Article Text

Breakthrough infections with the SARS-CoV-2 omicron (B.1.1.529) variant in patients with immune-mediated inflammatory diseases
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  1. Eileen W Stalman1,
  2. Luuk Wieske1,2,
  3. Koos P J van Dam1,
  4. Laura Y Kummer1,3,
  5. Zoé L E van Kempen4,
  6. Joep Killestein4,
  7. Adriaan G Volkers5,
  8. Sander W Tas6,
  9. Laura Boekel7,
  10. Gertjan J Wolbink8,9,
  11. Anneke J Van der Kooi1,
  12. Joost Raaphorst10,
  13. Mark Löwenberg5,
  14. R Bart Takkenberg5,
  15. Geert R A M D’Haens5,
  16. Phyllis I Spuls11,
  17. Marcel W Bekkenk12,
  18. Annelie H Musters12,
  19. Nicoline F Post12,
  20. Angela L Bosma12,
  21. Marc L Hilhorst13,
  22. Yosta Vegting13,
  23. Frederique J Bemelman13,
  24. Alexandre E Voskuyl14,
  25. Bo Broens15,
  26. Agner Parra Sanchez5,15,
  27. Cécile A C M van Els16,17,
  28. Jelle De Wit18,19,
  29. Abraham Rutgers20,
  30. Karina de Leeuw21,
  31. Barbara Horváth22,
  32. Jan J G M Verschuuren23,
  33. Annabel M Ruiter23,
  34. Lotte van Ouwerkerk24,
  35. Diane van der Woude25,
  36. C F Allaart26,
  37. Onno Y K Teng27,
  38. Pieter van Paassen28,
  39. Matthias H Busch29,
  40. Papay B P Jallah29,
  41. Esther Brusse30,
  42. Pieter A van Doorn30,
  43. Adája Elisabeth Baars30,
  44. Dirk Jan Hijnen31,
  45. Corine R G Schreurs31,
  46. W Ludo Van der Pol32,
  47. H Stephan Goedee32,
  48. Maurice Steenhuis3,
  49. Sofie Keijzer3,
  50. Jim B D Keijser3,
  51. Arend Boogaard3,
  52. Olvi Cristianawati3,
  53. Anja ten Brinke3,
  54. Niels J M Verstegen3,
  55. Koos A H Zwinderman33,
  56. Theo Rispens8,
  57. S Marieke van Ham8,
  58. Taco W Kuijpers34,
  59. Filip Eftimov35
  60. On behalf of the T2B! immunity against SARS-CoV-2 study group
  1. 1Department of Neurology and Neurophysiology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  2. 2Department of Clinical Neurophysiology, Sint Antonius Hospital, Nieuwegein, The Netherlands
  3. 3Department of immunopathology, Sanquin Research, Amsterdam, The Netherlands
  4. 4Department of Neurology, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
  5. 5Department of Gastroenterology and Hepatology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  6. 6Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
  7. 7Research, Reade, Amsterdam, The Netherlands
  8. 8Immunopathology, Sanquin Research an Landsteiner Laboratory, Amsterdam, The Netherlands
  9. 9rheumatology, Jan van Breemen Research Institute | Reade, Amsterdam, The Netherlands
  10. 10Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  11. 11Department of Dermatology, Public Health and Epidemiology, Immunity and Infections, Amsterdam University Medical Centres, Amsterdam, The Netherlands
  12. 12Department of Dermatology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  13. 13Department of Internal Medicine, Section of Nephrology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  14. 14Department of Rheumatology, Amsterdam UMC, Amsterdam, The Netherlands
  15. 15Department of Rheumatology and Clinical Immunology, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
  16. 16Centre for Infectious Disease Control, National Institute for Public Health and the Environment, RIVM, Bilthoven, The Netherlands
  17. 17Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
  18. 18Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK
  19. 19Center for Infectious Diseases, National Institute for Public Health and the Environment, Utrecht, The Netherlands
  20. 20Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands
  21. 21Department of Rheumatology and Clinical Immunology, University Medical Center, University of Groningen, Groningen, The Netherlands
  22. 22Dermatology, University Medical Center Groningen, Groningen, The Netherlands
  23. 23Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
  24. 24Rheumatology, Leiden Universitair Medisch Centrum, Leiden, The Netherlands
  25. 25Rheumatology, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  26. 26Rheumatology, LUMC, Leiden, The Netherlands
  27. 27Nephrology, Leiden University Medical Centre, Leiden, The Netherlands
  28. 28Department of Internal Medicine/Devision of Clinical & Experimental Immunology, Maastricht University Medical Centre, Maastricht, The Netherlands
  29. 29Department of Nephrology and Clinical Immunology, Maastricht Universitair Medisch Centrum+, Maastricht, The Netherlands
  30. 30Department of Neurology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands
  31. 31Department of Dermatology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands
  32. 32Department of Neurology and Neurosurgery, University Medical Centre, Utrecht, The Netherlands
  33. 33Clinical Research Unit, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  34. 34Department of Pediatric Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands
  35. 35Department of Neurology, University of Amsterdam, Amsterdam, The Netherlands
  1. Correspondence to Dr Filip Eftimov, Department of Neurology, University of Amsterdam, Amsterdam 1105, Netherlands; f.eftimov{at}amsterdamumc.nl

