T cell activation markers CD38 and HLA-DR indicative of non-seroconversion in anti-CD20-treated patients with multiple sclerosis following SARS-CoV-2 mRNA vaccination.

BACKGROUND: Messenger RNA (mRNA) vaccines provide robust protection against SARS-CoV-2 in healthy individuals. However, immunity after vaccination of patients with multiple sclerosis (MS) treated with ocrelizumab (OCR), a B cell-depleting anti-CD20 monoclonal antibody, is not yet fully understood. METHODS: In this study, deep immune profiling techniques were employed to investigate the immune response induced by SARS-CoV-2 mRNA vaccines in untreated patients with MS (n=21), OCR-treated patients with MS (n=57) and healthy individuals (n=30). RESULTS: Among OCR-treated patients with MS, 63% did not produce detectable levels of antibodies (non-seroconverted), and those who did have lower spike receptor-binding domain-specific IgG responses compared with healthy individuals and untreated patients with MS. Before vaccination, no discernible immunological differences were observed between non-seroconverted and seroconverted OCR-treated patients with MS. However, non-seroconverted patients received overall more OCR infusions, had shorter intervals since their last OCR infusion and displayed higher OCR serum concentrations at the time of their initial vaccination. Following two vaccinations, non-seroconverted patients displayed smaller B cell compartments but instead exhibited more robust activation of general CD4+ and CD8+ T cell compartments, as indicated by upregulation of CD38 and HLA-DR surface expression, when compared with seroconverted patients. CONCLUSION: These findings highlight the importance of optimising treatment regimens when scheduling SARS-CoV-2 vaccination for OCR-treated patients with MS to maximise their humoral and cellular immune responses. This study provides valuable insights for optimising vaccination strategies in OCR-treated patients with MS, including the identification of CD38 and HLA-DR as potential markers to explore vaccine efficacy in non-seroconverting OCR-treated patients with MS.

Longitudinal rheumatoid factor autoantibody responses after SARS-CoV-2 vaccination or infection.

Background: Rheumatoid factors (RFs) are autoantibodies that target the Fc region of IgG, and are found in patients with rheumatic diseases as well as in the healthy population. Many studies suggest that an immune trigger may (transiently) elicit RF responses. However, discrepancies between different studies make it difficult to determine if and to which degree RF reactivity can be triggered by vaccination or infection. Objective: We quantitatively explored longitudinal RF responses after SARS-CoV-2 vaccination and infection in a well-defined, large cohort using a dual ELISA method that differentiates between true RF reactivity and background IgM reactivity. In addition, we reviewed existing literature on RF responses after vaccination and infection. Methods: 151 healthy participants and 30 RA patients were included to measure IgM-RF reactivity before and after SARS-CoV-2 vaccinations by ELISA. Additionally, IgM-RF responses after a SARS-CoV-2 breakthrough infection were studied in 51 healthy participants. Results: Published prevalence studies in subjects after infection report up to 85% IgM-RF seropositivity. However, seroconversion studies (both infection and vaccination) report much lower incidences of 2-33%, with a trend of lower percentages observed in larger studies. In the current study, SARS-CoV-2 vaccination triggered low-level IgM-RF responses in 5.5% (8/151) of cases, of which 1.5% (2/151) with a level above 10 AU/mL. Breakthrough infection was accompanied by development of an IgM-RF response in 2% (1/51) of cases. Conclusion: Our study indicates that de novo RF induction following vaccination or infection is an uncommon event, which does not lead to RF epitope spreading.

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

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.

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity.

BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

Ocrelizumab Concentration Is a Good Predictor of SARS-CoV-2 Vaccination Response in Patients with Multiple Sclerosis.

Ocrelizumab, an anti-CD20 monoclonal antibody, counteracts induction of humoral immune responses after severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccinations in patients with multiple sclerosis (MS). We aimed to assess if serum ocrelizumab concentration measured at the time of vaccination could predict the humoral response after SARS-CoV-2 vaccination. In 52 patients with MS, we found ocrelizumab concentration at the time of vaccination to be a good predictor for SARS-CoV-2 IgG anti-RBD titers after vaccination (comparable to B-cell count). As the course of ocrelizumab concentration may be predicted using pharmacokinetic models, this may be a superior biomarker to guide optimal timing for vaccinations in B-cell depleted patients with MS. ANN NEUROL 2023;93:103-108.

