Background As most people now have established hybrid immunity, the need for regular, updated SARS-CoV-2 vaccine boosters in patients with immune-mediated inflammatory diseases (IMIDs) is unclear. The study aim was to assess humoral and cellular immunogenicity of a fifth bivalent vaccine dose in patients with IMID on tumour necrosis factor inhibitors (TNFi). Methods In the longitudinal, observational Nor-vaC study, we assessed anti-spike and neutralising antibodies against Wuhan, Omicron BA.1 and BA.4, as well as frequency and polyfunctionality of responding T cells, following a fourth monovalent and a fifth bivalent (BA.1 or BA.4/5) vaccine dose in patients with or without hybrid immunity using TNFi. Findings Between December 17, 2021, and June 20, 2023, 456 infection-naive patients with IMIDs using TNFi received a fourth vaccine dose and were otherwise eligible for inclusion. A total of 373/456 (82%) received a fifth vaccine dose, of these 190/373 (51%) had hybrid immunity defined as having had COVID-19 between the fourth and fifth dose. In patients with hybrid immunity, the fifth dose did not induce improved humoral responses compared to infection, neither with BA.1 (median anti-spike antibody concentrations 23,244 IU/ml (IQR 15,138-45,233) vs 36,341 IU/ml (11,887-53,710), p = 0.52) nor BA.4/5 (31,693 IU/ml (15,176-54,186), p = 0.30). Comparison of neutralising antibodies yielded similar results. In infection-naive patients, a fifth BA.4/5 vaccine, but not the BA.1, induced slightly higher humoral responses (18,890 IU/ml (6494-50,211)) compared to the fourth dose (7304 IU/ml (3245-17,260), p < 0.0001). CD8 T cell responses remained stable following a fourth dose (median frequency of spike-specific cells 0.039% (IQR 0.010-0.14)), infection (0.058% (0.026-0.17)) and a fifth dose (0.058% (0.013-0.20). Interpretation In patients on TNFi with hybrid immunity, there was no immunological benefit of an updated fifth SARS-CoV-2 booster dose. Stable CD8 cellular responses following four doses indicate established protective immunity. Patients whose only risk factor is TNFi may in future follow vaccine recommendations for the general population. Copyright (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapies have attenuated humoral vaccine responses and are prone to more severe infections. Assessing the persistence of cellular and humoral immunity following repeated SARS-CoV-2 vaccine doses and infection is important to evaluate the need for booster vaccine doses. Objectives: To assess the cellular and humoral responses to 4th (original) and 5th (updated BA.1 or BA.4/5) SARS-CoV-2 vaccine doses and to COVID-19 following a 4th vaccine dose (hybrid immunity) in IMID patients on tumour necrosis factor inhibitors (TNFi). Methods: The ongoing observational Nor-vaC study includes IMID patients receiving multiple SARS-CoV-2 vaccines. In the present analyses, patients using TNFi who were eligible for a 5th vaccine dose and/or undergoing COVID-19 following a 4th vaccine dose, provided serum and peripheral blood mononuclear cells (PBMCs) 2-4 weeks and 4-11 months following infection, and before, 2-4 weeks, and 6 months after their 5th vaccination. CD4 and CD8 T cell responses to SARS-CoV-2 spike, nucleocapsid and membrane peptides, and also IgG anti-spike antibodies, were analysed. T cell responses were measured by flow cytometry (≥0.01% increase in responding CD4 or CD8 cells compared to unstimulated cells). Results: Between December 17th, 2021, and June 20th, 2023, 394 IMID patients (86 rheumatoid arthritis, 72 psoriatic arthritis, 97 spondyloarthritis, 86 Crohn’s disease, 53 ulcerative colitis) on TNFi received a 4th and 5th vaccine dose, and/or had COVID-19 following a 4th vaccine dose. (Table 1). Infection induced a small increase in spike-specific CD4 T cell responses in individuals who had already received a 4th dose (median (IQR) frequencies); four vaccine doses vs. hybrid immunity, 0.068% (0.034-0.16) vs. 0.11% (0.080-0.17), p=0.048). CD4 T cell responses after hybrid immunity waned over 4-11 months (0.035% (0.026-0.072), (hybrid immunity at 2-4 weeks vs. 4-11 months, p=0.0008). CD8 T cell responses following 4th vaccine dose (0.040 % (0.010-0.14) remained stable after infection (0.054% (0.025-0.17) p=0.57), and also in the next 4-11 months (0.038% (0.013-0.17) p=0.63). (Figure 1) A 5th vaccine dose restored CD4 T cell responses to the level seen 2-4 weeks after infection (0.089% (0.046-0.15), p=0.0093) compared with levels prior to 5th vaccine dose. CD8 T cell responses to a 5th vaccine dose did not significantly differ from those post-infection (0.057% (0.016-0.21) p=0.63). After infection, 32/36 (89%) patients had nucleocapsid-specific CD4 T cell responses and 23/36 (64%) had membrane-specific CD4 T cell responses. Similarly, 30/36 (83%) and 22/36 (61%) patients had nucleocapsid- and membrane-specific CD8 T cell responses. These responses decreased over time and were not boosted by vaccination. Patients with hybrid immunity had higher IgG anti-spike antibody levels than patients receiving only 4th dose (median 23159 IU/mL (IQR 14588-44529) vs 7242 (3220-17259) p<0.001. This humoral response waned prior to the 5th dose but increased following the 5th vaccine dose, median 9109 (3603-19839) vs. 31198 (13976-51224), p<0.001). Conclusion: CD8 T cell responses after four immunisations showed no significant benefit of further boosting, suggesting long-lived cellular responses that could be clinically protective. CD4 T cell and humoral responses wane following both four vaccinations and infection but are restored by vaccine boosters, indicating that also IMID patients with hybrid immunity could benefit from a booster vaccine to maintain high levels of circulating antibodies and spike-specific T cells.Table 1. Patient characteristics REFERENCES: NIL. Acknowledgements: We thank the patients who have participated in the Nor-vaC study. We are grateful for the time and effort they have invested in the project. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. Many people have contributed to the study design and implementation of the study at The Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet hospital, and Oslo University Hospital. We thank all study personnel, laboratory personnel, and other staff at the clinical departments involved. Disclosure of Interests: Hilde S. Ørbo: None declared, Asia-Sophia Wolf: None declared, Taissa M. Kasahara: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Ingrid Jyssum: None declared, Joe Sexton: None declared, Anne Therese Tveter: None declared, Guri Solum: None declared, Ingrid Fadum Kjønstad: None declared, Ingrid E. Christensen: None declared, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Grete B. Kro: None declared, Jørgen Jahnsen AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, AbbVie/Abbott, Pfizer, Espen A. Haavardsholm Pfizer, UCB, Novartis, Abbvie, Pfizer, Eli Lilly, Ludvig A. Munthe Incyte, Janssen, Sella Aarrestad Provan: None declared, John Torgils Vaage: None declared, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Gunnveig Grødeland Bayer, Sanofi, ThermoFisher, Pfizer, Vitusapotek, GSK, Siri Mjaaland: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.Figure 1CD4 T cells and anti-spike antibody levels following a 4th vaccine dose are boosted by infection (4th dose hybrid), with subsequent waning prior to a 5th vaccine dose before increasing after a 5th dose, in contrast to stable CD8 T-cell responses.

BACKGROUND:Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. METHODS:This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies. FINDINGS:Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. INTERPRETATION:Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines. FUNDING:South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.

Background: Patients with inflammatory joint diseases on immunosuppressive therapies are vulnerable to severe COVID-19 and are recommended to receive targeted vaccine boosters. Since these patients were excluded from phase 3 vaccine trials, it is important to evaluate safety of the updated XBB.1.5 vaccine as a 3rd booster dose in this patient group. Knowledge on the frequency of vaccine side effects is also helpful to inform patients and alleviate vaccine hesitancy. Objectives: To compare the safety of a booster dose with the updated monovalent XBB.1.5 vaccine to that of the previous bivalent vaccine type (BA.1/BA.4/5). Methods: The present analyses included patients with inflammatory joint diseases participating in the observational prospective Nor-vaC study [1,2], who received six vaccine doses while using immunosuppressive therapies. Patients received vaccines according to the national Norwegian vaccination program. After primary vaccination with three doses and a first booster dose, the further 2nd booster was bivalent (BA.1/BA.4/5) and the 3rd booster was monovalent (XBB.1.5). Data on adverse events within two weeks from vaccination were self-reported through questionnaires. The safety data following the 2nd bivalent and the 3rd monovalent booster were compared with Fisher’s exact test. Results: Between September 14th 2022 and December 21th 2023 a total of 371 arthritis patients (192 