Abstract

Objectives To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections.

Methods Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants.

Results 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection.

Conclusions The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections.

  • Autoimmune Diseases
  • Covid-19
  • Autoimmunity
  • Vaccination

Data availability statement

Data are available on reasonable request. Aggregated data and code for reproducing the results of this analysis can be shared on reasonable request.

This article is made freely available for personal use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Some immunosuppressants used in patients with immune-mediated inflammatory diseases (IMIDs) impair humoral or cellular immune responses after SARS-CoV-2 vaccination.

  • These patients may, therefore, be at increased risk of (severe) SARS-CoV-2 breakthrough infections.

WHAT THIS STUDY ADDS

  • SARS-CoV-2 omicron breakthrough infections in patients with IMID on immunosuppressants are frequent but mostly mild and incidence and severity is similar to controls.

  • Humoral responses after primary immunisation, additional vaccinations and hybrid immunity, resulting from prior SARS-CoV-2 infections, were associated with a lower risk of SARS-CoV-2 omicron breakthrough omicron infections in both patients with IMID on immunosuppressants and controls.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Our findings suggest that additional vaccinations and development of hybrid immunity both contribute in reducing the risk of SARS-CoV-2 omicron breakthrough infections in patients with IMID, even despite the use of immunosuppressants. Severe SARS-CoV-2 breakthrough infections are rare for the omicron variant.

  • In case of new SARS-CoV-2 infection waves, it can be speculated that offering additional and/or updated vaccinations is an effective strategy to reduce risks, also for patients with IMID.

Introduction

The emergence of the SARS-CoV-2 variant omicron has led to an unprecedented number of SARS-CoV-2 cases worldwide. Multiple mutations in the receptor binding domain (RBD) of the spike (S) protein of this variant increased transmissibility and infectivity, and reduced effectiveness of standard SARS-CoV-2 vaccination regimens.1–3 In the general population, disease severity after infection with the SARS-CoV-2 omicron variant were shown to be generally mild and less severe compared with the delta variant.4–7 Booster vaccinations help to protect against symptomatic infection by increasing SARS-CoV-2 omicron neutralising antibodies and by broadening the antibody repertoire.8–12 However, in patients with immune-mediated inflammatory diseases (IMIDs) treated with specific immunosuppressants, cellular and humoral efficacy of (booster) vaccinations may be impaired.13–17 Therefore, these patients may be at increased risk for more severe SARS-CoV-2 breakthrough infections. We previously reported that there was no difference in incidence of SARS-CoV-2 delta variant breakthrough infections and disease severity between patients with IMID on immunosuppressants compared with controls, with the exception of anti-CD20 treatment in patients with additional risk factors (ie, older age and comorbidities).6 The primary objective of this study is to compare cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with IMID on immunosuppressants, and controls (patients with IMID not on immunosuppressants and healthy controls). The secondary objective is to explore determinants associated with the risk of SARS-CoV-2 omicron breakthrough infections, including use of immunosuppressants, humoral responses after primary immunisation, administration of additional vaccines and prior SARS-CoV-2 infections.

