Clinical and humoral responses after SARS-CoV-2 breakthrough infections in patients with immunosuppressants

Eileen W Stalman; Luuk Wieske; Jim B D Keijser; Koos P J van Dam; Laura Y L Kummer; Maarten F Wilbrink; Zoé L E van Kempen; Joep Killestein; Adriaan G Volkers; Sander W Tas; Laura Boekel; Gerrit J Wolbink; Anneke J van der Kooi; Joost 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; Frederique J Bemelman; Alexandre E Voskuyl; Bo Broens; Agner 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 Allaart; Y K Onno Teng; Pieter van Paassen; Matthias H Busch; Esther Brusse; Pieter A van Doorn; Adája E Baars; Dirkjan Hijnen; Corine R G Schreurs; W Ludo van der Pol; H Stephan Goedee; Maurice Steenhuis; Sofie Keijzer; Olvi Cristianawati; Anja Ten Brinke; Niels J M Verstegen; Koos A H Zwinderman; S Marieke van Ham; Theo Rispens; Matthijs R Welkers; Marcel Jonges; Filip Eftimov; Taco W Kuijpers; T2B! immunity against SARS-CoV-2 study group

doi:10.1016/j.jaci.2024.04.031

Clinical and humoral responses after SARS-CoV-2 breakthrough infections in patients with immunosuppressants

J Allergy Clin Immunol. 2024 May 17:S0091-6749(24)00503-7. doi: 10.1016/j.jaci.2024.04.031. Online ahead of print.

Authors

Eileen W Stalman¹, Luuk Wieske², Jim B D Keijser³, Koos P J van Dam⁴, Laura Y L Kummer⁵, Maarten F Wilbrink⁴, Zoé L E van Kempen⁶, Joep Killestein⁶, Adriaan G Volkers⁷, Sander W Tas⁸, Laura Boekel⁸, Gerrit J Wolbink⁸, Anneke J van der Kooi⁴, Joost Raaphorst⁴, Mark Löwenberg⁷, R Bart Takkenberg⁷, Geert R A M D'Haens⁷, Phyllis I Spuls⁹, Marcel W Bekkenk⁹, Annelie H Musters⁹, Nicoline F Post⁹, Angela L Bosma⁹, Marc L Hilhorst¹⁰, Yosta Vegting¹⁰, Frederique J Bemelman¹⁰, Alexandre E Voskuyl¹¹, Bo Broens¹¹, Agner Parra Sanchez¹², Cécile A C M van Els¹³, Jelle de Wit¹⁴, Abraham Rutgers¹⁵, Karina de Leeuw¹⁵, Barbara Horváth¹⁶, Jan J G M Verschuuren¹⁷, Annabel M Ruiter¹⁷, Lotte van Ouwerkerk¹⁸, Diane van der Woude¹⁸, Renée C F Allaart¹⁸, Y K Onno Teng¹⁹, Pieter van Paassen²⁰, Matthias H Busch²⁰, Esther Brusse²¹, Pieter A van Doorn²¹, Adája E Baars²¹, Dirkjan Hijnen²², Corine R G Schreurs²², W Ludo van der Pol²³, H Stephan Goedee²³, Maurice Steenhuis³, Sofie Keijzer³, Olvi Cristianawati³, Anja Ten Brinke³, Niels J M Verstegen³, Koos A H Zwinderman²⁴, S Marieke van Ham²⁵, Theo Rispens³, Matthijs R Welkers²⁶, Marcel Jonges²⁶, Filip Eftimov⁴, Taco W Kuijpers²⁷; T2B! immunity against SARS-CoV-2 study group

Affiliations

¹ Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address: e.w.stalman@amsterdamumc.nl.
² Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Clinical Neurophysiology, St Antonius Hospital, Nieuwegein, The Netherlands.
³ Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, the Netherlands.
⁴ Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, the Netherlands.
⁶ Department of Neurology, Amsterdam UMC, VU University medical center, Amsterdam, the Netherlands.
⁷ Department of Gastroenterology and Hepatology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
⁸ Amsterdam Rheumatology and immunology Center, Amsterdam UMC, Department of Rheumatology and Clinical Immunology, University of Amsterdam, Amsterdam, the Netherlands.
⁹ Department of Dermatology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
¹⁰ Department of Internal Medicine, Section of Nephrology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
¹¹ Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and immunology Center, VU University medical center, Amsterdam, the Netherlands.
¹² Amsterdam Rheumatology and immunology Center, Amsterdam UMC, Department of Rheumatology and Clinical Immunology, University of Amsterdam, Amsterdam, the Netherlands; Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and immunology Center, VU University medical center, Amsterdam, the Netherlands.
¹³ Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Faculty of Veterinary Medicine, Utrecht University Utrecht, The Netherlands.
¹⁴ Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
¹⁵ Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands.
¹⁶ Department of Dermatology, Center for Blistering Diseases, University Medical Center Groningen, University Groningen, Groningen, The Netherlands.
¹⁷ Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁸ Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.
¹⁹ Centre of expertise for lupus-, vasculitis- and complement-mediated systemic diseases, Department of Internal Medicine - Nephrology section, Leiden University Medical Centre, Leiden, The Netherlands.
²⁰ Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands.
²¹ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
²² Department of Dermatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
²³ Brain center UMC Utrecht, department of neurology and neurosurgery, Utrecht, the Netherlands.
²⁴ Clinical Research Unit, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands.
²⁵ Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, the Netherlands; Swammerdam Institute for Life Sciences, University of Amsterdam, the Netherlands.
²⁶ Medical Microbiology and Infection Prevention department, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands.
²⁷ Department of Pediatric Immunology, Rheumatology and Infectious Disease, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, the Netherlands.

PMID: 38763170
DOI: 10.1016/j.jaci.2024.04.031

Abstract

Background: Despite impaired humoral responses in patients treated with immunosuppressants (ISPs), recent studies found similar severity of SARS-CoV-2 breakthrough infections compared to controls. One potential explanation is the rapid generation humoral responses upon infection, but evidence is lacking.

Objectives: To investigate longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infections in patients with immune-mediated inflammatory diseases (IMID) on ISPs and controls.

Methods: As prospective sub-study of the national Target-to-B! (T2B!) consortium, we included IMID patients on ISPs and controls who reported SARS-CoV-2 breakthrough infections between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, three antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at four time points after SARS-CoV-2 breakthrough infections.

Results: We included 302 IMID patients on ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infections in both groups. However, in IMID patients on anti-CD20 therapy and sphingosine-1 phosphate receptor (S1P) modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild and hospitalization was required in less than 1% of the cases.

Conclusions: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones towards new viral variants. However, in patients treated with anti-CD20 therapy or S1P modulators, the dynamics were greatly impaired, and to a lesser extent in those anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

Keywords: Auto-immune disease; Breakthrough infections; Humoral responses; Immunosuppressants; SARS-CoV-2.