RESUMEN
BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefited most people worldwide. While healthy people can acquire sufficient humoral immunity against COVID-19 even in the elderly by vaccination with three doses of vaccine., recent studies have shown that complex factors other than age, including the type of vaccines and immunosuppressive drugs, are associated with immunogenicity in patients with rheumatic musculoskeletal disease (RMD). Identifying factors that contribute to the vulnerability of those patients to acquire not only humoral but also cellular immunity to SARS-CoV-2 despite multiple vaccinations is crucial for establishing an appropriate booster vaccine strategy.ObjectivesTo assess humoral,and T cell immune responses after third doses of mRNA vaccines against SARS-CoV-2.MethodsThis prospective observational study included consecutive RMD patients treated with immunosuppressant who received three doses of mRNA vaccines including BNT162b2 and mRNA-1273. Blood samples were obtained 2-6 weeks after second and third dose of mRNA vaccines. We measured neutralizing antibody titres, which against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 and seroconversion rates to evaluate the humoral responses. We also assessed T-cell immunity responses using interferon releasing assay against SARS-CoV-2.ResultsA total of 586 patients with RMD treated with mmunosuppressive treatments were enrolled. The mean age was 54 years, and 70% of the patients were female. Seroconversion rates and neutralizing antibody titres after third vaccination of SARS-CoV-2 were significantly higher compared to those after second vaccination (seroconversion rate, 94.5% vs 83.6%, p<0.001;titres of neutralizing antibody, 48.2 IU/mL vs 11.0 IU/mL, p<0.001, respectively). Interferon releasing assay after third vaccinations demonstrated that T cell reaction against SARS-CoV-2 was also increased from that of second vaccination (interferon for antigen 1, 1.11.9 vs 0.61.9, p=0.004,interferon for antigen 2, 1.72.6 vs 0.82.3, p=0.004). Humoral and cellular immunogenicity did not differ between the types of third vaccination including full dose of BNT162 and half dose of mRNA1273.(neutralizing antibody titers, 47.8±76.1 IU/mL vs 49.0±60.1 IU/mL, p<0.001;interferon for antigen 1, 1.12.0 vs 1.01.5, p=0.004, respectively). Attenuated humoral response to third vaccination was associated with BNT162b2 as second vaccination age (>60 years old), glucocorticoid (equivalent to prednisolone > 7.5 mg/day), and immunosuppressant use including mycophenolate, and rituximab. On another front, use of mycophenolate and abatacept or tacrolimus but not rituximab were identified as negative factors for T-cell reactions against SARS-CoV-2. Although 53 patients (9.0%) who had been immunised with third-vaccination contracted COVID-19 during Omicron pandemic phase, no one developed severe pulmonary disease that required corticosteroid therapy.ConclusionOur results demonstrated third mRNA vaccination booster of SARS-CoV-2 contributed to restore both humeral and cellular immunity in RMD patients with immunosuppressants. We also identified that certain immunosuppressive therapy with older RMD patients having BNT162b2 as a second vaccination may need additional booster vaccination.Reference[1]Furer V, Eviatar T, Freund T, et al. Ann Rheum Dis. 2022 Nov;81(11):1594-1602. doi: 10.1136/ard-2022-222550.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
RESUMEN
BackgroundAmid the coronavirus disease 2019 (COVID-19) crisis, two messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have benefitted most people worldwide. However, the safety of vaccine has not been established in patients with rheumatic arthritis (RA). Previous studies reported that flares of underlying RA following SARS–CoV-2 vaccination were not so frequent, and there was no report of severe flare. However, those reports did not assess patients' disease activity with validated disease activity measures and described only simple self-reported questionnaires. Hence, the effect of vaccination on disease activity in patients with RA is still unclear. Understanding the association between arthritis flare in patients in RA and vaccination is important to overcome vaccine hesitancy.ObjectivesTo clarify the effect of SARS-CoV-2 vaccination on disease activity in patients with RA and identify risk factors associated with RA flares following the vaccination.MethodsThis is a prospective cohort study in patients with rheumatic musculoskeletal disease including RA who received the SARS-CoV-2 mRNA vaccines BNT162b2 or mRNA-1273 from March 16, 2021, at Keio University Hospital. The disease activity was evaluated with disease activity score for 28 joints using C-reactive protein (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI) before vaccination and after second vaccination (within two months). RA flare was defined as ΔDAS28-CRP>0.6with requirement of treatment intensification. All analysis in this study was carried out with JMP.ResultsWe enrolled 318 patients with RA in this analysis. The mean age was 61 years old, and 283 (89%) were female. The mean DAS28-CRP before vaccination and after 2nd dose of vaccination were 1.70±0.71 and 1.78±0.81, respectively (p=0.84). The increase in DAS28-CPR after vaccination > 0.6 was observed in 53 patients (16.7%), and among them, 23 patients (8.2%) needed treatment intensification. The types of SARS-CoV-2 vaccine, humoral immunogenicity including neutralizing antibody titer and its adverse effects including systemic reaction (fever or general fatigue) were not different between the flare and non-flare groups (9.8 vs 9.1 IU/mL, p=0.88;31.2% vs 18.7%, p=0.32, respectively). In the flare group, swollen joint counts (SJC), hourly erythrocyte sedimentation rates, DAS28-CRP, and SDAI were significantly higher than those in the non-flare group (0.5 vs 0.0, p<0.000;13 vs 11 mm/h, p=0.01;1.57 vs 1.45, p<0.001;3.9 vs 2.4, p=0.02, respectively). Multivariable logistic regression analysis revealed that the number of swollen joints before vaccination contributed RA exacerbation after SARS-CoV-2 vaccination significantly (odds ratio 1.3, 95% confidence interval 1.06-1.65, p=0.01). The receiver operating curve analysis identified that having two or more swollen joint counts predicts RA flares after vaccination with an area under the curve of 0.64, a sensitivity of 42.3%, and a specificity of 86.9%.ConclusionDisease flare with requirement of treatment intensification is observed in 8.2% of patients with RA. Patients with higher disease activity, especially having two or more swollen joint counts are at high risk of flare following mRNA SARS-CoV-2 vaccination.Reference[1]Connolly CM, Ruddy JA, Boyarsky BJ, et al. Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination. Arthritis Rheumatol. 2022;74(1):28-32. doi: 10.1002/art.41924. Epub 2021 Dec 3.Figure 1.Risk factors associated with RA flares after vaccination[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.