Methods

Study design

This is a study on SARS-CoV-2 omicron breakthrough infections from an ongoing prospective multiple-arm multicentre cohort study, the T2B! study (Trial ID NL8900; Dutch Trial Register). The primary objective of the T2B! study was to assess humoral and cellular immune responses after SARS-CoV-2 vaccination in patients with various IMIDs treated with predefined types of immunosuppressants. Monitoring SARS-CoV-2 breakthrough infections is a predefined secondary outcome in the study. Full study protocol, data on patient characteristics, humoral and cellular responses and SARS-CoV-2 infections other than omicron has been published elsewhere.6 15–18

Participants

Patients with IMID on immunosuppressants during primary immunisation and a combined control group of patients with IMID without systemic immunosuppressants and healthy controls who had been included as part of the overall study between 2 February 2021 and 1 October 2021 were included. Participants were included if primary immunisation with either with two doses of BNT162b2 (Pfizer/BioNtech), CX-024414 (Moderna) or ChAdOx1 nCoV-19 (AstraZeneca), or one dose of Ad.26.COV2.S (Janssen/Johnson & Johnson) was completed. Participants with a SARS-CoV-2 infection prior to or within 90 days after first vaccination who had received only one dose of any of the above vaccines were also included. See online supplemental methods for the full inclusion and exclusion criteria.

Supplemental material

Vaccination campaign Netherlands

See online supplemental methods for information about the vaccination campaign in the Netherlands. In short, in September 2021 an additional (‘third’) vaccination was offered to several vulnerable groups, including patients with IMID treated with ‘strongly antibody-impairing immunosuppressants’ (see below) and from December 2021 onwards additional (‘booster’) vaccinations were offered to all individuals in the Netherlands.

Procedures

Electronic questionnaires were sent to participants every 2 months after first vaccination. An extra questionnaire was sent on 13 April 2022 to those who had not completed follow-up questionnaires. Demographics and data on SARS-CoV-2 (breakthrough) infections were retrieved from these questionnaires. Medical files were used to register IMID and start, and stop dates of all immunosuppressants. Testing for a SARS-CoV-2 infection was participant driven and performed independently of this study. When a participant indicated a positive PCR or antigen test they were contacted by a researcher at least 2 weeks after the positive test to verify and determine disease severity. If hospital admission was reported, clinical discharge letters were retrieved to assess disease severity.

From the ongoing T2B! cohort study, serum samples collected at baseline (before vaccination) and at 28 days after first and second vaccination (when applicable). Anti-RBD and anti-NP antibodies were measured at Sanquin as described before (see online supplemental methods).

Outcomes

The primary outcome was the cumulative incidence of reported breakthrough infections with the SARS-CoV-2 omicron variant in patients with IMID on immunosuppressants and controls. Patients with IMID not on immunosuppressants and healthy controls were combined in one control group because we did not observe differences between these groups in humoral responses after SARS-CoV-2 vaccination nor in the incidence of the delta variant breakthrough infections.6 17 A SARS-CoV-2 omicron breakthrough infection was defined as a reported PCR or antigen confirmed infection at least 14 days after primary immunisation occurring between 1 January 2022 and 1 April 2022 when the SARS-CoV-2 omicron variant (BA.1 and BA.2 subvariant) was dominant in the Netherlands.19

Disease severity and determinants for breakthrough infections were secondary outcomes. Disease severity was based on the WHO classification and was defined as either asymptomatic (WHO 1), mild symptomatic (WHO 2–3), hospitalised moderate disease (WHO 4–5), hospitalised severe disease (WHO 6–9) or dead (WHO 10).20 Definitions of immunosuppressants as monotherapy or as part of combination therapy and definition of active treatment are described in online supplemental methods. A SARS-CoV-2 infection prior to SARS-CoV-2 omicron breakthrough infection was defined as having one or more positive PCR or antigen tests prior to 1 January 2022, presence of anti-RBD antibodies in any serum sample obtained prior to vaccination or the presence of anti-NP antibodies prior to 1 January 2022. Seroconversion after primary immunisation was defined as an anti-RBD IgG response of >4.0 AU/mL measured at 28 days after primary immunisation.21

Analysis

Sample size calculation for the primary outcomes of the T2B! study have been described previously.17 As primary analysis, we calculated the 95% CIs for the cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections in patients with IMID on immunosuppressants and controls. A post hoc sensitivity analysis was done to compare characteristics of participants included for analyses compared with participants who were lost to follow-up. Differences in disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with IMID on immunosuppressants and controls were compared using the WHO COVID-19 Clinical Progression Scale.20