rheumatoid arthritis, 100 psoriatic arthritis, 79 spondyloarthritis) on immunosuppressive therapy (Table 1) received a 2nd and a 3rd booster dose. In total, 239/371 (64%) of patients responded to questionnaires asking for adverse events within two weeks following the 2nd booster, and 141/371 (38%) following the 3rd booster dose.A total of 47/239 (20%) vs 17/141 (12 %) reported any adverse event after a 2nd booster dose (bivalent), compared to the 3rd booster (monovalent) (p=0.07). The most frequent adverse events following the 3rd booster were pain at injection site (5%, n=7), fever (4%, n=6) and flu-like symptoms (4%, n=6). However, these adverse events were less frequent compared to after the 2nd booster (pain at injection site (13 %, n=30, p=0.02), fever (5 %, n=11, p=1.00) and flu-like symptoms (10 %, n=23, p=0.07)). In total (4 %, n=6) of patients reported a disease flare after receiving the 3rd, monovalent booster, compared to (6 %, n=14) after the 2nd, bivalent booster (p=0.63). No new safety signals emerged. Conclusion: There were less adverse events overall following the monovalent, 3rd booster, compared to the bivalent, 2nd booster, although not significant, indicating that the XBB.1.5 vaccine is safe in patients with inflammatory joint diseases. REFERENCES: [1] Syversen S.W. et al Arthritis Rheumatol 2022.[2] Bjørlykke K.H. et al Lancet Rheumatol 2022. Acknowledgements: We thank the patients who have participated in the Norwegian study of vaccine responses to COVID-19, and the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff at the clinical departments involved. Disclosure of Interests: Hilde S. Ørbo: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Ingrid E. Christensen: None declared, Joe Sexton: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Espen A. Haavardsholm Pfizer, UCB, Novartis, Abbvie, Pfizer, Eli Lilly, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.Figure 1Adverse events after a 3rd booster (XBB.1.5) compared to a 2nd bivalent booster dose (WT/BA.1 or WT/BA.4/5). Table 1Demographic characteristics and immunosuppressive medication in patients receiving a 2nd bivalent and a 3rd monovalent booster dose.CharacteristicsPatients, n (%)Total371Age (years), median (IQR)63 (55-71)Female224 (60)Immunosuppressive medicationTNFi monoa117 (32)TNFi comboa+b91 (25)Methotrexate100 (27)Rituximab15 (4)IL-inhibitorsc13 (4)JAK-inhibitorsd17 (5)Othere18 (5)2nd boosterBNT162b2 (WT/OMI BA.1)71 (19)BNT162b2 (WT/OMI BA.4/BA.5)58 (16)mRNA-1273.214 (WT/OMI BA.1)216 (58)mRNA-1273.214 (WT/OMI BA.4/BA.5)26 (7)3rd boosterComirnaty CBB15 (XBB.1.5)371 (100)Results in n (%) unless otherwise specified.aTumor necrosis factor inhibitors: Infliximab, etanercept, adalimumab, golimumab, certolizumab pegol.bCombination therapy: methotrexate, sulfasalazine, leflunomide, azathioprine.cInterleukin inhibitors: tocilizumab, secukinumab.dJanus kinase inhibitors: filgotinib, baricitinib, upadacitinib, tofacitinib.eOther: abatacept, sulfasalazine, leflunomide, azathioprine.

Background: Patients on immunosuppressive therapies have diminished humoral vaccine responses to SARS-CoV-2 vaccines. Cellular immunity is crucial for long-term protection against severe COVID-19. Interferon gamma release assay (IGRA) SARS-CoV-2 tests are now commercially available for evaluation of cellular responses in clinical practice. Knowledge on the durability of T cell responses is important to plan further booster doses. Objectives: To evaluate durability of cellular and humoral responses following a 5th vaccine dose. Methods: The observational, prospective Nor-VaC study examines vaccine responses in patients with inflammatory joint diseases on immunosuppressive therapies. The present analyses include a subgroup of patients eligible for a 5th vaccine dose with samples available for analyses. CD4, plus combined CD4 and CD8 T-cell responses (CD4;CD8), were determined by interferon gamma release assay (IGRA) Elecsys QuantiFERON SARS-CoV-2, along with spike IgG antibodies measured by Elecsys Anti-SARS-CoV 2 S immunoassay (Roche), prior to and 2-4 weeks and 6 months following the 5th dose. T-cell responses were defined as negative (<0.030 IU/mL), uncertain (0.030-0.050 IU/mL) or positive (>0.050 IU/mL). Serologic poor responders were defined by response <2000 IU/mL. SARS-CoV-2 infections were defined as a positive PCR or antigen test, self-reported by patients. Results: Between Nov 10, 2022, and Apr 19, 2023, a total of 63 patients (37 rheumatoid arthritis, 15 psoriatic arthritis, 11 spondyloarthritis) using TNFia (n=28), methotrexate (n=20) or other DMARDb (n=15), median age 63 (IQR 55-69), 65 % female, were included. Patients received a 5th bivalent BA.1 (13%) or BA.4/5 (79%) vaccine dose. Five patients were lost to follow-up after the pre-vaccination sample.2-4 weeks after the 5th dose, there was an increase in both CD4 (p=0.001) and CD4;CD8 T cell activity (p=0.002) compared to prior 5th dose (Table 1, Figure 1), with subsequent waning in activity after 6 months for both CD4 (p=0.006) and CD4;CD8 (p=0.044). (Table 1, Figure 1) Prior to the 5th vaccine dose vs 2-4 weeks post-vaccination, 18% (10/57) vs 9% (5/57) had negative CD4-responses, and 9 % (5/57) vs 4% (2/56) had negative CD4;CD8 T cell responses. In comparison, 6 months post-vaccination 4% (2/52) had negative CD4 and 2% (1/52) had negative CD4;CD8 T cell responses. This reduction of patients with negative CD4 and CD4;CD8 T cell responses after six months may be attributed to undergoing SARS-CoV-2 infection prior to the 6-month sample. Overall, 6 patients (10%) reported a SARS-CoV-2 infection between the 5th vaccine dose and the 6-month sample. In addition, subclinical infections may have occurred. Anti-spike antibody levels increased 2-4 weeks post- vs pre-vaccination, p=0.002, with a decrease at 6 months compared to 2-4 weeks post-vaccination (p=0.003). (Table 1) Among the serologic poor responders (n=7), two had negative CD4 responses following a 5th vaccine dose, but all showed positive or intermediate CD4;CD8 responses. Conclusion: Despite a decline in both cellular and humoral immunity over the observation period, most patients had detectable T cell activity and high antibody levels six months after receiving a 5th vaccine dose of the updated SARS-CoV-2 vaccine. Individualised testing of cellular immunity in patients with poor serologic responses to vaccines could be valuable to determine timing of future vaccine boosters.Table 1. Cellular and humoral immune responses pre-, 2-4 weeks- and 6 months post-vaccination.a Tumour necrosis factor inhibitors in mono- or combination therapyb Rituximab, interleukin inhibitors, janus kinase inhibitors, abatacept REFERENCES: NIL. Acknowledgements: We thank the patients who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff at the clinical departments involved, particularly Margareth Sveinsson, May Britt Solem, and Kjetil Bergsmark. Disclosure of Interests: Hilde S. Ørbo: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Andreas Lind: None declared, Veselka P. Dimova-Svetoslavova: None declared, Ingrid E. Christensen: None declared, Joe Sexton: None declared, Kristin Hammersbøen Bjørlykke Janssen-Cilag, Tore K. Kvien Grünenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Espen A. Haavardsholm Pfizer, UCB, Novartis, Abbvie, Pfizer, Eli Lilly, Kristin Kaasen Jørgensen Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll AbbVie/Abbott, Galapagos, Pfizer, UCB.Figure 1Cellular responses measured by SARS-CoV-2 IGRA pre-, 2-4 weeks, and 6 months post-5th vaccine dose. *<0.05, **<0.01.

Objectives To assess incidence, severity and predictors of COVID-19, including protective post-vaccination levels of antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD), informing further vaccine strategies for patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive medication.Methods IMIDs on immunosuppressives and healthy controls (HC) receiving SARS-CoV-2 vaccines were included in this prospective observational study. COVID-19 and outcome were registered and anti-RBD antibodies measured 2–5 weeks post-immunisation.Results Between 15 February 2021 and 15 February 2023, 1729 IMIDs and 350 HC provided blood samples and self-reported COVID-19. The incidence of COVID-19 was 66% in patients and 67% in HC, with re-infection occurring in 12% of patients. Severe COVID-19 was recorded in 22 (2%) patients and no HC. No COVID-19-related deaths occurred. Vaccine-induced immunity gave higher risk of COVID-19 (HR 5.89 (95% CI 4.45 to 7.80)) than hybrid immunity. Post-immunisation anti-RBD levels <6000 binding antibody units/mL were associated with an increased risk of COVID-19 following three (HR 1.37 (95% CI 1.08 to 1.74)) and four doses (HR 1.28 (95% CI 1.02 to 1.62)), and of COVID-19 re-infection (HR 4.47 (95% CI 1.87 to 10.67)).Conclusion Vaccinated patients with IMID have a low risk of severe COVID-19. Hybrid immunity lowers the risk of infection. High post-immunisation anti-RBD levels protect against COVID-19. These results suggest that knowledge on COVID-19 history, and assessment of antibody levels post-immunisation can help individualise vaccination programme series in high-risk individuals.Trial registration number NCT04798625.

