MSACL 2022 Abstract

Afucosylated IgG Responses to BNT162b2 mRNA Vaccine Against Sars-CoV-2 Differ in Naïve and Antigen-experienced Individuals

Julie Van Coillie (1,2,†), Tamas Pongracz (5,†), Johann Rahmöller (3,4,†), Chiara Geyer (6), Hung-Jen Chen (11), Lonneke A. Vlught (6,7), Jana S. Buhre (3), Tonći Šuštić (1,2), Maurice Steenhuis (2,8), Williane W. Hoepel (9,10), Wenjun Wang (5), Anne S. Lixenfeld (3), Jan Nouta (5), Sofie Keijzer (2,8), Federica Linty (1,2), Remco Visser (1,2), Mads Larsen (1,2), Emily L. Martin (3), Inga Künsting (3), Selina Lehrian (3), Vera von Kopylow (3), Carsten Kern (3), Hanna Lunding (3), Menno de Winther (11), Niels van Mourik (6,7), Theo Rispens (2,8), Tobias Graf (12), Marleen A. Slim (6,7), René Minnaar (13), Alexander P. J. Vlaar (7), Ellen C. van de Schoot (1,2), Jeroen den Dunnen (6), Manfred Wuhrer (5,‡,*), Marc Ehlers (3,14,‡,*), Gestur Vidarsson (1,2,‡,*)
(1) Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands (2) Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands (3) Laboratories of Immunology and Antibody Glycan Analysis, Institute of Nutritional Medicine, University of Lübeck and University Medical Center of Schleswig-Holstein, Lübeck, Germany (4) Department of Anesthesiology and Intensive Care, University of Lübeck and University Medical Center of Schleswig-Holstein, Lübeck, Germany. (5) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands (6) Center for Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam (7) Department of Intensive Care, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands (8) Department of Immunopathology, Sanquin Research, Amsterdam, Netherlands. (9) Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands (10) Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands (11) Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam Infection and Immunity, Amsterdam UMC, University of Amsterdam, Netherlands (12) Medical Department 3, University Medical Center of Schleswig-Holstein, Lübeck, Germany. (13) Amsterdam UMC Biobank, Amsterdam UMC, Amsterdam, Netherlands (14) Airway Research Center North, University of Lübeck, German Center for Lung Research (DZL), Lübeck, Germany

Tamás Pongrácz, PhD (Presenter) Karolinska Institute

Presenter Bio: I am an analytical chemist with expertise in developing and refining advanced analytical methods and bioinformatics tools for high-throughput, mass spectrometry-based analysis of complex sugar molecules (glycans) that are key structural components of most proteins, including antibodies.

My research focuses on exploring the glycomic landscape of human diseases, elucidating the link between antibody glycosylation and function, and contextualizing these findings within clinical disease proxies across various conditions.

Currently, I am a postdoctoral researcher and bioinformatician in the group of Charlotte Thålin at Karolinska Institute, where we investigate the role of IgA glycosylation in mucosal immunity. This position has provided an ideal continuation of my academic career path following a PhD and postdoctoral training at Leiden University Medical Center, where I worked in a highly interdisciplinary environment at the interface of analytical chemistry, bioinformatics and clinical research.

Driven by a strong commitment to translational science, bridging the gap between fundamental research and patient care is my major ambition. I believe that glycan-based diagnostics and therapeutics hold transformative potential and will play a central role in the next generation of medical innovation.

Relevant Financial Disclosures (within past 24 months, reported on Apr 29, 2025) Grant/Research Support European Union H2020-MSCA-ITN; grant agreement number 721815 Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

Introduction

Immunoglobulin G (IgG) antibodies can exert their functions via both their Fab-mediated neutralization and Fc-mediated effector functions, both of which are crucial for protective immunity in COVID-19[1]. The effector functions of the latter depend on the subclass and type of Fc N-glycosylation[2]. Severe SARS-CoV-2 infection is characterized by initial afucosylated IgG1 responses against the viral spike (S) protein, that enhances FcγRIII-mediated inflammatory responses[3-6]. Intriguingly, afucosylated IgG1 responses have been reported to be protective in HIV[7], in spite of the massive inflammation they cause in COVID-19[3-5] and Dengue fever[8]. In general, such afucosylated responses seem to occur exclusively when the presence of the target antigen is on the surface of host cell[5, 9]. The new mRNA- or adenovirus-based SARS-CoV-2 vaccines induce host cell production of the SARS-CoV-2 spike (S) protein and its presentation on the cell membrane. Vaccine-induced afucosylated IgG1 Abs may therefore provide protection when such an immune response is mounted before encountering the virus, allowing for quick removal of viral particles and infected cells, preventing its buildup.

Aims

The aim of this study was to investigate whether the BNT162b2 SARS-CoV-2 mRNA vaccine also induces afucosylated IgG1 against the S protein – as expected for foreign antigens expressed on host cell surfaces – and to follow the dynamics of glycosylation over time in both naïve and antigen-experienced individuals. Furthermore, our aim was to assess functional consequences of differential glycosylation.

Methods

In this prospective-longitudinal, multi-center cohort study, IgG Fc glycosylation analysis was performed by nano liquid chromatography – time-of-flight mass spectrometry for a total of 101 individuals. Associations between glycosylation trait levels, glycosyltransferase expression, antibody levels, IL-6 response and complement activation were additionally investigated.

Results

Up to 25% of early anti-S IgG1 was afucosylated in naïve individuals, which was predictive of a strong booster response. Surprisingly, IgG1-afucosylation levels quickly decreased, also after booster immunization. In contrast, antigen-experienced individuals showed low afucosylation levels before vaccination, that slightly increased after immunization. This tendency correlated with different plasma cell subset responses and fucosyltransferase 8 expression levels therein as well as with the potency to activate myeloid cells.

Conclusions

Our data indicate qualitatively distinct IgG immune responses between mRNA vaccinated naïve and antigen-experienced individuals. The strong neutralizing IgG response in both groups after booster is likely to play a dominant role in the protection of the vaccine. Future efforts, focused on inducing stabilized and prominent afucosylated IgG responses, should be initiated to study their protective capacity in anti-viral immunity and beyond. Furthermore, such concerted methodological approaches will be beneficial to assess vaccine efficacy, inflammatory potential and protective capacity of vaccine-induced IgG from both body fluids and specific tissues in the future.

References

[1] Yamin, R., et al. (2021) Nature, 2021. 599(7885): p. 465-470
[2] Dekkers, G., et al. (2017) Front Immunol, 8: p. 877
[3] Chakraborty, S., et al. (2021) Nat Immunol, 22(1): p. 67-73
[4] Hoepel, W., et al. (2021) Sci Transl Med, 13(596)
[5] Larsen, M.D., et al. (2021) Science, 371(6532)
[6] Pongracz, T., et al. (2021), medRxiv
[7] Ackerman, M.E., et al. (2013) J Clin Invest, 123(5): p. 2183-92
[8] Wang, T.T., et al. (2017) Science, 355(6323): p. 395-398
[9] Larsen, M.D., et al. (2021) Nat Commun, 12(1): p. 5838.