Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy - 21/06/24

Doi : 10.1016/j.jaci.2024.04.031

Eileen W. Stalman, MD ^a,^⁎ , Luuk Wieske, MD, PhD ^a,^b, Jim B.D. Keijser, MSc ^c, Koos P.J. van Dam, MD ^a, Laura Y.L. Kummer, MD ^a,^c, Maarten F. Wilbrink, Bsc ^a, Zoé L.E. van Kempen, MD, PhD ^d, Joep Killestein, MD, PhD ^d, Adriaan G. Volkers, MD, PhD ^e, Sander W. Tas, MD, PhD ^f, Laura Boekel, BSc ^f, Gerrit J. Wolbink, MD, PhD ^g, Anneke J. van der Kooi, MD, PhD ^a, Joost Raaphorst, MD, PhD ^a, Mark Löwenberg, MD, PhD ^e, R. Bart Takkenberg, MD, PhD ^e, Geert R.A.M. D’Haens, MD, PhD ^e, Phyllis I. Spuls, MD, PhD ^h, Marcel W. Bekkenk, MD, PhD ^h, Annelie H. Musters, MD ^h, Nicoline F. Post, MD ^h, Angela L. Bosma, MD ^h, Marc L. Hilhorst, MD, PhD ⁱ, Yosta Vegting, MD ⁱ, Frederique J. Bemelman, MD, PhD ⁱ, Alexandre E. Voskuyl, MD, PhD ^j, Bo Broens, MD ^j, Agner Parra Sanchez, MD ^f,^j, Cécile A.C. M. van Els, PhD ^k,^l, Jelle de Wit, PhD ^k, Abraham Rutgers, MD, PhD ^m, Karina de Leeuw, MD, PhD ^m, Barbara Horváth, MD, PhD ⁿ, Jan J.G.M. Verschuuren, MD, PhD ^o, Annabel M. Ruiter, MD ^o, Lotte van Ouwerkerk, MD ^p, Diane van der Woude, MD, PhD ^p, Renée C.F. Allaart, MD, PhD ^p, Y.K. Onno Teng, MD, PhD ^q, Pieter van Paassen, MD, PhD ^r, Matthias H. Busch, MD ^r, Esther Brusse, MD, PhD ^s, Pieter A. van Doorn, MD, PhD ^s, Adája E. Baars, MD ^s, Dirkjan Hijnen, MD, PhD ^t, Corine R.G. Schreurs, MD ^t, W. Ludo van der Pol, MD, PhD ^u, H. Stephan Goedee, MD, PhD ^u, Maurice Steenhuis, PhD ^c, Sofie Keijzer, MSc ^c, Olvi Cristianawati, PhD ^c, Anja ten Brinke, PhD ^c, Niels J.M. Verstegen, PhD ^c, Koos A.H. Zwinderman, PhD ^v, S. Marieke van Ham, PhD ^c,^w, Theo Rispens, PhD ^c, Matthijs R. Welkers, MD, PhD ^x, Marcel Jonges, PhD ^x, Filip Eftimov, MD, PhD ^a, Taco W. Kuijpers, MD, PhD ^y
on behalf of the
T2B! immunity against SARS-CoV-2 study group
^a Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands
^b Department of Clinical Neurophysiology, St Antonius Hospital, Nieuwegein, The Netherlands
^c Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
^d Department of Neurology, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
^e Department of Gastroenterology and Hepatology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
^f Amsterdam Rheumatology and Immunology Center, Amsterdam UMC, Department of Rheumatology and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands
^g Amsterdam Rheumatology and Immunology Center, location Reade, Department of Rheumatology, Amsterdam, The Netherlands
^h Department of Dermatology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
ⁱ Department of Internal Medicine, Section of Nephrology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
^j Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
^k Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
^l Faculty of Veterinary Medicine, Utrecht University Utrecht, Utrecht, The Netherlands
^m Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands
ⁿ Department of Dermatology, Center for Blistering Diseases, University Medical Center Groningen, University Groningen, Groningen, The Netherlands
^o Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
^p Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
^q Centre of Expertise for Lupus-, Vasculitis-, and Complement-Mediated Systemic Diseases, Department of Internal Medicine–Nephrology Section, Leiden University Medical Centre, Leiden, The Netherlands
^r Department of Nephrology and Clinical Immunology, Maastricht University Medical Center, Maastricht, The Netherlands
^s Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
^t Department of Dermatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
^u Department of Neurology and Neurosurgery, Brain Center UMC Utrecht, Utrecht, The Netherlands
^v Clinical Research Unit, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands
^w Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
^x Medical Microbiology and Infection Prevention Department, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands
^y Department of Pediatric Immunology, Rheumatology, and Infectious Disease, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands

^∗Corresponding author: Eileen W. Stalman, MD, Department of Neurology and Neurophysiology, Amsterdam Neuroscience, Amsterdam UMC, location AMC, Meibergdreef, University of Amsterdam, Amsterdam, The Netherlands.Department of Neurology and NeurophysiologyAmsterdam NeuroscienceAmsterdam UMClocation AMCMeibergdreefUniversity of AmsterdamAmsterdamThe Netherlands

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Abstract

Background

Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking.

Objectives

We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls.

Methods

As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection.

Results

We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor 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 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 toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

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Key words : SARS-CoV-2, autoimmune disease, immunosuppressants, breakthrough infection, humoral response

Abbreviations used : COVID-19, ELISA, IMID, ISP, MMF, Omicron RBD, RBD, RiVM, S, S1P, SARS-CoV-2, T2B!, Wild-type RBD, Wild-type S

Plan

Methods

Study design

Participants

Vaccination campaign in the Netherlands

Dynamics after SARS-CoV-2 delta breakthrough infection

Dynamics after SARS-CoV-2 omicron breakthrough infection

Dynamics after SARS-CoV-2 breakthrough infection compared between IMID patients receiving different types of ISPs and controls

Determinants for increased peak humoral response after SARS-CoV-2 omicron breakthrough infection

Discussion

Disclosure statement

The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be considered senior author.