ABSTRACT
Introduction: Immune responses following SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) are not well characterised, and limited data is available regarding the humoral immune response related to the underlying bowel disease and serum concentrations of biologics and thiopurine metabolites. Aims & Methods: This prospective, observational study included adult patients with ulcerative colitis (UC) and Crohn's disease (CD), and healthy controls. Sera were analysed for antibodies binding the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, and anti-RBD >=70 AU/ml was defined as serologic response. Anti-RBD and serum concentrations of the ongoing immunosuppressive medications were measured prior to, and 2-5 weeks after the second vaccine dose. The aims of this study were to explore the serologic response associated with the underlying bowel disease and immunosuppressive medications including serum concentrations of biologics and thiopurine metabolites. Result(s): The study included 958 IBD patients (380 UC, 578 CD), median age 40 (Q1;Q3 29;52), and 323 healthy controls, age 44 (33;56). The type and frequency of ongoing immunosuppressive therapy was comparable between the UC and CD patients. The median (Q1;Q3) anti-RBD level (AU/ml) was lower in patients (618 (192;4370)) compared to controls (3355 (896;7849)) post vaccination (p<0.001), and the antibody levels were lower in CD (439 (174;3304)) compared to UC (1088 (251;5975)) (p<0.001). No association between serum concentration and serologic response was demonstrated in patients treated with tumor necrosis factor inhibitor (TNFi) monotherapy, TNFi + thiopurines, vedolizumab, and ustekinumab. Patients treated with TNFi + thiopurines with low 6-thioguanine nucleotides (6-TGN) levels (<3.5 pmol/8x108RBC) demonstrated a higher response rate (93%) than patients who had 6-TGN levels within the therapeutic range (>=3.5 pmol/8x108RBC) (53%) (p=0.003). In the multiple regression model, UC as compared to CD, higher BMI, and mRNA-1273 vaccine were associated with higher odds for serologic response (Table). Older age and patients on treatment with TNFi + thiopurines were associated with lower odds ratios for a serologic response (Table). Treatment with TNFi monotherapy, disease activity (CRP, calprotectin, disease indices) gender and smoking were not associated with serologic response. Conclusion(s): No association between serum drug concentrations for any biologics and the humoral immune response to SARS-CoV-2 vaccines were demonstrated. However, TNFi in combination with thiopurines were associated with an attenuated serologic response, and the serologic response in general was significantly reduced in CD compared to UC patients. Our results indicate that SARS-CoV-2 vaccines can be provided without consideration to the timing of biologic doses in IBD patients and will aid decision-making regarding re-vaccinations and tailoring of medication in order to keep vulnerable IBD patients protected against serious SARSCoV-2 infection.
ABSTRACT
Introduction: Limited data is available regarding long-term effectiveness of SARS-CoV-2 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy. Whether the persistence of vaccine-induced humoral immunity differs between IMID patients and the general public is currently unknown. Aims & Methods: IMID patients on immunosuppressive medication and healthy controls were enrolled in the prospective, observational Nor-vaC study. Serum samples were collected at two time points following two dose SARS-CoV-2 vaccination (first assessment within 6-48 days and second within 49-123 days). Sera were analysed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Anti-RBD <200 BAU /ml were defined as low levels. The estimated percent reduction in anti-RBD standardised to 30 days was calculated and factors associated with reduction were identified in multivariable regression models. The aims of the study were to compare the persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses between IMID patients and healthy controls, and to identify predictors of antibody decline. Result(s): A total of 1097 patients (190 Crohn's disease, 129 ulcerative colitis, 400 rheumatoid arthritis, 189 psoriatic arthritis, 189 spondyloarthritis) (median age 54 years [IQR 43-64];56% women) and 133 controls (age 45 years [35-56];83% women) provided blood samples within the defined intervals (median 19 days [IQR 15-24] and 97 days [86-105] after second vaccine dose). Of the patients, 464 used tumor necrosis factor inhibitor (TNFi) monotherapy, 259 TNFi + metabolite inhibitor(s), 212 methotrexate monotherapy, 42 interleukin inhibitors, 34 vedolizumab, 29 rituximab, and 23 janus kinase inhibitors. Antibody