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. 2024 Jul;79(7):1952-1961.
doi: 10.1111/all.16089. Epub 2024 Mar 4.

Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination

Anika M Valk  1   2   3 , Jim B D Keijser  1   3 , Koos P J van Dam  4 , Eileen W Stalman  4 , Luuk Wieske  4   5 , Maurice Steenhuis  1 , Laura Y L Kummer  1   3   4 , Phyllis I Spuls  6 , Marcel W Bekkenk  6 , Annelie H Musters  6 , Nicoline F Post  6 , Angela L Bosma  6 , Barbara Horváth  7 , Dirk-Jan Hijnen  8 , Corine R G Schreurs  8 , Zoé L E van Kempen  9 , Joep Killestein  9 , Adriaan G Volkers  10 , Sander W Tas  11 , Laura Boekel  12 , Gerrit J Wolbink  1   12 , Sofie Keijzer  1   3 , Ninotska I L Derksen  1   3 , Melanie van Deelen  1 , Gerard van Mierlo  1   3 , Taco W Kuijpers  1   3   13 , Filip Eftimov  4 , S Marieke van Ham  1   2   3 , Anja Ten Brinke  1   3 , Theo Rispens  1   3 ; T2B! Immunity against SARS‐CoV‐2 study group
Affiliations

Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination

Anika M Valk et al. Allergy. 2024 Jul.

Abstract

Background: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated.

Methods: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination.

Results: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based.

Conclusions: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization.

Keywords: IgG4 class switching; TNFi; dupilumab; mRNA vaccination; tolerance.

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