Background Patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapies are known to be at greater risk of severe COVID-19 disease, hospitalisation and death. Protective levels of anti-Spike antibodies following vaccination are yet to be determined. Objectives To examine whether post-vaccination anti-Spike antibody levels were predictive of breakthrough infection and the clinical outcome of COVID-19. Methods The Nor-vaC study is a prospective cohort study that includes IMID patients on immunosuppressive therapies[1]. In the present analyses we included patients who provided post-vaccination samples and responded to follow-up questionnaires after three vaccine doses. Hospital records and the Norwegian Death Cause Registry provided information on hospital admissions and cause of death. Anti-Spike antibody levels were measured 2 – 4 weeks after vaccination. Analyses were performed using a cox-regression with time running from two weeks post 3rd vaccine dose until COVID-19 or a 4th vaccine dose, adjusting for age, sex, diagnosis, medication and comorbidity, with calendar month as a time varying covariate. Results A total of 1051 IMID patients (375 rheumatoid arthritis (RA), 148 psoriatic arthritis (PsA), 155 spondyloarthritis (SpA), 215 Crohn's disease (CD), 158 ulcerative colitis (UC)) on immunosuppressive therapies were included in these analyses, median age 56 (IQR 43 – 65), and 586 (56%) female, with an observation period spanning from July 7th 2021 to December 14th 2022. Patients had received either BNT162b2 (61%) or mRNA-1273 (39%) as a 3rd dose. Immunosuppressive medication included TNF inhibitors (TNFi) monoa- (41%) or combination therapyb (23%), methotrexate (16%), interleukin (IL) inhibitorsc (5%), janus kinase (JAK) inhibitorsd (3%), vedolizumab (5%) and other medicatione(2%).During the observation period 265 patients (25%) were registered with COVID-19 after the 3rd vaccine dose. In total, 24 patients had COVID-19 before the Omicron variant became predominant in Norway (1st January 2022). Symptoms of COVID-19 for more than two weeks were reported by 53 patients (20 %). One patient was hospitalised, and no patients died due to COVID-19 during the observation period.A post-vaccination antibody level above 12.000 BAU/ml gave a reduced risk of clinical COVID-19 infection (hazard ratio (HR) 0.56, p=0.007, 95% CI (0.36, 0.85) (Figure 1). Antibody levels above this cut-off were found in 10 % of patients.The presence of comorbidities (HR 1.85, p = 0.001, 95% CI (1.27,2.70)) or UC (HR 1.6, p= 0.001, 95 %CI (1.11, 2.35) increased the risk of breakthrough infections.Post-vaccination anti-Spike antibody levels were not associated with duration of COVID-19 over two weeks. Conclusion Patients with the highest post-vaccination anti-Spike levels had a lower risk of COVID-19 infection, supporting the role of repeated vaccination in IMID patients on immunosuppressive therapies. These results also underline the good prognosis of Omicron infections in vaccinated IMID patients. Though patients knowing they had low anti-Spike levels may have shielded during periods of high transmission, the absence of severe infections and deaths in this large cohort indicates that low antibody levels did not greatly increase risk of severe COVID-19.aTNF inhibitors: infliximab, etanercept, adalimumab, golimumab, certolizumab pegol.bCombination therapy: methotrexate, sulfasalazine, leflunomide, azathioprine.cIL-inhibitors: tocilizumab, secukinumab.dJAK-inhibitors: filgotinib, baricitinib, upadacitinib, tofacitinib.eOther: abatacept, sulfasalazine, leflunomide, azathioprine. Reference [1]Syversen S.W et al Arthritis Rheumatol. 2022 Acknowledgements We thank the patients and health-care workers who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff involved at the clinical departments involved, particularly Synnøve Aure, Margareth Sveinsson, May Britt Solem, Elisabeth Røssum-Haaland, and Kjetil Bergsmark. Disclosure of Interests Hilde Ørbo: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Janssen-Cilag, Joseph Sexton: None declared, Anne Therese Tveter: None declared, Ingrid Jyssum: None declared, Ingrid E. Christensen: None declared, Grete B. Kro: None declared, Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi, ThermoFisher, Consultant of: AstraZeneca, Siri Mjaaland: None declared, John Torgils Vaage: None declared, Kristin Kaasen Jørgensen Speakers bureau: Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott, Galapagos, Pfizer, UCB, Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.Figure 1Cumulative hazard of infection for patients with antibodies above 12.000 BAU/ml (green) and those with antibodies below 12.000 BAU/ml (red). Patients with post-vaccination antibody levels above 12.000 BAU were less likely to develop COVID-19 during follow-up.

