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Boekel, Laura, Stalman, Eileen W.; Wieske, Luuk, Hooijberg, Femke, van Dam, Koos P. J.; Besten, Yaëlle R.; Kummer, Laura Y. L.; Steenhuis, Maurice, van Kempen, Zoé L. E.; Killestein, Joep, Volkers, Adriaan G.; Tas, Sander W.; van der Kooi, Anneke J.; Raaphorst, Joost, Löwenberg, Mark, Takkenberg, R. Bart, D'Haens, Geert R. A. M.; Spuls, Phyllis I.; Bekkenk, Marcel W.; Musters, Annelie H.; Post, Nicoline F.; Bosma, Angela L.; Hilhorst, Marc L.; Vegting, Yosta, Bemelman, Frederike J.; Voskuyl, Alexandre E.; Broens, Bo, Parra Sanchez, Agner, van Els, Cécile A. C. M.; de Wit, Jelle, Rutgers, Abraham, de Leeuw, Karina, Horváth, Barbara, Verschuuren, Jan J. G. M.; Ruiter, Annabel M.; van Ouwerkerk, Lotte, van der Woude, Diane, Allaart, Cornelia F.; Teng, Y. K. Onno, van Paassen, Pieter, Busch, Matthias H.; Jallah, Papay B. P.; Brusse, Esther, van Doorn, Pieter A.; Baars, Adája E.; Hijnen, Dirk Jan, Schreurs, Corine R. G.; van der Pol, W. Ludo, Goedee, H. Stephan, Vogelzang, Erik H.; Leeuw, Maureen, Atiqi, Sadaf, van Vollenhoven, Ronald, Gerritsen, Martijn, van der Horst-Bruinsma, Irene E.; Lems, Willem F.; Nurmohamed, Mike T.; Boers, Maarten, Keijzer, Sofie, Keijser, Jim, van de Sandt, Carolien, Boogaard, Arend, Cristianawati, Olvi, ten Brinke, Anja, Verstegen, Niels J. M.; Zwinderman, Koos A. H.; van Ham, S. Marieke, Rispens, Theo, Kuijpers, Taco W.; Wolbink, Gertjan, Eftimov, Filip, de Jongh, Rivka, van de Sandt, Carolien, Kuijper, Lisan, Duurland, Mariel, Hagen, Ruth, van den Dijssel, Jet, Kreher, Christine, Bos, Amelie, Palomares Cabeza, Viriginia, Konijn, Veronique, Elias, George, Vallejo, Juan, van Gils, Marrit, Ashhurst, Tom, Nejentsev, Sergey, Mirfazeli, Elham.
The Lancet Rheumatology ; 2022.
Article in English | ScienceDirect | ID: covidwho-1815345

ABSTRACT

Summary 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.

2.
J Allergy Clin Immunol ; 2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1783444

ABSTRACT

BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We studied humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult IEI patients. METHODS: In a prospective, controlled, multicenter study 505 IEI patients (common variable immunodeficiency (CVID), isolated or undefined antibody deficiencies, X-linked agammaglobulinemia (XLA), combined immunodeficiency (CID), phagocyte defects) and 192 controls were included. All participants received two doses of the mRNA-1273 COVID-19 vaccine. Levels of SARS-CoV-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to healthy controls, but seroconversion rates in patients with more severe IEI, like CVID and CID, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to controls in all IEI cohorts, with the exception of CVID patients. The presence of non-infectious complications and the use of immunosuppressive drugs in CVID patients were negatively correlated with the antibody response. CONCLUSION: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with CID and CVID. Lowest response was detected in XLA and in CVID patients with non-infectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision-making for additional vaccinations.

3.
The Lancet. Rheumatology ; 2022.
Article in English | EuropePMC | ID: covidwho-1749824

ABSTRACT

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).

4.
BMC Med ; 20(1): 100, 2022 03 02.
Article in English | MEDLINE | ID: covidwho-1724485

ABSTRACT

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.


Subject(s)
COVID-19 Vaccines , COVID-19 , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Cohort Studies , Female , Humans , Prospective Studies , Risk Factors , SARS-CoV-2 , Vaccination/adverse effects
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320402

ABSTRACT

Background: Accumulating evidence points to an overactive immune response in Covid-19 disease and potential clinical benefit of the interleukin-6 inhibitor tocilizumab. We assessed the efficacy of early tocilizumab treatment for hospitalized patients in a randomized phase II study.Methods: Patients admitted to the general ward with proven Covid-19 and in need of supplemental oxygen were randomly assigned to receive standard of care with or without intravenous tocilizumab 8 mg/kg (maximal 800 mg). A second dose of tocilizumab was permitted if hypoxia persisted after 8 hrs. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α=0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days.Findings: A total of 354 patients (67% men;median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR)=0.62 (90% CI 0.39-0.98;p=0.086). 21% of patients were admitted to the ICU in each arm (p=0.89). The median stay in the ICU was 16 days (IQR 8-30) in the standard arm versus 9 days (IQR 5-16) in the tocilizumab arm (p=0.025). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98;p=0.042).Interpretation: Various studies have suggested a beneficial effect of tocilizumab in the treatment of COVID-19. This randomized phase II study, which met its primary endpoint, confirms these observations and demonstrates a clinically meaningful efficacy when given early in the disease course in hospitalized patients who need oxygen support, even when concomitantly treated with dexamethasone.Trial Registration: The trial was designed as a prospective randomized (1:1) open label phase II trial and was registered in the Netherlands Trial register (https://www.trialregister.nl/trial/8504).Funding Statement: Academic study, funded by participating hospitals. Roche supplied tocilizumab.Declaration of Interests: None to declare. Ethics Approval Statement: The trial was approved by the relevant medical ethical committee and was performed in accordance with Good Clinical Practice guidelines and the Helsinki Declaration.

6.
JAMA ; 326(6): 499-518, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1413703

ABSTRACT

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Interleukin-6/antagonists & inhibitors , Aged , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Cause of Death , Coinfection , Disease Progression , Drug Therapy, Combination , Female , Glucocorticoids/therapeutic use , Hospitalization , Humans , Male , Middle Aged , Prospective Studies , Randomized Controlled Trials as Topic , Respiration, Artificial
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