Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses

Tam, Jerry C.H., Sibayan, Abbie C., Seow, Jeffrey, Graham, Carl, Kurshan, Ashwini, Merrick, Blair, Stanton, Richard J. ORCID: https://orcid.org/0000-0002-6799-1182 and Doores, Katie J. 2025. Spike-specific IgG4 generated post BNT162b2 mRNA vaccination is inhibitory when directly competing with functional IgG subclasses. Cell Reports 44 (7) , 116000. 10.1016/j.celrep.2025.116000

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Abstract

COVID-19 vaccines proved vital in controlling the SARS-CoV-2 pandemic. Both neutralizing and effector-function activities of Spike-specific antibodies are important for their protective activity. Several studies have reported that COVID-19 mRNA vaccines can lead to elevated levels of Spike-specific immunoglobulin G4 (IgG4), an anti-inflammatory subclass with reduced binding to Fcγ receptors. We show that Spike-specific IgG4 levels following BNT162b2 vaccination are impacted by the interval between and frequency of vaccine boosts, prior or post SARS-CoV-2 infection and bivalent vaccine boosters. Through expression of IgG1, IgG2, IgG3, and IgG4 subclasses of SARS-CoV-2 antibodies, we demonstrate that while IgG4 has reduced effector-function activity, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular phagocytosis, IgG4 is only inhibitory when directly competing with functional IgG subclasses binding to overlapping epitopes. ADCC and ADCD activity in plasma was not depleted by adding a cocktail of Spike-specific IgG4 monoclonal antibodies, suggesting that the non-stimulatory effect of Spike-specific IgG4 may be hidden in polyclonal mixes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Publisher:	Cell Press
ISSN:	2211-1247
Funders:	Wellcome
Date of First Compliant Deposit:	17 July 2025
Date of Acceptance:	20 June 2025
Last Modified:	17 Jul 2025 09:00
URI:	https://orca.cardiff.ac.uk/id/eprint/179858

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