Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has infected millions of individuals, resulted in >4 million deaths, and greatly disrupted societies worldwide (Dong et al., 2020). Recovered individuals mostly exhibit robust humoral and cellular SARS-CoV-2 immunity (Grifoni et al., 2020; Koutsakos et al., 2021; Mathew et al., 2020; Sekine et al., 2020; Thevarajan et al., 2020) and generate immunological memory. In addition, multiple effective vaccines have been deployed to induce immune-mediated protection against SARS-CoV-2 leading to a substantial risk reduction of developing severe disease. Several studies in healthy individuals demonstrated that the mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), successfully induce SARS-CoV-2-specific humoral (Gaebler et al., 2021; Ma et al., 2020) and cellular immunity (Collier et al., 2021; Minervina et al., 2021; Oberhardt et al., 2021; Sahin et al., 2021) and are highly efficacious (>94%) in reducing transmissibility and induction of serious disease and hospitalization of most variants (Baden et al., 2021; Lyngse et al., 2021; Polack et al., 2020; Tenforde and Patel, 2021). In addition to long-lived antibodies, the efficacy of these vaccines greatly relies on the induction of memory B and T cells.

However, about 4% of the world’s population is affected by one of over 80 different types of autoimmune disease, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA) (National Stem Cell Foundation, 2021). Autoimmune diseases are often treated with immunosuppressants which successfully suppress autoreactive immune responses (Burmester and Pope, 2017; Cronstein and Aune, 2020; Edwards et al., 2004; Edwards and Cambridge, 2006; Mulero et al., 2018; Wolinsky et al., 2020), but simultaneously also affect the functionality of the adaptive immune system during infection or vaccination, depending on the immunosuppressant that is used. The severity of COVID-19 in individuals on immunosuppressants varies from mild to severe, depending on the type of immunosuppressants (Gianfrancesco et al., 2020; Möhn et al., 2020; Sparks et al., 2021; Strangfeld et al., 2021) and other underlying risk factors (Baden et al., 2021; Chaudhry et al., 2021; Hughes et al., 2021; Möhn et al., 2020; Pablos et al., 2020; Sparks et al., 2021; Strangfeld et al., 2021; Williamson et al., 2020; Zabalza et al., 2021). It is not well understood how immunosuppressants affect the formation of protective immunological B and T cell memory upon SARS-CoV-2 infection or vaccination, in part because these patient groups were excluded from many phase 3 clinical trials. Failure to induce effective immunological memory could leave these patients at risk for symptomatic re-infections. As SARS-CoV-2-specific immunity may not be very long-lived and/or can be breached by novel variants, like omicron that has mutated antibody recognition sites, it is important to evaluate if treatment with immunosuppressants allows efficient induction of SARS-CoV-2-specific B and broad-protective T cell memory upon SARS-CoV-2 exposure and subsequent reactivation of memory cells upon SARS-CoV-2 antigen recall (Apostolidis et al., 2021; Felten et al., 2022; Goel et al., 2022; Haberman et al., 2022; Mahil et al., 2021). To assess the latter, ex vivo evaluation of SARS-CoV-2 immune dynamics in patients with autoimmune diseases treated with immunosuppressants following recovery of SARS-CoV-2 infection and subsequent vaccination is required. Recent studies demonstrated that a single dose of mRNA vaccine in SARS-CoV-2 experienced healthy individuals resulted in stronger and broader immune responses than with vaccination alone, the so-called hybrid immunity (Reynolds et al., 2021; Stamatatos et al., 2021; Tauzin et al., 2021; Wang et al., 2021a). It remains to be established whether SARS-CoV-2 experienced individuals treated with immunosuppressants also induce a similar recall response upon vaccination. In this study, we aim to understand if and how immunosuppressive medication may interfere with the formation of protective immunological memory against SARS-CoV-2 to refine and/or optimize vaccine strategies to generate long-lasting, protective immunological memory in individuals using immunosuppressants.

