EBioMedicine (Mar 2025)

Evolution of SARS-CoV-2 antibody repertoire after successive mRNA vaccinations under immunosuppressive treatmentResearch in context

  • Jim B.D. Keijser,
  • Eileen W. Stalman,
  • Luuk Wieske,
  • Maurice Steenhuis,
  • Koos P.J. van Dam,
  • Laura Y.L. Kummer,
  • Zoé L.E. van Kempen,
  • Joep Killestein,
  • Adriaan G. Volkers,
  • Sander W. Tas,
  • Laura Boekel,
  • Gerrit J. Wolbink,
  • Laura Fernandez Blanco,
  • Niels J.M. Verstegen,
  • Sofie Keijzer,
  • Gerard van Mierlo,
  • Olvi Cristianawati,
  • Arend J. Boogaard,
  • Karlijn van der Straten,
  • Jacqueline van Rijswijk,
  • Marit J. van Gils,
  • Anja ten Brinke,
  • S. Marieke van Ham,
  • Taco W. Kuijpers,
  • Filip Eftimov,
  • Theo Rispens,
  • Anneke J. Van der Kooi,
  • Joop Raaphorst,
  • Mark Löwenberg,
  • R. Bart Takkenberg,
  • Geert R.A.M. D'Haens,
  • Phyllis I. Spuls,
  • Marcel W. Bekkenk,
  • Annelie H. Musters,
  • Nicoline F. Post,
  • Angela L. Bosma,
  • Marc L. Hilhorst,
  • Yosta Vegting,
  • Frederike J. Bemelman,
  • Alexandre E. Voskuyl,
  • Bo Broens,
  • Agner R. Parra Sanchez,
  • Cécile A.C.M. Van Els,
  • Jelle De Wit,
  • Abraham Rutgers,
  • Karina De Leeuw,
  • Barbara Horváth,
  • Jan J.G.M. Verschuuren,
  • Annabel M. Ruiter,
  • Lotte Van Ouwerkerk,
  • Diane Van der Woude,
  • Renée C.F. Van Allaart,
  • Y.K. Onno Teng,
  • Pieter Van Paassen,
  • Matthias H. Busch,
  • Papay B.P. Jallah,
  • Esther Brusse,
  • Pieter A. Van Doorn,
  • Adája E. Baars,
  • Dirk Jan Hijnen,
  • Corine R.G. Schreurs,
  • W. Ludo Van der Pol,
  • H. Stephan Goedee,
  • Koos A.H. Zwinderman,
  • Rivka De Jongh,
  • Carolien E. Van de Sandt,
  • Lisan H. Kuijper,
  • Mariël C. Duurland,
  • Ruth R. Hagen,
  • Jet Van den Dijssel,
  • Christine Kreher,
  • Amélie V. Bos,
  • Virginia Palomares Cabeza,
  • Veronique A.L. Konijn,
  • George Elias,
  • Elham S. Mirfazeli

Journal volume & issue
Vol. 113
p. 105620

Abstract

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Summary: Background: Repeated antigen exposure can result in a shifting antibody repertoire. The mechanisms by which this occurs and consequences for cross-variant protection against evolving pathogens remain incompletely understood, particularly in the context of immunosuppressive treatments used in patients with immune-mediated inflammatory diseases (IMID). Methods: To investigate this, we characterised longitudinal changes in the anti-SARS-CoV-2 antibody repertoire over the course of three SARS-CoV-2 mRNA vaccinations in patients with IMIDs treated with methotrexate (MTX) and/or tumour necrosis factor-inhibitors (TNFi), anti-CD20 monoclonal antibodies, no systemic therapy, and healthy controls (total N = 878). We determined serum antibody titres against the receptor-binding domain (RBD) of Wuhan-Hu-1 (WH1) and Omicron BA.1 spike proteins, and assessed ratios thereof between groups as a proxy for cross-reactivity. Findings: We observe emerging anti-BA.1 RBD reactivity over time, notably following a third vaccination. This may be partly explained by affinity maturation, as evaluated by inhibition of ACE2-RBD interactions. Similar trends were seen in patients treated with MTX and/or TNFi, but not in patients on anti-CD20 therapy. SARS-CoV-2 infection prior to vaccination accelerated these effects initially while leading to comparable results after three vaccinations. Interpretation: MTX and TNFi do not qualitatively alter the evolution of the antibody repertoire in response to repeated antigen exposure, whereas anti-CD20 does. These insights may help to optimise vaccination strategies for patients with immune-mediated inflammatory diseases. Funding: This study was supported by ZonMw (The Netherlands Organization for Health Research and Development) and SGF (Collaborating Health Funds).

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