levels were significantly lower in patients compared to controls at both assessments, with median anti-RBD 1468 BAU/ml [IQR 500-5062] in patients and 5514 BAU/ml [2528-9580] in controls (p<0.0001) and 298 BAU/ml [IQR 79-500] in patients and 715 BAU/ ml [28-2870] in controls (p<0.0001), at first and second assessment respectively. At the second assessment, anti-RBD antibody levels decreased below 200 BAU/ml in 452 (41%) patients and in 1 (0.8%) control (p<0.0001) (Table). The percentage change in anti-RBD levels were -86 % in patients and -77 % in controls (p<0.0001). In the multivariable regression analyses, patients had a greater decline in anti-RBD levels compared to controls beta -3.7 (95% CI -6.0, -1.4) (p<0.001). Use of TNFi in mono- or combination therapy was associated with the greatest decline compared to controls, beta -6.1 (95% CI -8.1, -4.1) and beta -6.4 (-8.4, -4.2) respectively (p<0.001). Conclusion(s): Within four months after the second vaccine dose, anti-Spike antibody levels declined considerably in both IMID patients and controls. Patients had lower antibody levels at the first assessment and a more pronounced decline compared to controls, and were consequently more likely to have low antibody levels four months after the second vaccine dose. Our results support that IMID patients lose humoral protection and need additional vaccine doses sooner than healthy individuals. (Table Presented).
ABSTRACT
Introduction: Humoral vaccine responses to SARS-Cov-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID). Concerns have been raised regarding their protection against severe COVID-19 disease. Knowledge regarding efficacy and safety of repeated vaccination in this large patient group is currently lacking. Aims & Methods: The prospective observational Nor-vaC study (NCT04798625) enrolled adult patients on immunosuppressive therapy for inflammatory bowel-and joint diseases. Healthy controls were health care workers from participating hospitals. All participants received standard vaccines according to the national vaccination program with three doses in patients and two doses in controls. The third dose was offered to IMID patients >4 weeks after the second dose. Anti-Spike antibodies were assessed 2-4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2-4 weeks following three-and two-dose vaccination in patients and controls, respectively. Levels were compared across groups by Mann-Whitney U test. Factors associated with anti-Spike antibody level following the third dose were assessed by uni-and multivariable linear regression adjusted for time between vaccine and sampling. The aim of the study was to evaluate humoral immune responses and safety of repeated vaccination in IMID patients. Result(s): Overall, 1100 patients (156 ulcerative colitis, 217 Crohn's disease, 366 rheumatoid arthritis, 177 spondyloarthritis, and 184 psoriatic arthritis;median age 54 [IQR 42-64];602 women [55%]) and 303 controls (median age 43 [IQR 33-55];226 women [75 %]) were included. Immunosuppressants were tumor necrosis factor inhibitor (TNFi) monotherapy (n=461), TNFi with concomitant immunomodulator (n=254), methotrexate (n=220), vedolizumab (n=46), janus kinase inhibitors (n=33), and other (n=86). Vaccine series were Pfizer BNT162b2 (54% patients, 54% controls), Moderna mRNA-1273 (17% patients, 23% controls), or combination of vaccines (29% patients, 23% controls)). Patients received the third vaccine dose a median of 126 (IQR 105-154) days after the second dose. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/ml (2138-8732) compared to 4495 (1591-6639) in controls receiving two doses, p=0.27. In patients, anti-Spike antibody levels increased by a median of 1932 BAU/ ml (IQR 150-4978) from the second to the third dose, p<0.001. Factors associated with response were a greater interval between the second and third vaccine dose (>5 months) (p=0.03), vaccination with mRNA-1273 (p<0.001), and a combination of vaccines (p<0.001). Antibody levels had a slower decline-rate following the third vaccine dose, as compared to after the second dose, with a significant difference (p<0.001). Adverse events were reported by 488 (53%) and 464 (47%) patients after second and third dose, respectively, and by 196 (68%) controls. Disease flares were reported by 50 (5%) and 70 (7%) patients following the second and third dose. Conclusion(s): This large observational study shows that additional vaccine doses to IMID patients contributes to strong and sustained immune-responses comparable to healthy persons vaccinated twice. This study highlights the importance of repeated vaccination of IMID patients to ensure a stronger and more durable protection from severe COVID-19.