B cell-depleting anti-CD20 monoclonal antibody (anti-CD20) therapies such as ocrelizumab (OCR) and rituximab (RTX) are successfully used to treat multiple diseases including MS (Edwards et al., 2004; Edwards and Cambridge, 2006; Mulero et al., 2018; Wolinsky et al., 2020). However, B cells play a critical role in the formation of protective humoral immunity during viral infections. With help from cognate CD4⁺ T follicular helper cells (T_fh cells), B cells differentiate into memory B cells and plasmablasts or long-lived plasma cells that secrete class-switched, high-affinity antibodies upon antigen stimulation through infection or vaccination (Elsner and Shlomchik, 2020; Nutt et al., 2015; Verstegen et al., 2021). SARS-CoV-2 infection in otherwise healthy individuals has demonstrated that both B and T_fh cells are of great importance for the formation of a protective humoral immunity (Koutsakos et al., 2021; Mathew et al., 2020; Ng et al., 2020; Thevarajan et al., 2020; Wang et al., 2021b). However, the majority of patients on anti-CD20 therapies did not generate significant SARS-CoV-2-specific antibody titers following the natural infection (Koutsakos et al., 2021; Simon et al., 2021; Zabalza et al., 2021) or vaccination (Apostolidis et al., 2021; Deepak et al., 2021; van Kempen et al., 2022). A study in SARS-CoV-2 naïve anti-CD20-treated MS patients demonstrated that low vaccination-induced SARS-CoV-2 antibody titers correlate with reduced frequencies of circulating B cells (in line with anti-CD20-mediated B cell depletion) and low T_fh cells (Apostolidis et al., 2021). Interestingly, SARS-CoV-2 naïve anti-CD20-treated MS patients which induced the lowest antibody titers displayed the highest induction of activated CD8⁺ T cells after vaccination (Apostolidis et al., 2021; Brill et al., 2021; Gadani et al., 2021; Madelon et al., 2021). CD8⁺ T cells form an important second line of protection against severe illness and mortality, as they are essential for the viral clearance (Kundu et al., 2022; Tan et al., 2021). To date, it remains to be evaluated if patients treated with anti-CD20 induce enough immunological B and T cell memory upon primary infection to be efficiently recalled upon re-exposure and/or with targeted vaccination.

Methotrexate (MTX) is another widely used immunosuppressant, which is one of the most common and effective medications to treat RA (Burmester and Pope, 2017; Cronstein and Aune, 2020). MTX has broad immunomodulating functions affecting multiple arms of the immune system and has been shown to reduce circulating leukocytes numbers (neutrophils and lymphocytes), their proliferation capacity, T cell receptor (TCR) activation, T cell lytic capacity, inhibiting pro-inflammatory pathways, neutrophil recruitment, extracellular trap formation and cytokine expression by macrophages and increasing the number of regulatory T cells (T_regs) (Cronstein and Aune, 2020). Although the immune-modulatory function of MTX effectively mitigates effects of autoimmune inflammatory reactions and potentially contributes to reduced severity of COVID-19 (Sparks et al., 2021; Strangfeld et al., 2021), it has also been reported to reduce antibody titers after SARS-CoV-2 vaccination in SARS-CoV-2 naïve autoimmune patients (Deepak et al., 2021; Furer et al., 2021; Haberman et al., 2020; Spiera et al., 2021). In contrast to anti-CD20-treated MS patients, mRNA vaccination of SARS-CoV-2 naïve MTX-treated patients with immune-mediated inflammatory disease (IMID) did not induce activated CD8⁺ T cells following mRNA vaccination (Haberman et al., 2020). Proportions of spike-specific B cells, T_fh, and activated CD4⁺ T cells were reported to be induced to similar levels as observed in healthy individuals and IMID patients without MTX treatment although induction of antibody titers was less (Haberman et al., 2020). However, it is currently unknown whether MTX affects immunological memory formation after natural SARS-CoV-2 infection and/or B and T cell reactivation upon re-infection and/or vaccination.