RESUMEN
Background: The SARS-CoV-2 messenger RNA (mRNA) vaccines BNT162b2 (Pfzer-BioNTech) and mRNA-1273 (Moderna) have beneftted all countries amid the coronavirus disease 2019 (COVID-19) crisis. Whereas both of them have shown efficacy in preventing COVID-19 illness in healthy participants, there is paucity of data about immunogenicity and safety of mRNA COVID-19 vaccines in patients with autoimmune, infammatory rheumatic disease. Recent observational studies evaluated mainly BNT162b2, suggesting that glucocorticoids, immunosuppressive agents impair SARS-CoV-2 vaccine responses. However, difference in immune reactions and safety between BNT162b2 and mRNA-1273 have not been clarifed in patients with infammatory rheumatic diseases. Objectives: To assess humoral and T cell immune responses and safety profiles after two doses of different mRNA vaccine against SARS-CoV-2;BNT162b2 and mRNA-1273. Methods: We enrolled consecutive, previously uninfected patients with infam-matory rheumatic diseases receiving mRNA vaccine including BNT162b2 and mRNA-1273. Healthy participants receiving BNT162b2 were also recruited as control. Blood samples were obtained 3weeks, 2 months, 3 months, 4 months, and 6 months after second dose of vaccines. We measured titres of neutralizing antibodies against SARS-CoV-2 and calculated seroconversion rates to evaluate humoral responses. We also assessed T-cell immunity responses by using interferon releasing assay against SARS-CoV-2 in a part of the patients. Answers to questionnaires about adverse reactions were obtained from participants. Results: A total of 974 patients with infammatory rheumatic diseases and healthy 630 control participants were enrolled. Among them, 796 patients received BNT162b2, 178 patients received mRNA-1273, and all control participants received BNT162b2. Seroconversion rates and neutralizing antibody titres 3 weeks after vaccination were signifcantly higher in patients with mRNA-1273 and healthy participants with BNT162b2 compared with patients with BNT162b2;seroconver-sion rates, 97.2% vs 99.5% vs 83.3%, p<0.001;titers of neutralizing antibodies, 29.4±33.9 IU/mL vs 23.9±14.2 IU/mL vs 10.8±16.5 IU/mL, p<0.001, respectively. On another front, T cell reaction against SARS-CoV-2 was similar in both patients with mRNA-1273 and BNT162b2;interferon gamma levels for antigen 1, 1.2±2.1 IU/mL vs 0.8±2.5 IU/mL, p=0.23;and for antigen 2, 1.4±1.9 IU/mL vs 1.0±2.1 IU/mL, p=0.11, respectively. Regarding adverse reaction of each mRNA vaccine, the frequency of systemic adverse reactions including fever and general fatigue are also signifcantly higher in patients with mRNA-1273 and healthy controls than patients with BNT162b2;fever, 48.0% vs 44.9% vs 10.2%, p<0.001;general fatigue, 70.4% vs 61.8% vs 31.2%, p<0.001, respectively). In longitudinal measurement, neutralizing antibody titres in patients with BNT162b2 were decreased more rapidly than those in healthy controls;3.3±3.2 IU/mL in patients with BNT162b2 at 4 months and 3.2±4.7 IU/mL in healthy controls with BNT162b2 at 6 months. We identifed age, glucocorticoid dose (prednisolone > 7.5mg), use of immunosuppressants including methotrexate, mycophenolate, cyclophosphamide, and tacrolimus are associated with rapid attenuation of humoral responses in patients with BNT162b2. Conclusion: Our results demonstrated a signifcant higher humoral immuno-genicity and frequency of systemic adverse reaction of the SARS-CoV-2 mRNA-1273 (Moderna) compared with the BNT162b2 (Pfzer-BioNTech) in infammatory rheumatic disease patients. Glucocorticoid and immunosuppressive agents impaired induction and sustention of neutralizing antibody, and earlier third booster vaccination may be required within 4 months, especially for those receiving BNT162b2.