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

L Carissa Aurelia; Ruth A Purcell; Robert M Theisen; Andrew Kelly; Robyn Esterbauer; Pradhipa Ramanathan; Wen Shi Lee; Bruce D Wines; P Mark Hogarth; Jennifer A Juno; Lilith F Allen; Katherine A Bond; Deborah A Williamson; Janine M Trevillyan; Jason A Trubiano; Thi Ho Nguyen; Katherine Kedzierska; Adam K Wheatley; Stephen J Kent; Kelly B Arnold; Kevin John Selva; Amy W Chung

doi:10.1126/sciadv.ads1482

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

L Carissa Aurelia, Ruth A Purcell, Robert M Theisen, Andrew Kelly, Robyn Esterbauer, Pradhipa Ramanathan, Wen Shi Lee, Bruce D Wines, P Mark Hogarth, Jennifer A Juno, Lilith F Allen, Katherine A Bond, Deborah A Williamson, Janine M Trevillyan, Jason A Trubiano, Thi Ho Nguyen, Katherine Kedzierska, Adam K Wheatley, Stephen J Kent, Kelly B ArnoldKevin John Selva, Amy W Chung

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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

Original language	English
Article number	eads1482
Number of pages	14
Journal	Science Advances
Volume	11
Issue number	9
Early online date	26 Feb 2025
DOIs	https://doi.org/10.1126/sciadv.ads1482
Publication status	Published - 28 Feb 2025

Keywords

Humans
Immunoglobulin G/immunology
SARS-CoV-2/immunology
Receptors, IgG/metabolism
Spike clycoprotein, Coronavirus/immunology
COVID-19/immunology
Antibodies, Viral/immunology
Antibody-dependent cell Cytotoxicity/immunology
Polymorphism, Genetic
Immunoglobulin Fc fragments/immunology
COVID-19 vaccines/immunology
Phagocytosis
Receptors, Fc/genetics
Male
Female

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Aurelia-2025-Increased-SARS-CoV-2-SciAdv-11-eads1482-CCBY
Copyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution license 4.0 (CC BY).
Final published version, 1.98 MBLicence: CC BY

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Aurelia, L. C., Purcell, R. A., Theisen, R. M., Kelly, A., Esterbauer, R., Ramanathan, P., Lee, W. S., Wines, B. D., Hogarth, P. M., Juno, J. A., Allen, L. F., Bond, K. A., Williamson, D. A., Trevillyan, J. M., Trubiano, J. A., Nguyen, T. H., Kedzierska, K., Wheatley, A. K., Kent, S. J., ... Chung, A. W. (2025). Increased SARS-CoV-2 IgG4 has variable consequences dependent upon Fc function, Fc receptor polymorphism, and viral variant. Science Advances, 11(9), Article eads1482. https://doi.org/10.1126/sciadv.ads1482

@article{aaf91dcd301c46e4a7598581b82270e8,

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

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

keywords = "Humans, Immunoglobulin G/immunology, SARS-CoV-2/immunology, Receptors, IgG/metabolism, Spike clycoprotein, Coronavirus/immunology, COVID-19/immunology, Antibodies, Viral/immunology, Antibody-dependent cell Cytotoxicity/immunology, Polymorphism, Genetic, Immunoglobulin Fc fragments/immunology, COVID-19 vaccines/immunology, Phagocytosis, Receptors, Fc/genetics, Male, Female",

author = "Aurelia, {L Carissa} and Purcell, {Ruth A} and Theisen, {Robert M} and Andrew Kelly and Robyn Esterbauer and Pradhipa Ramanathan and Lee, {Wen Shi} and Wines, {Bruce D} and Hogarth, {P Mark} and Juno, {Jennifer A} and Allen, {Lilith F} and Bond, {Katherine A} and Williamson, {Deborah A} and Trevillyan, {Janine M} and Trubiano, {Jason A} and Nguyen, {Thi Ho} and Katherine Kedzierska and Wheatley, {Adam K} and Kent, {Stephen J} and Arnold, {Kelly B} and Selva, {Kevin John} and Chung, {Amy W}",

note = "Funding: this study is supported by the Medical Research Future Fund (MRFF) GNT #2016062 to J.A.J., J.A.T., T.H.N., K.K., A.K.W., S.J.K., and A.W.c. and an NHMRC investigator grant#2008093 to A.W.c. J.A.J. is supported by a Sylvia and Chatles Viertel Senior Medical Research Fellowships. W.S.l., J.A.J., t.h.n., K.K., A.K.W., and S.J.K. are also supported by NHMRC investigator grants.",