To understand how immunosuppressive medications like OCR and MTX affect the induction of immunological memory and subsequent recall response, the humoral and cellular immune responses in SARS-CoV-2 experienced RA-MTX and MS-OCR patients were established and compared to SARS-CoV-2 experienced healthy individuals following the first and second dose of the Moderna mRNA vaccine. The immune dynamics of the recall response were elucidated by measuring SARS-CoV-2-specific antibody responses and deep-immune profiling of B and T cell responses in fresh peripheral blood. This study shows that OCR-treated MS patients exhibit a preserved recall response of CD8⁺ T cells following first vaccination compared to healthy controls (HCs) and a normal CD4⁺ T_fh1 and T_h1 dynamics, whereas humoral and B cell responses were strongly impaired. In contrast, RA patients treated with MTX displayed a delayed induction of the humoral recall responses after the first vaccination, but antibody levels were comparable to HCs following a second vaccination. However, MTX treatment delayed and/or hampered CD4⁺ and CD8⁺ T cell reactivation as demonstrated by the absence of co-expression of multiple dynamic markers.

The formation of immunological memory following infection and/or vaccination and the subsequent recall response is of great importance to prevent severe disease when re-exposed to the same pathogen. This study aimed to unravel the SARS-CoV-2 immunological recall potential in SARS-CoV-2-experienced patients using two frequently prescribed immunosuppressive medications OCR and MTX. As an alternative to re-exposure with SARS-CoV-2, the immunological recall was investigated following SARS-CoV-2 Moderna mRNA vaccination of SARS-CoV-2 experienced RA-MTX and MS-OCR patients. Results were compared to vaccinated SARS-CoV-2 experienced HCs. Our study provides a comprehensive analysis of the SARS-CoV-2 vaccine-induced recall immune response in SARS-CoV-2 experienced RA-MTX and MS-OCR patients. Despite the small group sizes, both immunosuppressants were shown to affect the vaccine-induced immunological recall response differently.

The quality (measured by the number per µl blood) and quality (measured by the percentage of responding cells and the co-expression of dynamic markers) of the SARS-CoV-2 vaccine-induced CD8⁺ T cell responses was established. Although MS-OCR patients had a smaller CD8⁺ T_cm population compared to HC before vaccination and upon second vaccination, substantial stronger quality of the CD8⁺ T_cm cell recall response in OCR-treated MS patients was observed compared to those of SARS-CoV-2 experienced HCs following first vaccination. Even though the percentage of responding cells remained high in MS-OCR patients following the second vaccination, HCs displayed responses of slightly higher quality. In general, the overall quality of the CD4⁺ T_fh1, T_h1, and T_h1-like recall response was still intact in SARS-CoV-2 experienced OCR-treated MS patients. The dynamic CD4⁺ T_fh1 recall response profile was somewhat surprising considering the lack of B cells and significantly smaller CD4⁺ T_fh1 population before vaccination. Mice studies previously demonstrated that B cells contribute to the CD4⁺ T cell activation (Bouaziz et al., 2007). However, others also observed CD4⁺ T_fh1 cells activation following SARS-CoV-2 vaccination of unexperienced OCR-treated MS patients (Apostolidis et al., 2021). One interesting observation was the lack of CTLA-4 expression in SARS-CoV-2 experienced MS-OCR patients. CTLA-4 is known to increase on activated T cells to inhibit their immune response, which could indicate that by day 7 post vaccination the recall immune response in HCs is already declining (Chikuma, 2017). Whether failure to induce CTLA-4 expression on CD4⁺ T_fh1 cells in MS-OCR patients is the result of a less tolerant immune system as part of the autoimmune disease or a direct result of missing B cells in the germinal response which may normally be responsible for the induction of CTLA-4 on CD4⁺ T_fh1 cells as part of a negative feedback loop remains to be established. In addition, the lack of B cell immunity in MS-OCR patients may have resulted in an altered T_h response, which focused more on the activation of CD4⁺ T_h1 responses, skewing the recall immune response to a preserved CD8⁺ T cell performance. This is in accordance with other studies where low antibody responses following SARS-CoV-2 vaccination of unexperienced MS-OCR patients are also correlated to superior CD8⁺ T cell responses (Apostolidis et al., 2021; Brill et al., 2021; Gadani et al., 2021; Madelon et al., 2021). In contrast to the T cell recall and despite the surprising presence of low SARS-CoV-2 antibody titers before vaccination, anti-CD20 treatment severely impaired the antigen-specific humoral and B cell recall responses following vaccination, which coincidenced with failure to increase antibody titers and/or seroconversion. OCR treatment is known to eliminate CD20⁺ B cell populations for prolonged periods (van Lierop et al., 2022), which likely hampered the formation of SARS-CoV-2-specific B cell memory in MS patients and indeed memory B cells were undetectable before vaccination. Together, OCR treatment deprived MS patients of an effective B cell recall response, which in part could explain the failure to induce any humoral immunity upon vaccination. It remains to be established why MS-OCR patients seroconverted following the initial infection and if these antibodies have had similar neutralizing qualities as those found in healthy individuals. One possibility is that OCR treatment mainly eradicated circulating CD20⁺ B cell populations, while B cells in secondary lymphoid organs may have been less affected (Kamburova et al., 2013).