Background Safety and efficacy of updated bivalent vaccines, containing both the original vaccine variant of SARS-CoV-2 Spike and either Omicron variants BA.1 or BA.4/5, are of particular interest in arthritis patients on immunosuppressive therapies. With the continuous emergence of new viral variants, it is important to evaluate whether updated vaccines induce more adverse events in this patient group. Objectives To examine if a second booster dose with updated bivalent vaccine increases the risk of adverse events, compared to the first booster dose with monovalent vaccines. Methods The prospective Nor-vaC study investigates vaccine responses in patients with immune mediated inflammatory diseases using immunosuppressive therapies (1). The present analyses included arthritis patients who received two booster doses. Patients received available vaccines according to the Norwegian vaccination program. The current recommendation in the Norwegian arthritis population is a three-dose primary vaccination series followed by two booster doses. Adverse events following vaccines doses were self-reported through questionnaires. Adverse events following the first (monovalent) and second (bivalent) booster were compared with McNemar's test. Results Between 7th of July 2021 and 6th of December 2022 a total of 243 arthritis patients (127 rheumatoid arthritis, 65 psoriatic arthritis, 51 spondyloarthritis) on immunosuppressive therapies (Table 1) received a first, monovalent (BNT162b2, mRNA-1273) and a second, bivalent booster dose (BNT162b2 (WT/OMI BA.1), mRNA-1273.214, BNT162b2 (WT/OMI BA.4/BA.5)). Adverse events were recorded within 2 weeks in all patients (Figure 1). In total, 45 vs 49 (19% vs 20 %) patients reported any adverse event after a second, bivalent booster dose, compared to the first, monovalent booster, respectively. There was no significant difference in adverse events overall (p= 0.57). The most common adverse events after the second booster were pain at injection site (12 %), flu-like symptoms (9 %) and headache (6 %). No new safety signals emerged. A total of 15 (6 %) patients reported a disease flare after receiving the second, bivalent booster, compared to 21 (8 %) after the first, monovalent booster. Conclusion There was no difference in adverse events between the monovalent, first booster, and the bivalent, second booster, indicating that bivalent vaccines are safe in this patient group. Reference [1]Syversen S.W. et al Arthritis Rheumatol 2022 Acknowledgements We thank the patients and health-care workers who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff involved at the clinical departments involved, particularly Synnøve Aure, Margareth Sveinsson, May Britt Solem, Elisabeth Røssum-Haaland, and Kjetil Bergsmark. Disclosure of Interests Hilde Ørbo: None declared, Ingrid Jyssum: None declared, Anne Therese Tveter: None declared, Ingrid E. Christensen: None declared, Joseph Sexton: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Janssen-Cilag, Grete B. Kro: None declared, Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi, ThermoFisher, Consultant of: AstraZeneca, Siri Mjaaland: None declared, John Torgils Vaage: None declared, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Kristin Kaasen Jørgensen Speakers bureau: Bristol-Myers Squibb, Roche, Sella Aarrestad Provan: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott, Galapagos, Pfizer, UCB, Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.Figure 1Adverse events after bivalent vaccine as a 2nd booster dose compared to a monovalent vaccine as a 1st booster dose.Table 1Demographic characteristics and immunosuppressive medication in patients receiving a 1st monovalent and a 2nd bivalent booster dose.CharacteristicsPatients, n (%)Total243Age (years), median (IQR)61 (52-67)Female152 (63)Immunosuppressive medicationTNFi monoa75 (31)TNFi comboa+b72 (30)Methotrexate62 (26)Rituximab9 (4)IL-inhibitorsc6 (2)JAK-inhibitorsd11 (5)Othere8 (3)1st boosterBNT162b2106 (44)mRNA-1273137 (56)2nd boosterBNT162b2 (WT/OMI BA.1)65 (25)BNT162b2 (WT/OMI BA.4/BA.5)120 (47)mRNA-1273.214 (WT/OMI BA.1)58 (23)Results in n (%) unless otherwise specified.aTumor necrosis factor inhibitors: infliximab, etanercept, adalimumab, golimumab, certolizumab pegol.bCombination therapy: methotrexate, sulfasalazine, leflunomide, azathioprine.cInterleukin inhibitors: tocilizumab, secukinumab.dJanus kinase inhibitors: filgotinib, baricitinib, upadacitinib, tofacitinib.eOther: abatacept, sulfasalazine, leflunomide, azathioprine.