ABSTRACT
Background: Limited data is available regarding long-term effectiveness of SARS-CoV-2 vaccines in patients with immune-mediated infammatory diseases (IMIDs) on immunosuppressive therapy. Whether the persistence of vaccine-induced humoral immunity against SARS-CoV-2 differs between this patient population and the general public is currently unknown. Objectives: To compare the persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses between IMID patients using immunosuppressive medication and healthy controls and identify predictors of antibody decline. Methods: We included patients with infammatory joint-and bowel diseases on immunosuppressive medication and healthy controls enrolled in the prospective observational Nor-vaC study. Serum samples were collected at two time points following two dose SARS-CoV-2 vaccination (frst assessment within 6-48 days and second within 49-123 days). Sera were analysed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Anti-RBD <200 BAU/ml were defned as low levels. The estimated percent reduction in anti-RBD standardised to 30 days was calculated and factors associated with reduction were identifed in multivariable regression models. Results: A total of 1097 patients (400 rheumatoid arthritis, 189 psoriatic arthritis, 189 spondyloarthritis, 129 ulcerative colitis, 190 Crohńs disease) (median age 54 years [IQR 43-64];56% women) and 133 controls (median age 45 years [IQR 35-56];83% women) provided blood samples within the defined intervals (median 19 days [IQR 15-24] and 97 days [86-105] after second vaccine dose). Antibody levels were significantly lower in patients compared to controls at both assessments, with median anti-RBD 1468 BAU/ml [IQR 500-5062] in patients and 5514 BAU/ml [2528-9580] in controls (p<0.0001) and 298 BAU/ml [IQR 79-500] in patients and 715 BAU/ml [28-2870] in controls (p<0.0001), at first and second assessment respectively. Figure 1 show antibody levels at both assessments after medication group. At the second assessment, anti-RBD antibody levels decreased below 200 BAU/ml in 452 (41%) patients and in 1 (0.8%) control (p<0.0001) (Table 1). The percentage change in anti-RBD levels were-86 % in patients and-77 % in controls (p<0.0001). The majority of patients using rituximab had low antibody levels at both assessments, Figure 1. In the multivariable regression analyses, patients had a greater decline in anti-RBD levels compared to controls β-3.7 (95% CI-6.0,-1.4) (p<0.001). Use of tumor necrosis factor inhibitors in mono-or combination therapy was associated with the greatest decline compared to controls, β-6.1 (95% CI-8.1,-4.1) and β-6.4 (-8.4,-4.2) respectively (p<0.001). Conclusion: Within four months after the second vaccine dose, anti-Spike antibody levels declined considerably in both IMID patients and controls. Patients had lower antibody levels at the frst assessment and a more pronounced decline compared to controls, and were consequently more likely to have low antibody levels four months after the second vaccine dose. Our results support that IMID patients lose humoral protection and need additional vaccine doses sooner than healthy individuals.