As a secondary analysis, we investigated possible determinants of SARS-CoV-2 omicron breakthrough infections. Previously, we showed that seroconversion after primary immunisation and hybrid immunity (ie, immunity after both infection and vaccination) were the most important determinants of breakthrough infections with the delta variant.6 To this end, we compared the cumulative incidences of SARS-CoV-2 omicron breakthrough infections between participants with and without seroconversion after primary immunisation. In addition, we defined three medication groups: (1) treatment with anti-CD20 (combination) therapy, S1P modulators or MMF (combination) therapy as ‘strongly antibody-impairing immunosuppressants’ as we previously showed strongly reduced seroconversion rates with these treatments, (2) other immunosuppressants or (3) no immunosuppressants.17 We compared the cumulative incidences of SARS-CoV-2 omicron breakthrough infections between these three medication groups. To investigate the role of additional vaccinations, that is, vaccinations after primary immunisation, we compared the cumulative incidence of SARS-CoV-2 omicron breakthrough infections in participants with and without additional vaccinations, separately for patients with IMID on immunosuppressants and controls. Participants vaccinated against SARS-CoV-2 less than 14 days prior to a SARS-CoV-2 omicron breakthrough infection (N:32) were analysed as not having received an additional vaccination. Also, we compared the proportion of participants with a SARS-CoV-2 omicron breakthrough infection who had received 0, 1 or 2 additional vaccinations separately for the three medication groups. To assess the impact of hybrid immunity, the incidence of SARS-CoV-2 omicron breakthrough infections was compared between participants with and without a prior SARS-CoV-2 infection at the start of the SARS-CoV-2 omicron wave on 1 January 2022, separately for patients with IMID on immunosuppressants and controls.

A time-to-event curve was constructed from the start of the omicron wave (ie, 1 January 2022) up to the time of SARS-CoV-2 omicron breakthrough infection or 1 April 2022 stratified for the different determinants except for seroconversion (due to low number of observations in subgroups) and medication group (due to no observed difference; see online supplemental figure 1 for curves). As the proportional hazard assumption was not met for all determinants, we used a multivariate logistic regression model (reported with relative risk and 95% CIs) to investigate risk associations for the potential determinants. The following determinants were studied: medication group (strongly antibody-impairing immunosuppressants/other immunosuppressants/no immunosuppressants), prior SARS-CoV-2 infection at the start of the omicron wave (yes/no), additional vaccination (yes/no) and seroconversion after primary immunisation (yes/no). Age and sex were added as confounders to the multivariate model. Interaction terms between determinants were explored, but were not significant. Differences between cumulative incidences were analysed using a χ2 test. Analysis was done using R V.4.2.0.

Results

A total of 1593 patients with IMID on immunosuppressants and 579 controls, consisting of 398 patients with IMID not on immunosuppressants and 181 healthy controls were included. Figure 1 shows the flow chart of this study. Table 1 shows baseline characteristics of all participants. The mean age of patients with IMID on immunosuppressants was 51 years (SD 14) and controls 52 years (SD 12), and most participants were female (62% and 67%, respectively). A total of 336/1593 (21.1%) patients with IMID were treated with strongly antibody-impairing immunosuppressants (anti-CD20 (combination) therapy, S1P modulators or MMF (combination) therapy). Online supplemental table 1 shows characteristics of participants included for analyses compared with those who were lost to follow-up. Participants included for analyses were older (51 years (SD 13) vs 41 years (SD 14), p<0.01) and more frequently female (36% vs 46%, p<0.01) compared with those lost to follow-up. Online supplemental table 2 shows characteristics separate for patients with IMID on immunosuppressants, patients with IMID not on immunosuppressants and healthy controls. Online supplemental table 3 shows characteristics separately for the different strongly antibody-impairing immunosuppressants.

Figure 1

Shows baseline characteristics of flow chart. Figure showing the flow chart of the study. IMID, immune-mediated inflammatory disease.

Table 1

Baseline characteristics

Cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections

SARS-CoV-2 omicron breakthrough infections were reported by 472/1593 (29.6%; 95% CI 27% to 32%) patients with IMID on immunosuppressants and by 181/579 (31.3%; 95% CI 28% to 35%) controls (p=0.42; controls: 126/398 (32%) patients with IMID not on immunosuppressants and 55/181 (30.4%) healthy controls). Figure 2 shows the incidence rate of SARS-CoV-2 omicron breakthrough infections per week during the observation period. No difference in trends of incidence rates was observed between patients with IMID on immunosuppressants and controls.

