exploits unique set in-house, recombinant human monoclonal Spike nucleocapsid proteins demonstrate reduction titres across all groups 6 months post-vaccination. observe marked binding activity recently newly emerged Omicron including XBB 1.5 highlight significant increase cross-protective following third dose (boost) vaccine. These illustrate how virological factors such as immune escape mutations combined with host demographic age vaccinated individual influence

Language: Английский

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