MTX treatment in RA patients resulted in delayed immunological recall responses compared to HCs. This was best observed by the antigen-specific humoral immune response following the first vaccination. Despite inducing a rise in antibody titers by day 7, similar levels to SARS-CoV-2 experienced HCs were not reached till day 42 just before the second vaccination. Previous studies observed that de novo antibody titers following SARS-CoV-2 vaccination of MTX-treated RA patients were reduced compared to HCs (Deepak et al., 2021; Furer et al., 2021; Haberman et al., 2020; Spiera et al., 2021). Here, we show that recall humoral immunity is merely delayed. MTX is known to hamper the proliferation of lymphocytes (Cronstein and Aune, 2020), which could have affected the formation of memory B cells following the initial infection in RA patients and thereby the effectiveness of the recall response, hampering the formation of plasmablasts and plasma cells, which was indeed observed in most RA-MTX patients. Whether delayed humoral recall was the result of lower pre-existing B cell memory before vaccination and/or reduced proliferation and differentiation capacity of the B cells, both observed during the course of this study, remains to be established by measuring antigen-specific B cells in these patients over time. However, the immunosuppressive effect of MTX was most striking in the CD8⁺ T cell compartment. SARS-CoV-2 experienced RA-MTX patients had a significantly smaller total CD8⁺ T cell population which was mainly driven by a smaller than expected CD8⁺ T_naïve population, whereas their CD8⁺ T_cm population seemed intact. In accordance with the suppressive activity of MTX and in contrast to MS-OCR patients, the memory CD8⁺ T cell populations in RA-MTX patients did not increase during the course of the study. In addition, responding CD8⁺ T_cm and T_naïve populations only increased following the second vaccination. Furthermore, their ability to upregulate the co-expression of multiple dynamic responding markers was severely hampered in CD8⁺ T_cm cells, suggesting that the overall quality of the response was either compromised or delayed, as was observed for antigen-specific humoral recall immunity. A similar effect, albeit less strong, was observed in CD4⁺ T_fh1 and T_h1 cells. Studies that included multiple additional time points are warranted to elucidate the possible explanations.

Of specific interest is the response of CD8⁺ T_naïve cells in MS-OCR patients and HCs following the first vaccination. This indicates that next to immunological recall a novel CD8⁺ T cell response is generated, which could result in a broader immune response. Further investigation is warranted to establish whether these cells recruit novel clonotypes directed to similar epitopes as during the initial infection or CD8⁺ T cells directed against additional epitopes. The effect of both vaccinations on the CD8⁺ T cells response in RA-MTX patients seemed limited, however, it cannot be fully excluded that responses in CD8⁺ T_naïve cells were delayed and not captured by the time points in this study.