Figure 2

Incidence rates for SARS-CoV-2 omicron breakthrough infections. Figure showing the incidence rates for SARS-CoV-2 omicron breakthrough infections per week of the year for patients with immune-mediated inflammatory disorder (IMID) treated with strongly antibody-impairing immunosuppressants (ie, anti-CD20 (combination) therapy, S1P modulators or MMF (combination) therapy), patients with IMID treated with other immunosuppressants and controls (patients with IMID without immunosuppressants and healthy controls). MMF, mycophenolate mofetil.

Determinants of SARS-CoV-2 omicron breakthrough infection

A total of 1746/1961 (89.0%) of all participants reached seroconversion after primary immunisation. Patients with IMID on strongly antibody-impairing immunosuppressants reached seroconversion in 150/314 (47.8%), while 1100/1143 (96.2%) in patients with IMID on other immunosuppressants and 496/504 (98.4%) in controls reached seroconversion. SARS-CoV-2 omicron breakthrough infections were detected in 81/215 (37.7%) of participants without seroconversion after primary immunisation compared with 508/1746 (29.1%) of participants with seroconversion (p=0.01). SARS-CoV-2 omicron breakthrough infections were detected in 122/336 (36.3%) of patients with IMID on strongly antibody-impairing immunosuppressants as opposed to 350/1257 (27.8%) of patients with IMID on other immunosuppressants (p<0.01). SARS-CoV-2 omicron breakthrough infections were observed more frequently in patients with IMID on S1P modulators compared with other immunosuppressants (table 1).

In 1403/1593 (88.1%) of patients with IMID on immunosuppressants and 490/579 (84.6%) of controls, additional vaccinations were administered. In patients with IMID on immunosuppressants, 387/472 (82.0%) with a SARS-CoV-2 omicron breakthrough infection had received any additional vaccination compared with 1016/1121 (90.6%) without a SARS-CoV-2 omicron breakthrough infection (p<0.01). In controls, 134/181 (74.0%) with a SARS-CoV-2 omicron breakthrough infection had received any additional vaccination compared with 356/398 (89.4%) without a SARS-CoV-2 omicron breakthrough infection (p<0.01). Figure 3 displays the proportion of SARS-CoV-2 omicron breakthrough according to the number of additional vaccines received for the different medication groups. Only in patients with IMID treated with strongly antibody-impairing immunosuppressants, we observed a lower proportion of breakthrough infections in those who had received two additional vaccinations as compared with one additional vaccination.

Figure 3

Proportion of SARS-CoV-2 omicron breakthrough infections and number of additional vaccinations received. Figure showing the proportion with 95% CI of SARS-CoV-2 omicron breakthrough infections for patients with immune-mediated inflammatory disorder (IMID) treated with strongly antibody-impairing immunosuppressants (ie, anti-CD20 (combination) therapy, S1P modulators or MMF (combination) therapy), patients with IMID treated with other immunosuppressants and controls (patients with IMID without immunosuppressants and healthy controls) stratified for the number of additional vaccines received. MMF, mycophenolate mofetil.

A total of 344/1593 (21.6%) patients with IMID on immunosuppressants and 158/579 (27.3%) controls had one or more prior SARS-CoV-2 infections. In patients with IMID on immunosuppressants, 78/472 (16.5%) with a SARS-CoV-2 omicron breakthrough infection had a prior SARS-CoV-2 infection compared with 266/1121 (23.7%) without a SARS-CoV-2 omicron breakthrough infection (p<0.01; table 1). In controls, 38/181 (21.1%) with a SARS-CoV-2 omicron breakthrough infection had a prior SARS-CoV-2 infection compared with 120/398 (30.2%) without a SARS-CoV-2 omicron breakthrough infection (p=0.03; table 1).

Figure 4 shows the combined effects of additional vaccination and prior SARS-CoV-2 infections on the cumulative incidence of SARS-CoV-2 omicron breakthrough infections. The cumulative incidence of SARS-CoV-2 omicron breakthrough infections ranged from 72/381 (18.8%) for participants with additional vaccination(s) and prior SARS-CoV-2 infection to 88/158 (55.7%) for participants without additional vaccination and prior SARS-CoV-2 infection. Figure 5 shows the results when combining the potential determinants into a logistic regression model. Reaching seroconversion after primary immunisation, any additional vaccination and a prior SARS-CoV-2 infection were associated with decreased risks for SARS-CoV-2 omicron breakthrough infections while the type of immunosuppressants was not a risk factor.