ABSTRACT
Background: Patients with immune-mediated infammatory diseases (IMIDs) on immunosuppressive therapy have an inadequate serologic response following two-dose SARS-CoV-2 vaccination, and a standard vaccination strategy of three doses for this patient group is currently under implementation in several countries. However, the serological response and safety of this strategy has not been evaluated. Objectives: To assess serological response and safety of a three-dose vaccination strategy in IMID patients on immunosuppressive therapy as compared to standard two-dose vaccination of healthy controls. Methods: The prospective observational Nor-vaC study (NCT04798625) enrolled adult patients on immunosuppressive therapy for infammatory joint-and bowel diseases. Healthy controls were health care workers from participating hospitals. All participants received standard vaccines according to the national vaccination program with three doses in patients and two doses in controls. The third dose was offered to IMID patients >4 weeks after the second dose. Analyses of antibodies binding the receptor-binding domain of the SARS-CoV-2 Spike protein were performed prior to, and 2-4 weeks after the second and third vaccine doses. Levels were compared across groups by Mann-Whitney U tests and multi-variate linear regression was used to identify predictors of response. Results: Overall, 961 patients (315 rheumatoid arthritis, 156 spondyloarthritis, 171 psoriatic arthritis, 132 ulcerative colitis and182 Crohn's disease) (median age 54 years [IQR 43-64];56 % women) and 227 controls (median age 44 years [IQR 32-55];83 % women) were included in the present analyses. TNFi mon-otherapy was used by 399 patients, 229 used TNFi in combination with other immunomodulators, 189 methotrexate monotherapy, 39 vedolizumab, 32 JAKi and 73 patients used other drugs. Patients on rituximab were not included. Patients were vaccinated with Pfzer BNT162b2 (54% patients, 14% controls), Moderna mRNA-1273 (16% patients, 40% controls) or a combination of vaccines (30% patients, 46% controls). Patients received the third vaccine dose a median of 120 (IQR 102-143) days after the second dose. After two doses, median antiSpike antibody levels were signifcantly lower in patients (861 BAU/ml (IQR 418-4275) than controls (6318 BAU/ml (IQR 2468-9857)), p<0.001 (Figure 1). Following the third dose, patients achieved antibody levels comparable to the two-dose vaccinated controls (median 5480 BAU/ml (IQR 1081-12069), p=0.28) (Figure 1). In the patients anti-Spike antibody levels increased by a median of 2685 BAU/ml (IQR 265-9129) from the second to the third dose. Main factors associated with increased antibody level after the third dose were younger age (β-87.7 (p=0.002)), and vaccine status (mRNA-1273 vaccine (β 5549 (p<0.001)) or a combination of vaccines (β 4367.3 (p<0.001)). Adverse events were reported by 438 (48%) of patients after the third dose as compared to 471 (54%) after the second dose and 193 (78 %) of controls. Disease fares were reported by 42 (5%) and 69 (8%) patients after the second and third dose, respectively. Conclusion: This study suggests that a third vaccine dose for immunosup-pressed patients closes the gap in serological response between patients and the healthy population. Antibody levels following the three-dose regimen in IMID patients were comparable to healthy controls vaccinated twice, and no new safety issues emerged. This fnding was consistent across all diagnoses and treatment groups, supporting the implementation of a three-dose vaccine regimen as standard in the IMID population.
ABSTRACT
Introduction: The immunogenicity and safety following standard two-dose SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are not well characterised, and data on third dose vaccination in this patient group are currently lacking. Methods & Aims: This prospective, observational cohort study included adult patients on immunosuppressive therapy for Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and healthy controls receiving standard two-dose SARS CoV-2 vaccination. Patients with a weak serologic response (<100 AU/ml) were allotted a third vaccine dose. Serum samples were collected prior to, and after vaccination for analyses of antibodies to the receptor-binding domain (RBD) of the SARSCoV- 2 spike protein. The aim of the study was to evaluate the immunogenicity and safety following standard and three dose SARS-CoV-2 vaccination in IMID patients on immunosuppressive therapies. Results: a total of 1641 patients (280 CD, 195 UC, 566 RA, 305 SpA, 295 PsA, median age 52 [IQR 40-63], 899 [55%] women), and 1114 healthy controls (median age 43 [IQR 32-55], 854 [77%] women), were included in the study. After standard SARS-CoV-2 two dose vaccination, 1504 (91%) patients compared to 1096 (98%) healthy controls were responders, p<0,001. Anti-RBD levels were