Overall, this study demonstrated that MTX and OCR immunosuppressive therapies prevent the induction of a larger-than-expected humoral and cellular recall response that was previously observed in SARS-CoV-2 experienced HCs (Reynolds et al., 2021; Stamatatos et al., 2021; Tauzin et al., 2021; Wang et al., 2021a). Despite lacking humoral and B cell immunity, the MS-OCR patients did have a preserved reactive CD8⁺ T cell recall response. CD8⁺ T cells are known to form an important second-line defense. Although CD8⁺ T cells do not prevent infection, they have a key role in viral clearance which contributes to the resolution of symptoms (Kundu et al., 2022; Thevarajan et al., 2020) and robust CD8⁺ T cell immunity has been shown to result in overall milder symptoms in SARS-CoV-2 patients (Rydyznski Moderbacher et al., 2020; Tan et al., 2021). Furthermore, CD8⁺ T cells recognize conserved epitopes allowing for high cross-reactivity between different SARS-CoV-2 variants (Alison Tarke et al., 2021; Gao et al., 2022; GeurtsvanKessel et al., 2021; Keeton et al., 2021; Liu et al., 2022; Rowntree et al., 2022). While CD8⁺ T cells immunity will not prevent infection, high proportions of CD8⁺ T cells have been associated with clinically favorable outcomes (Kundu et al., 2022; Tan et al., 2021). Ongoing research in this area will be important, particularly in regard to immunosuppressed populations facing novel variants of concern. MTX treatment of RA patients also had impaired recall immune responses after vaccination. Despite a clear delay in the SARS-CoV-2-specific antibody response, further studies including more time points are required to confirm whether the lower response observed in the cellular arm of the immunological recall is delayed or remains impaired over time and how this affects the immune protection of individuals under MTX therapy when infected with new SARS-CoV-2 variants. Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may benefit from vaccines that aim to induce a broad CD8⁺ T cell response. RA-MTX patients lack similar broad-protective cellular immune responses and are likely to benefit more from revaccination strategies with vaccines updated for new variants of concern to induce broad-protective antibody responses.

All raw and processed data presented in this study are available at https://flowrepository.org/id/FR-FCM-Z52K.

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Author details

1. Niels JM Verstegen

   Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

   Contribution

   Designed the experiments; analyzed the data; provided intellectual input into the study; wrote the manuscript

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5732-4979

2. Ruth R Hagen

   1. Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands
   2. Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands

   Contribution

   Performed the experiments

   Contributed equally with

   Jet van den Dijssel, Lisan H Kuijper, Christine Kreher and Thomas Ashhurst

   Competing interests

   No competing interests declared

3. Jet van den Dijssel

   1. Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands
   2. Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands

   Contribution

   Performed the experiments

   Contributed equally with

   Ruth R Hagen, Lisan H Kuijper, Christine Kreher and Thomas Ashhurst

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4849-0374

4. Lisan H Kuijper

   Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

   Contribution

   Performed the experiments

   Contributed equally with

   Ruth R Hagen, Jet van den Dijssel, Christine Kreher and Thomas Ashhurst

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3009-0943

5. Christine Kreher

   Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

   Contribution

   Performed the experiments

   Contributed equally with

   Ruth R Hagen, Jet van den Dijssel, Lisan H Kuijper and Thomas Ashhurst

   Competing interests

   No competing interests declared

6. Thomas Ashhurst

   1. Sydney Cytometry Core Research Facility, Charles Perkins Centre, Centenary Institute, and The University of Sydney, Sydney, Australia
   2. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia

   Contribution

   Analyzed the data; provided intellectual input into the study

   Contributed equally with

   Ruth R Hagen, Jet van den Dijssel, Lisan H Kuijper and Christine Kreher

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7269-7773

7. Laura YL Kummer

   Department of Neurology and Neurophysiology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands

   Contribution

   Managed the participant database; involved in clinical recruitment

   Competing interests

   No competing interests declared

8. Maurice Steenhuis

   Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

   Contribution

   Performed the experiments

   Competing interests

   No competing interests declared

9. Mariel Duurland

   Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

   Contribution

   Performed the experiments

   Competing interests

   No competing interests declared

10. Rivka de Jongh

    Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Performed the experiments

    Competing interests

    No competing interests declared

11. Nina de Jong

    Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Performed the experiments

    Competing interests

    No competing interests declared

12. C Ellen van der Schoot

    Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, Netherlands

    Contribution

    Provided intellectual input into the study

    Competing interests

    No competing interests declared

13. Amélie V Bos

    Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Provided intellectual input into the study

    Competing interests

    No competing interests declared

14. Erik Mul

    Department of Research Facilities, Sanquin Research, Amsterdam, Netherlands

    Contribution

    Provided intellectual input into the study

    Competing interests

    No competing interests declared

15. Katherine Kedzierska

    1. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
    2. Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan

    Contribution

    Provided intellectual input into the study

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6141-335X

16. Koos PJ van Dam

    Department of Neurology and Neurophysiology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    No competing interests declared

17. Eileen W Stalman

    Department of Neurology and Neurophysiology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    No competing interests declared

18. Laura Boekel

    Department of Rheumatology, Amsterdam Rheumatology and immunology Center, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    No competing interests declared

19. Gertjan Wolbink

    1. Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands
    2. Department of Rheumatology, Amsterdam Rheumatology and immunology Center, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    No competing interests declared

20. Sander W Tas

    Amsterdam Rheumatology and immunology Center, Department of Rheumatology and Clinical Immunology, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    No competing interests declared

21. Joep Killestein

    Amsterdam UMC, Vrije Universiteit, Department of Neurology, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    has speaking relationships with Merck, Biogen, TEVA, Sanofi, Genzyme, Roche and Novartis. AmsterdamUMC, location VUmc, MS Center Amsterdam has received financial support for research activities from Merck, Celgene, Biogen, GlaxoSmithKline, Immunic, Roche, Teva, Sanofi, Genzyme, and Novartis

22. Zoé LE van Kempen

    Amsterdam UMC, Vrije Universiteit, Department of Neurology, Amsterdam, Netherlands

    Contribution

    Involved in clinical recruitment

    Competing interests

    No competing interests declared

23. Luuk Wieske

    1. Department of Neurology and Neurophysiology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands
    2. Department of Clinical Neurophysiology, St Antonius Hospital, Nieuwegein, Netherlands

    Contribution

    Managed the participant database; involved in clinical recruitment

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-2522-4081

24. Taco W Kuijpers

    Department of Pediatric Immunology, Rheumatology and Infectious Disease, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Conceived the study; involved in clinical recruitment

    Competing interests

    No competing interests declared

25. Filip Eftimov

    Department of Neurology and Neurophysiology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Conceived the study; involved in clinical recruitment

    Competing interests

    No competing interests declared

26. Theo Rispens

    Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Conceived the study

    Competing interests

    No competing interests declared

27. S Marieke van Ham

    1. Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands
    2. Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Conceived the study; led the study; supervised the study; provided intellectual input into the study; wrote the manuscript

    Contributed equally with

    Anja ten Brinke and Carolien E van de Sandt

    Competing interests

    No competing interests declared

28. Anja ten Brinke

    Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands

    Contribution

    Supervised the study; provided intellectual input into the study; wrote the manuscript

    Contributed equally with

    S Marieke van Ham and Carolien E van de Sandt

    For correspondence

    a.tenbrinke@sanquin.nl

    Competing interests

    No competing interests declared

29. Carolien E van de Sandt

    1. Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, Netherlands
    2. Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia

    Contribution

    Supervised the study; designed the experiments; performed the experiments; analyzed the data; provided intellectual input into the study; wrote the manuscript

    Contributed equally with

    S Marieke van Ham and Anja ten Brinke

    For correspondence

    cvandesandt@unimelb.edu.au

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4155-7433

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