year = "2025",

month = feb,

day = "28",

doi = "10.1126/sciadv.ads1482",

language = "English",

volume = "11",

journal = "Science Advances",

issn = "2375-2548",

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Aurelia, LC, Purcell, RA, Theisen, RM, Kelly, A, Esterbauer, R, Ramanathan, P, Lee, WS, Wines, BD, Hogarth, PM, Juno, JA, Allen, LF, Bond, KA, Williamson, DA, Trevillyan, JM, Trubiano, JA, Nguyen, TH, Kedzierska, K, Wheatley, AK, Kent, SJ, Arnold, KB, Selva, KJ & Chung, AW 2025, 'Increased SARS-CoV-2 IgG4 has variable consequences dependent upon Fc function, Fc receptor polymorphism, and viral variant', Science Advances, vol. 11, no. 9, eads1482. https://doi.org/10.1126/sciadv.ads1482

TY - JOUR

T1 - Increased SARS-CoV-2 IgG4 has variable consequences dependent upon Fc function, Fc receptor polymorphism, and viral variant

AU - Aurelia, L Carissa

AU - Purcell, Ruth A

AU - Theisen, Robert M

AU - Kelly, Andrew

AU - Esterbauer, Robyn

AU - Ramanathan, Pradhipa

AU - Lee, Wen Shi

AU - Wines, Bruce D

AU - Hogarth, P Mark

AU - Juno, Jennifer A

AU - Allen, Lilith F

AU - Bond, Katherine A

AU - Williamson, Deborah A

AU - Trevillyan, Janine M

AU - Trubiano, Jason A

AU - Nguyen, Thi Ho

AU - Kedzierska, Katherine

AU - Wheatley, Adam K

AU - Kent, Stephen J

AU - Arnold, Kelly B

AU - Selva, Kevin John

AU - Chung, Amy W

N1 - Funding: this study is supported by the Medical Research Future Fund (MRFF) GNT #2016062 to J.A.J., J.A.T., T.H.N., K.K., A.K.W., S.J.K., and A.W.c. and an NHMRC investigator grant#2008093 to A.W.c. J.A.J. is supported by a Sylvia and Chatles Viertel Senior Medical Research Fellowships. W.S.l., J.A.J., t.h.n., K.K., A.K.W., and S.J.K. are also supported by NHMRC investigator grants.

PY - 2025/2/28

Y1 - 2025/2/28

N2 - Repeated mRNA COVID-19 vaccination increases spike-specific immunoglobulin G4 (IgG4) titers. Here, we characterized the influence of increased IgG4 titers on a range of Fc-mediated responses. Elevated spike-specific IgG4 reduced binding to FcγRIIIa and decreased antibody-dependent cellular cytotoxicity. However, in individuals with lower total spike-specific IgG, IgG4 acted in synergy with other IgG subclasses to improve FcγRI and FcγRIIa binding and consequently antibody-dependent cellular phagocytosis. Furthermore, this trend was more pronounced with more recent SARS-CoV-2 variants where vaccination induced comparably lower total spike-specific titers. These observations were further confirmed by in silico modeling where antibody subclass concentrations and FcγR polymorphisms were modulated. Collectively, we illustrate that the impact of elevated IgG4 titers upon Fc functions is dependent on multiple interconnected antibody and antigen factors, which should be taken into consideration when dissecting the mechanisms driving an effective Fc-mediated response following vaccination.

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

KW - Humans

KW - Immunoglobulin G/immunology

KW - SARS-CoV-2/immunology

KW - Receptors, IgG/metabolism

KW - Spike clycoprotein, Coronavirus/immunology

KW - COVID-19/immunology

KW - Antibodies, Viral/immunology

KW - Antibody-dependent cell Cytotoxicity/immunology

KW - Polymorphism, Genetic

KW - Immunoglobulin Fc fragments/immunology

KW - COVID-19 vaccines/immunology

KW - Phagocytosis

KW - Receptors, Fc/genetics

KW - Male

KW - Female

U2 - 10.1126/sciadv.ads1482

DO - 10.1126/sciadv.ads1482

M3 - Article

C2 - 40009690

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 9

M1 - eads1482

ER -

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

Abstract

Keywords

UN SDGs

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