Background T cells are critical for control of viral infection with SARS-CoV-2, but knowledge is lacking on cellular immune responses following repeated vaccination and breakthrough infection in immunosuppressed patients. Objectives To examine longitudinal T cell responses across diagnoses, following vaccine series and COVID-19 in patients on tumor necrosis factor inhibitors (TNFi). Methods The prospective, observational Nor-vaC study included patients with arthritis (spondyloarthritis, rheumatoid arthritis, psoriatic arthritis) or inflammatory bowel disease (IBD) (ulcerative colitis, Crohns disease) on immunosuppressive therapies [1]. Here, we included patients on TNFi mono- or combination therapy immunised with up to four SARS-CoV-2 vaccine doses with or without breakthrough infection, collecting peripheral blood mononuclear cells (PBMCs) 2-4 weeks after each immunisation. Samples were incubated with SARS-CoV-2 spike, nucleocapside or membrane peptides. The percentage of responding T cells was measured by flow cytometry (2) (≥0.01% increase in responding CD4 cells, ≥0.001% increase in responding CD8 cells, compared to baseline). Results Between February 2021 and December 2022, 144 patients on TNFi (monotherapy n=86 (60%), combination with methotrexate or azathioprine n=58 (40%)) were included (median age 48 years [IQR 33-57]; 51% women) (Table 1).The proportions of arthritis vs IBD patients with CD4 responses after 2 vaccine doses were 75% (12/16 patients) vs 86% (25/29), and after 3 doses 83% (10/12) vs 93% (28/30). In total, 80% (4/5) of arthritis patients showed further increases in CD4 responses after a 4th vaccine dose.Conversely, 81% (13/16) of arthritis patients vs. 55% (16/29) of IBD patients had CD8 T cell responses after two doses, and 67% (8/12) vs. 62% (18/29) after three doses. A 3rd and 4th dose induced higher CD8 responses compared to the previous dose in 55% (6/11) and 100% (5/5) of arthritis patients.Arthritis patients had lower T cell responses than IBD patients after the 3rd dose; median CD4 response 0.024% [IQR 0.009-0.036] vs 0.098% [IQR 0.040-0.182], p=0.0004; median CD8 response 0.003% [IQR 0.001-0.016] vs 0.044% [IQR 0.009-0.140], p=0.0032 (Figure 1). This difference remained robust after adjusting for age and sex, p<0.001, but was no longer detected after the 4th vaccine dose.Breakthrough infection elicited increased T cell responses across all diagnoses to spike (p<0.0001), and to nucleocapsid (p=0.002) and membrane proteins (p=0.001) compared to unstimulated T cells. Also, Spike-specific T cell responses increased compared to the 3rd dose (median CD4 T cell response 0.18% vs. 0.06%, p=0.003; CD8 T cell response 0.08% vs. 0.01%, p<0.0001), but to a lesser extent compared to the 4th dose (median CD4 response 0.18% vs. 0.12%, p=0.05; CD8 response 0.08% vs. 0.05%, p=0.26).There were no differences in cellular response between patients on TNFi mono- or combination therapy (p=0.93). Conclusion Patients on TNFi show improved cellular responses following each immunisation, with infection generating a strong and broad T cell response. Arthritis patients had significantly lower CD4+ responses compared to IBD patients after three vaccine doses, but with no difference after the 4th dose. These results support giving a 4th vaccine dose to TNFi-treated patients, with particular benefit for arthritis patients. References [1]Syversen S.W et al Arthritis Rheumatol. 2022[2]Kared H et al Nature Communications. 2022 Acknowledgements We thank the patients and health-care workers who have participated in the Norwegian study of vaccine response to COVID-19. We thank the patient representatives in the study group, Kristin Isabella Kirkengen Espe and Roger Thoresen. We thank all study personnel, laboratory personnel, and other staff involved at the departments involved, particularly Synnøve Aure, Margareth Sveinsson, May Britt Solem, Elisabeth Røssum-Haaland, and Kjetil Bergsmark. Disclosure of Interests Hilde Ørbo: None declared, Asia -Sophia F. M. Wolf: None declared, Kristin Hammersbøen Bjørlykke Speakers bureau: Speakers bureaus for Janssen-Cilag, Sarah Josefsson: None declared, Guri Solum: None declared, Ingrid Fadum Kjønstad: None declared, Ingrid Jyssum: None declared, Ingrid E. Christensen: None declared, Anne Therese Tveter: None declared, Joseph Sexton: None declared, Grete B. Kro: None declared, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi, ThermoFisher, Consultant of: AstraZeneca, Tore K. Kvien Speakers bureau: Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, Jørgen Jahnsen Speakers bureau: AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, Consultant of: AbbVie/Abbott, Pfizer, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Roche, Sandoz, Takeda, Grant/research support from: Boehringer-Ingelheim, John Torgils Vaage: None declared, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie, Boehringer-Ingelheim, Eli Lilly, Gilead, Sella Aarrestad Provan: None declared, Hassen Kared: None declared, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Kristin Kaasen Jørgensen Speakers bureau: Bristol-Myers Squibb, Roche, Silje Watterdal Syversen: None declared, Siri Mjaaland: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott, Galapagos, Pfizer, UCB, Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.Table 1Number of patients providing T cells after vaccine doses and after COVID-19.Disease, n (%)Patients totala (n=144)2 vaccines (n=49)3 vaccines (n=86)4 vaccines (n=44)Hybrid immunityb (n=62)Arthritis25 (17)17 (35)19 (22)5 (11)5 (8)IBD119 (83)32 (65)67 (78)39 (89)57 (92)aSampled at minimum one timepointb3 or 4 vaccine doses, followed by COVID-19Figure 1CD4 and CD8 T-cell responses to the 3rd (V3) and 4th (V4) vaccine doses/ three vaccine doses and COVID-19 infection in arthritis and IBD patients measured by TNFα+ CD40L+ (% of CD4+) and IFNγ+ TNFα+ (% of CD8+).

