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Introduction: Knowledge regarding the development of protective immunity after COVID-19 vaccines is needed to guide medical, political and public health measures against the current and future pandemics. Objectives and Aims: To characterise and compare the safety, immunogenicity and efficacy of mRNA-COVID-19 vaccines in people with multiple sclerosis (pwMS) and healthy controls (HCs). Method(s): All pwMS vaccinated against COVID-19 in Norway were invited to participate in an ongoing observational cohort study (NevroVAX) from March 2021. Demographic-, immunisation-and disease-specific data were acquired from patient journals, web-questionnaires, the Norwegian Immunization Registry and Surveillance System for Communicable Diseases. Antibodies to full length spike protein and the receptor-binding domain (RBD) from SARS-CoV-2 were measured using a bead-based flow cytometric assay, while cellular immunity was investigated using high dimensional multiparameter analyses. Results and Conclusion(s): To date, 5545 pwMS were included with results available regarding humoral responses in 3021 (mean follow-up time 257 days), cellular responses in 140, and clinical efficacy in 900 pwMS. Those treated with anti-CD20 therapy or sphingosine-1-phosphate receptor modulators (S1PM) had weak humoral immune responses after two doses of mRNA-COVID-19 vaccines (80% and 91% <200 BAU/ml, respectively). Additional vaccine doses were safe and associated with a modest increase of anti-SARS-CoV-2 spike RBD IgG antibodies (72% and 83% <200 BAU/ml after three, 74% and 89% <200 BAU/ml after four doses). Humoral responses were weaker after all vaccine doses in pwMS (also in those without treatment) compared to HCs. Cellular responses were significantly attenuated in pwMS treated with S1PM. An elevated rate of non-omicron breakthrough infections was observed in the anti-CD20 (19%), S1PM (18%), and HSCT (14%) group, compared to pwMS on other high-or low-efficacy DMTs or without treatment (13%, 10%, and 7%, respectively). Among 900 pwMS treated at the same hospital, 12 (1%) were hospitalized due to COVID-19, one requiring intensive care. Our results show that antibody responses correlated with the rate of breakthrough infections but is not necessarily indicative of a failed cellular or clinical response to vaccination, and that pwMS have weaker humoral responses than HCs regardless of treatment status. Updated, real-world data from NevroVAX will be presented at ECTRIMS 2022.
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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.
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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).
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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.
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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.
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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.
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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.
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Introduction: Expert organizations worldwide recommend that all patients with multiple sclerosis (MS) should be vaccinated against acute respiratory syndrome coronavirus 2 disease of 2019 (COVID- 19). However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. There is increasing evidence of altered protective humoral immunity after mRNA-COVID-19 vaccines among patients treated with fingolimod, rituximab and ocrelizumab. However, the role of cellular immunity is still unknown. Appropriate knowledge regarding the development of protective immunity is of paramount importance in respect to medical, political and public health measures to aid the fight against the COVID-19 pandemic. Objectives and Aims: We aimed to characterize humoral and cellular immunity after mRNA-COVID-19 vaccines in patients with MS treated with high-efficacy DMTs (NEVROVAX). Methods: All patients treated with alemtuzumab, natalizumab, fingolimod, rituximab or cladribine, and vaccinated with BNT162b2- or mRNA-1273-COVID-19 vaccine were invited. We assessed protective humoral immunity by measuring acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG response using anti-spike protein-based serology in all included patients before, and 3-6 weeks after full vaccination (NEVROVAX-HUMORAL). Cellular immunity was investigated using high dimensionality multiparameter analyses in 50 pre-selected individuals (10 patients in each treatment group;NEVROVAX-CELLULAR) and in all patients not developing protective humoral immunity in the former group (NEVROVAX-EXTENSION). Results and Conclusions: Over 900 patients were invited and, to date, more than 300 patients have been included in our study. Preliminary results show altered protective humoral immunity in MS patients treated with rituximab and fingolimod. Continuous analysis of cellular immunity is conducted in these patients. The percentage of vaccinated inhabitants in Norway is still under 10%. We expect to complete all analyses by September 2021 and will present our results during ECTRIMS 2021.
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Objectives: To assess the strength and duration of the immunological response to coronavirus disease 2019 (COVID-19) vaccines in patients treated with immunosuppressive medication for inflammatory arthritis. Methods: Adult patients with a clinical diagnosis of rheumatoid arthritis (RA), spondyloarthritis (SpA) or psoriatic arthritis (PsA) on treatment with any biological, conventional synthetic, or targeted synthetic disease-modifying anti-rheumatic drug (bDMARD, csDMARD, or tsDMARD) or prednisolone in doses above 7.5 mg/day are eligible for inclusion in the Nor-vaC observational study. Exclusion criteria are allergy and/or intolerance to elements of the COVID-19 vaccines. Cohorts of healthy controls have also been established, recruiting healthcare workers at Diakonhjemmet Hospital, Akershus University Hospital, and Oslo University Hospital. Serum samples are obtained from all participants before the first vaccine dose and 1-4 weeks after full vaccination. Samples are analysed for antibodies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) using Microsphere Affinity Proteomics (MAP) (1). Demographic data and data regarding immunosuppressive medication and adverse events related to vaccination are recorded. Information regarding vaccination status, and potential COVID-19 testing and disease are obtained from relevant registers. To further elucidate the immune response to COVID-19 vaccines, we also plan to evaluate the T-cell response in a subgroup of vaccinated patients. Serum samples are planned to be collected for assessment every 3-6 months during the study period of 5 years. Results: From 15 February to 6 April 2021, 1735 patients were enrolled in the study, with at least one serum sample obtained from 892;and 130 participants have also provided samples for T-cell analyses. The distribution of diagnoses and medication is shown in Table PP25. Study recruitment, and serological and cellular analyses are currently ongoing, with the first results expected in early autumn 2021. Conclusions: Arthritis patients on long-term immunosuppressive medication may be at risk for a reduced vaccine response. Determining how robust is their immune response, and how long-lasting, will be crucial in decision making with regard to adjustments in medication and to assess a possible need for revaccination. This question is of urgent importance to Norwegian patients as well as for the global population.