lower in patients (median 619 AU/ml [IQR 192-4191]) than controls (median 3355 AU/ml [IQR 896–7849]), p<0,001. Response was shown in ≤90% of patients receiving methotrexate, tumor necrosis factor inhibitor (TNFi) monotherapy, ustekinumab, tozilizumab and vedolizumab, in 80–90% of patients receiving TNFi combination therapy and secukinumab and in £ 80% for JAK inhibitors (78%), and abatacept (53%) (fig.1). Lower age (OR 0.96 [95% CI 0.95–0.98]) and receiving the mRNA-1273 vaccine (OR 5.4 [95% CI 2.4–11.9]) were predictors of response. Of 153 patients with a weak response receiving a third vaccine dose, 129 (84%) became responders. After standard two dose vaccination, adverse events (AE) were reported in 50% of patients and in 78% of controls, with a comparable safety profile. Following the third dose, 44% of patients reported AEs, without new safety issues emerging. No serious AEs were reported. Conclusion: Response rate as well as anti-RBD levels were lower in IMID patients than healthy controls following standard vaccination. Third dose vaccination in serologically weak responders was safe and resulted in a response in most patients. Our data facilitate identification of patient groups at risk of an attenuated vaccine response eligible for post-vaccination serological monitoring. The data also support a third vaccine dose following standard SARS-CoV-2 vaccination to weak-responding IMID-patients. (Figure Presented) Fig.1 Anti-SARS-CoV-2 IgG antibodies following standard two dose SARS-CoV-2 vaccination according to medication group, compared to healthy controls. Violin plot showing the probability density of the data at different values, smoothed by a kernel density estimator. Each data point is a participant, and the solid orange line show the group median. The last row (CTRL vs) shows p-values for a comparison (Mann-Whitney U test) of anti-SARS-COV 2 antibodies between medication groups and healthy controls. ACE=Angiotensin converting enzyme, FL=full length, CTRL=Controls, TNF=Tumor necrosis factor inhibitor, TNF+= Tumor necrosis factor inhibitor combination therapy, MTX=methotrexate, VDZ=vedolizumab, JAK=Janus kinase inhibitor, TCZ=tocilizumab, UST=ustekinumab, ABA=abatacept, SCK=secukinumab.
ABSTRACT
Background: The immunogenicity and safety following standard twodose SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are not well characterised, and data on third dose vaccination in this patient group are currently lacking. Methods: This prospective, observational cohort study included adult patients on immunosuppressive therapy for Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and healthy controls receiving standard two-dose SARS CoV-2 vaccination. Patients with a weak serologic response (<100 AU/ml) were allotted a third vaccine dose. Serum samples were collected prior to, and after vaccination for analyses of antibodies to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The aim of the study was to evaluate the immunogenicity and safety following standard and three dose SARS-CoV-2 vaccination in IMID patients on immunosuppressive therapies. Results: A total of 1641 patients (280 CD, 195 UC, 566 RA, 305 SpA, 295 PsA, median age 52 [IQR 40-63], 899 [55%] women), and 1114 healthy controls (median age 43 [IQR 32-55], 854 [77%] women), were included in the study. After standard SARS-CoV-2 two dose vaccination, 1504 (91%) patients compared to 1096 (98%) healthy controls (p<0,001) were responders. Anti-RBD levels were lower in patients (median 619 AU/ml [IQR 192-4191]) than controls (median 3355 AU/ml [IQR 896-7849]), p<0,001. Response was shown in ≥90% of patients receiving methotrexate, tumor necrosis factor inhibitor (TNFi) monotherapy, ustekinumab, tozilizumab and vedolizumab, in 80-90% of patients receiving TNFi combination therapy and secukinumab and in ≤ 80% for JAK inhibitors (78%), and abatacept (53%) (Fig 1). Lower age (OR 0.96 [95% CI 0.95-0.98]) and receiving the mRNA-1273 vaccine (OR 5.4 [95% CI 2.4-11.9]) were predictors of response. Of 153 patients with a weak response receiving a third vaccine dose, 129 (84%) became responders. After standard two dose vaccination, adverse events (AE) were reported in 50% of patients and in 78% of controls, with a comparable safety profile. Following the third dose, 44% of patients reported AEs, without new safety issues emerging. No serious AEs were reported. Conclusion: Response rate as well as anti-RBD levels were lower in IMID patients than healthy controls following standard vaccination. Third dose vaccination in serologically weak responders was safe and resulted in a response in most patients. Our data facilitate identification of patient groups at risk of an attenuated vaccine response eligible for post-vaccination serological monitoring. The data also support a third vaccine dose following standard SARS-CoV-2 vaccination to weakresponding IMID-patients.