Figure 4

Cumulative event curves for SARS-CoV-2 omicron breakthrough infections. Figure showing the cumulative incidence for SARS-CoV-2 Omicron breakthrough infections stratified for having received an additional vaccination and prior SARS-CoV-2 infection.

Figure 5

Risk estimates of determinants for SARS-CoV-2 omicron breakthrough infections. Figure showing the estimated relative risks (RR; shown with 95% CI) for SARS-CoV-2 Omicron breakthrough infections for the different determinants. *N: 209 participants excluded because of missing serological data after primary vaccination.

Disease severity of reported SARS-CoV-2 omicron breakthrough infections

SARS-CoV-2 omicron breakthrough infections were asymptomatic in 6/472 (1.3%) of patients with IMID on immunosuppressants compared with 5/181 (2.8%) in controls, mild symptomatic in 464/472 (98.3%) compared with 175/181 (96.7%) in controls, while hospitalisation was required in 2/472 (0.4%) compared with 1/181 (0.6%) in controls. Four out of 472 (0.8%) patients with IMID on immunosuppressants had been treated with recombinant anti-SARS-CoV-2 monoclonal antibodies during January–March 2022 and were not admitted to the hospital. Of the three hospitalised participants, none required oxygen therapy. The first hospitalised patient with IMID on immunosuppressants was treated with anti-CD20 therapy, did not reach seroconversion after primary immunisation and had received an additional vaccination. The second patient with IMID was treated with corticosteroids, reached seroconversion after primary immunisation and had not received an additional vaccination. The third participant did not use any immunosuppressants, reached seroconversion and had received an additional vaccination. None of the hospitalised participants had a prior SARS-CoV-2 infection.

Discussion

A cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections of 30% was found that did not differ between patients with IMID on immunosuppressants and controls. Overall disease severity of SARS-CoV-2 infections was mild as hospitalisation was seen in only a few cases and disease severity did not differ between patients with IMID on immunosuppressants and controls. As part of exploratory analyses, we established that the risk of SARS-CoV-2 omicron breakthrough infections was lower in participants with seroconversion after primary immunisation, with additional vaccinations, and with prior SARS-CoV-2 infections.

We found that the incidence of SARS-CoV-2 breakthrough infections with the omicron variant was considerably higher than with the delta variant of SARS-CoV-2, as observed by others and by us.6 22 23 Disease severity of reported SARS-CoV-2 omicron breakthrough infections was generally mild in line with other studies in healthy controls22 23and similar to what we observed earlier for delta breakthrough infections, irrespective of the use of immunosuppressants for patients with IMID.6 22 24 Others have reported increased disease severity of delta variant breakthrough infections when compared with omicron infections in healthy controls.4 7 Comparing disease severity between variant strains is challenging, because of the many determinants involved, including differences in risk behaviour and evolving immunological protection induced by repeated vaccinations and/or infections with SARS-CoV-2 leading to an increased proportion of individuals having hybrid immunity which has been shown to be superior to other forms of immunity.25–28

Our study focused on possible determinants mitigating the risks of SARS-CoV-2 omicron breakthrough infections in patients with IMID on immunosuppressants. First, we confirm that a poor humoral response after primary immunisation is a risk factor. This is in line with previously found data for delta variant breakthrough infections and observations in other SARS-CoV-2 vaccination trials.6 Of note, the humoral response after primary immunisation in this analysis should not be interpreted as a direct reflection of humoral immunity at the moment of the omicron breakthrough infections (eg, antibody titres or antibody affinity), but more as an indirect risk factor reflecting an overall decreased (humoral) response after (repeated) vaccination. In many individuals with demonstrated poor humoral responses after primary immunisation, a ‘third’ or additional vaccination did not increase humoral response rates up to levels seen in the general population.17 Ongoing decreased immunological responses, despite repeated vaccinations, are a likely cause for the observed increased incidence of breakthrough infections in patients with IMID on strongly antibody-impairing immunosuppressants, like anti-CD20 (combination) therapy, S1P modulators or MMF (combination) therapy, that have previously been shown to greatly impair humoral and (variably) cellular vaccination responses.16 17 29–31 Second, for the first time we demonstrate in patients with IMID on immunosuppressants that additional vaccinations are associated with decreased risk of SARS-CoV-2 omicron breakthrough infections. This is in line with recent studies in healthy individuals showing that additional vaccinations were either highly effective against infection or disease severity with various SARS-CoV-2 variants.8–12 Moreover, in patients with IMID treated with strongly antibody-impairing immunosuppressants, two additional vaccinations seem to be better compared with a single additional vaccination whereas this added benefit could not be observed in other groups. Third, similar to our previous results on the delta variant, we found that prior SARS-CoV-2 infections are associated with a decreased risk of new, in this case, omicron SARS-CoV-2 breakthrough infections.6 Also in other studies, hybrid immunity, as opposed to vaccine responses only, was associated with increased protection against a SARS-CoV-2 breakthrough infections due to an increased breadth of humoral and cellular immune responses.25 26 28