SARS-CoV-2 omicron breakthrough infections in patients with multiple sclerosis.

BACKGROUND: It is unclear which patients with multiple sclerosis (MS) are most susceptible for omicron breakthrough infections. METHODS: We assessed omicron breakthrough infections in vaccinated patients with MS with and without disease-modifying therapies enrolled in an ongoing large prospective study. We longitudinally studied humoral responses after primary and booster vaccinations and breakthrough infections. RESULTS: Omicron breakthrough infections were reported in 110/312 (36%) patients with MS, and in 105/110 (96%) infections were mild. Omicron breakthrough infections occurred more frequently in patients treated with anti-CD20 therapies and sphingosine-1 phosphate receptor (S1PR) modulators, patients with impaired humoral responses after primary immunisation (regardless of treatment) and patients without prior SARS-CoV-2 infections. After infection, antibody titres increased in patients on S1PR modulator treatment while anti-CD20 treated patients did not show an increase. CONCLUSIONS: SARS-COV-2 omicron breakthrough infections are more prevalent in patients with MS on anti-CD20 therapies and S1PR modulators compared with other patients with MS, which correlated with decreased humoral responses after vaccination. Humoral responses after infection were higher in S1PR modulator-treated patients in comparison to patients on anti-CD20 therapies, suggesting that immunological protection from contracting infection or repeated exposures may differ between these therapies.

Longitudinal SARS-CoV-2 humoral response in MS patients with and without SARS-CoV-2 infection prior to vaccination.

Introduction: During the COVID-19 pandemic, certain disease modifying therapies (DMTs) used in multiple sclerosis (MS), such as anti-CD20 therapies, have been associated with decreased humoral responses after SARS-CoV-2 vaccination. Hybrid immunity, referring to immunity after both vaccination and SARS-CoV-2 infection might increase humoral responses. Methods: This was a substudy of two prospective cohort studies on SARS-CoV-2 antibodies after SARS-CoV-2 infection and vaccination. RBD-specific IgG titers of patients with MS and healthy controls who had experienced SARS-CoV-2 infection prior to the first vaccination were compared with those patients and healthy controls without prior infection. Humoral responses were measured at various time points after SARS-CoV-2 infection in convalescent patients and all patients prior to the first vaccination, 28 days after the first vaccination, and 28 days after the second vaccination. Results: One hundred and two individuals [of which 34 patients with MS and DMTs (natalizumab or ocrelizumab), 30 patients without DMTs, and 38 healthy controls] were included. Fifty one of these individuals were convalescent. Median SARS-CoV-2 antibody titers were higher after the first vaccination in convalescent individuals compared with individuals without infection prior to vaccination. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers were comparable after the second vaccination in patients with MS with and without prior infection. However, in the convalescent ocrelizumab-treated patients, SARS-CoV-2 antibody titers did not increase after vaccinations. Conclusion: In patients with MS without anti-CD20 therapies, SARS-CoV-2 infection before vaccination increases humoral responses after the first vaccination, similar to the healthy controls. In patients with MS treated with ocrelizumab (convalescent and non-convalescent), humoral responses remained low.

Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273.

Background: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants. Methods: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. Results: OCR-treated MS patients exhibit a preserved recall response of CD8+ T central memory cells following first vaccination compared to HCs and a similar CD4+ circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4+ and CD8+ T cells. Conclusions: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8+ T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients. Funding: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871).

Longitudinal T-Cell Responses After a Third SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis on Ocrelizumab or Fingolimod.

OBJECTIVES: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod. METHODS: This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2-specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated. RESULTS: In ocrelizumab-treated patients (N = 24), IFN-γ-producing SARS-CoV-2-specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2-specific T cells were detected after second (N = 12) and third (N = 9) vaccinations. DISCUSSION: In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination.

Breakthrough SARS-CoV-2 infections with the delta (B.1.617.2) variant in vaccinated patients with immune-mediated inflammatory diseases using immunosuppressants: a substudy of two prospective cohort studies.

Background: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. Methods: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. Findings: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. Interpretation: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. Funding: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study.

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders. Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses. Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment. Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited. Funding: ZonMw (The Netherlands Organization for Health Research and Development).

Risk factors associated with short-term adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases.

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.