Together, these observations suggest that for the majority of patients with IMID on immunosuppressants, immunological protection against severe disease can be achieved through vaccination and previous SARS-CoV-2 infection (or both) and that short-term as well as long-term protective immunological mechanisms are in play despite immunosuppressive treatment. No seroconversion after primary immunisation remains a risk factor, but this is only relevant for a relatively small subgroup of patients with IMID on immunosuppressants. To better understand risk profiles for individual patients with IMID, vaccinations and prior infections should be taken into account besides other known risk factors, like older age and comorbidities as suggested by our previous study in delta breakthrough infections.6

A limitation of our study is that we relied on a participant driven test approach to identify SARS-CoV-2 infections and did not employ a test-negative design as has been used in (phase 4) studies on vaccine efficacy. Given the mild disease course in the majority of SARS-CoV-2 omicron breakthrough infections, it is likely that the true rate of infections was higher due to undetected asymptomatic infections. We, therefore, limit our conclusions to reported infections and not all infections as antigen testing was used frequently and studies show a broad variety of sensitivity in symptomatic SARS-CoV-2 cases.32 However, as this underestimation of the incidence of SARS-CoV-2 infections would occur throughout the cohort and would not have led to a difference between the groups. Also, we were unable to correct for risk behaviour in our analyses. Participants were aware of their SARS-CoV-2 antibody titre after vaccination and could have adapted their behaviour accordingly. In particular patients with IMID with immunosuppressants might be stricter in adhering to the infection preventive measures which could have led to an underestimation of the incidence of SARS-CoV-2 breakthrough infection in this group. Also, we did not analyse the actual humoral immune response after additional vaccination(s) or prior to breakthrough infection. Finally, although our cohort is a broad disease-overarching reflection of IMID, this inherently leads to an under-representation of various other known risk factors for increased incidence or severity of breakthrough infections. Most importantly, our cohort is composed of relatively young participants and consequently the burden of comorbidities, such as diabetes, is low. Age and comorbidities have been identified as important risk factors in many other studies and our results should therefore be interpreted with caution when dealing with older patients with IMID and/or patients with IMID with comorbidities or other known risk factors relevant for (breakthrough) infections.33 An important strength of this study is the use of a well-characterised ongoing large cohort of participants that has been prospectively studied clinically and serologically from before the start of primary immunisation.

In conclusion, we found that the cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections is relatively high compared with the delta variant, but similar between patients with IMID on immunosuppressants and controls, and that disease severity of SARS-CoV-2 infections was almost exclusively mild. Seroconversion after primary immunisation, additional vaccinations, and prior SARS-CoV-2 infections were associated with decreased risks of SARS-CoV-2 omicron breakthrough infections. Our findings suggest that offering additional vaccinations can be an effective strategy to reduce risks of (future) breakthrough infections also in patients with IMID.

Data availability statement

Data are available on reasonable request. Aggregated data and code for reproducing the results of this analysis can be shared on reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by the medical ethical committee of the Amsterdam UMC, location AMC. Reference number: 2020.194. Participants gave informed consent to participate in the study before taking part.

Acknowledgments

We thank ZonMw (The Netherlands Organization for Health Research and Development, grant 10430072010007) for the funding of the study and the T2B partners, including the patient groups, and Health Holland for the support in this study. This collaboration project is financed by the PPP Allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) under project number LSHM18055-SGF to stimulate public–private partnerships and co-financing by health foundations that are part of the SGF. We also thank E P Moll van Charante (Department of Public and Occupational Health and Department of General Practice, Amsterdam UMC, University of Amsterdam; and Amsterdam Public Health Research Institute, Amsterdam, Netherlands), J A Bogaards (Department of Epidemiology and Data Science, Amsterdam UMC), and R A Scholte (Clinical Research Unit, Amsterdam UMC, University of Amsterdam) for their guidance in the data safety monitoring board.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Handling editor Josef S Smolen

  • EWS and LW contributed equally.

  • Contributors All authors met the criteria for authorship set by the International Committee of Medical Journal Editors. TR, MS, SK, JK, AB and OC did the serological assays; all other authors contributed in data acquisition. EWS, LW, TWK and FE wrote the first draft of the manuscript. EWS and LW did the data analyses. EWS, LW, PJKvD and LYK had full access to and verified the underlying data. All authors helped to revise the manuscript for important intellectual content and had final responsibility for the decision to submit for publication. TWK and FE are joint last authors. FE was the guarantor.

  • Funding This study was supported by ZonMw (The Netherlands Organization for Health Research and Development, grant 10430072010007). The sponsor had no role in the design, analyses or reporting of the study.

  • Competing interests FE and TWK report (governmental) grants from ZonMw to studyimmune response after SARS-Cov-2 vaccination in autoimmune diseases.FE also reports grants from Prinses Beatrix Spierfonds, CSL Behring,Kedrion, Terumo BCT, Grifols, Takeda Pharmaceutical Company, andGBS-CIDP Foundation; consulting fees from UCB Pharma and CSlBehring; and honoraria from Grifols. AJvdK reports grants from CSLBehring and participation on an advisory board for Argen-X. ML reports agrant from Galapagos not related to this study, and honoraria from BristolMyers Squibb, Pfizer, Takeda, and Tillotts. PIS is involved in clinical trialswith many pharmaceutical industries that manufacture drugs used for thetreatment of, for example, psoriasis and atopic dermatitis, for whichfinancial compensation is paid to the department or hospital, and is achief investigator of the TREAT NL registry taskforce and SECURE-ADregistry. MWB is a secretary for the Dutch Experimental DermatologyBoard; head of the pigmentary disorders group within the DutchDermatology Board; and reports honoraria from Pfizer, Sanofi, Novartis,and Fondation René Touraine. JK has speaking relationships with MerckSerono, Biogen Idec, TEVA, Sanofi, Genzyme, Roche, and Novartis;received financial support to his institution for researchactivities from Merck Serono, Bayer Shcering Pharma, Biogen Idec,GlaxoSmithKline (GSK), Roche, Teva, Sanofi, Genzyme, and Novartis. BHreports unpaid positions as a medical adviser for several patient groups, aboard position for ERN-SKIN, and associate editor for The British Journalof Dermatology; reports grants from AbbVIe, Akari Therapeutics, Celgene, and Novartis; consulting fees from UCB Pharma, Novartis, and Janssen; and honoraria from AbbVie. JJGMV reports consulting fees from Argenx,Alexion, and NMD Pharma, and is a co-inventor on patent applicationsbased on MuSK-related research. DJH reportsgrants from AbbVie, AstraZeneca, Janssen, LEO Pharma, and UCB;honoraria from AbbVie, Galderma, Janssen, Lilly, Pfizer, Sanofi, and UCB;and a paid position on an advisory board for BIOMAP IMI. PAvDparticipated on an advisory board for Octapharma. PvP reports grantsfrom Alexion Pharma and GSK, and participation on advisory boards forGSK and Vifor Pharma. GRAMD’H reports consulting fees from AbbVie,Agomab, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, BristolMyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, ExeliomBiosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido,Roche, Gilead, GSK, Gossamerbio, Pfizer, Immunic, Johnson andJohnson, Origo, Polpharma, Procise Diagnostics, PrometheusLaboratories, Prometheus Biosciences, Progenity, and Protagonist;honoraria from AbbVie, Arena, Galapagos, Gilead, Pfizer, Bristol MyersSquibb, and Takeda; and participation on advisory boards for AbbVie,Seres Health, Galapagos, and AstraZeneca. RBT reports honoraria fromSobi and Norgine, and participation on an advisory board for Norgine.SHG is a board member of the Dutch Society of Clinical Neurophysiology(unpaid), reports grants from Prinses Beatrix Spierfonds, and receivedspeaker fees from Shire/Takeda. KAHZ reports paid data safetymonitoring board positions for Torrent and Foresee. All other authorsdeclare no competing interests.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.