Objectives Humoral vaccine responses to SARS-CoV-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID) following two vaccine doses. To protect these vulnerable patients against severe COVID-19 disease, a three-dose primary vaccination strategy has been implemented in many countries. The aim of this study was to evaluate humoral response and safety of primary vaccination with three doses in patients with IMID. Methods Patients with IMID on immunosuppressive therapy and healthy controls receiving three-dose and two-dose primary SARS-CoV-2 vaccination, respectively, were included in this prospective observational cohort study. 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 doses in patients with IMID and two doses in controls. Additional outcomes were the antibody decline rate and adverse events. Results 1100 patients and 303 controls were included. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/mL (2138–8732) compared with 4495 (1591–6639) in controls receiving two doses, p=0.27. Anti-Spike antibody levels increased with median 1932 BAU/mL (IQR 150–4978) after the third dose. The interval between the vaccine doses and vaccination with mRNA-1273 or a combination of vaccines were associated with antibody levels following the third dose. Antibody levels had a slower decline-rate following the third than the second vaccine dose, p<0.001. Adverse events were reported by 464 (47%) patients and by 196 (78%) controls. Disease flares were reported by 70 (7%) patients. Conclusions This study shows that additional vaccine doses to patients with IMID contribute to strong and sustained immune-responses comparable to healthy persons vaccinated twice, and supports repeated vaccination of patients with IMID. Trial registration number NCT04798625 .

BackgroundPatients with immune-mediated inflammatory 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.ObjectivesTo 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.MethodsThe prospective observational Nor-vaC study (NCT04798625) enrolled adult patients on immunosuppressive therapy for inflammatory 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 multivariate linear regression was used to identify predictors of response.ResultsOverall, 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 monotherapy 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 Pfizer 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 anti-Spike antibody levels were significantly 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 flares were reported by 42 (5%) and 69 (8%) patients after the second and third dose, respectively.ConclusionThis study suggests that a third vaccine dose for immunosuppressed 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 finding was consistent across all diagnoses and treatment groups, supporting the implementation of a three-dose vaccine regimen as standard in the IMID population.Disclosure of InterestsIngrid Jyssum: None declared, Anne Therese Tveter: None declared, Joe Sexton: None declared, Ingrid E. Christensen: None declared, Trung T. Tran: None declared, Siri Mjaaland: None declared, David J Warren: None declared, Tore K. Kvien Speakers bureau: Amgen,Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, Consultant of: Abbvie, Amgen, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: Grants to institution (Diakonhjemmet Hospital): Abbvie, Amgen, BMS, MSD, Novartis, Pfizer, UCB, Kristin Hammersbøen Bjørlykke: None declared, Grete B. Kro: None declared, Jørgen Jahnsen Speakers bureau: AbbVie, Astro Pharma, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Gilead, Hikma, Janssen Cilag, Meda, MSD, NappPharma, Novartis, Orion Pharma Pfizer, Pharmacosmos, Roche, Takeda, Sandoz, Consultant of: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Gilead, Janssen Cilag MSD, Napp Pharma, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Takeda, Sandoz, Unimedic Pharma, Grant/research support from: Abbvie, Pharmacosmos, Ferring, Ludvig A. Munthe Speakers bureau: Novartis, Cellgene, Espen A Haavardsholm: None declared, John Torgils Vaage: None declared, Gunnveig Grodeland Speakers bureau: Bayer, Sanofi Pasteur, Thermo Fisher, Consultant of: Consulting fees from the Norwegian System of Compensation to Patients and AstraZeneca, Fridtjof Lund-Johansen: None declared, Sella Aarrestad Provan: None declared, Kristin Kaasen Jørgensen Speakers bureau: Roche, BMS, Consultant of: Celltrion, Norgine, Guro Løvik Goll Speakers bureau: AbbVie, Pfizer, UCB, Sandoz, Orion Pharma, Novartis, Consultant of: Pfizer, AbbVie, Silje Watterdal Syversen: None declared

Background The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline. Methods IMID patients on immunosuppressive medication enrolled in the prospective observational Nor-vaC study were included. Participants received two-dose SARS-CoV-2 vaccination. Serum collected at two time points following vaccination (first assessment within 6-48 days, second within 49-123 days) were analyzed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Multivariable regression models estimated percent reduction in anti-RBD over 30 days and factors associated with reduction. Results A total of 1108 patients (403 rheumatoid arthritis, 195 psoriatic arthritis, 195 spondyloarthritis, 124 ulcerative colitis, 191 Crohn's disease) and 134 controls provided blood samples within the defined intervals (median 19 days [IQR 15-24] and 97 days [87-105] after second vaccine dose). Antibody levels were lower in patients compared to controls at both time points, with median anti-RBD 2806 BAU/ml [IQR 1018-6068] in patients and 6187 BAU/ml [4105-7496] in controls (p<0.001) at first assessment, and 608 BAU/ml [IQR 58-1053] in patients and 1520 BAU/ml [979-3766] in controls (p<0.001) at second assessment. At second assessment, low anti-RBD antibody levels (defined as <200 BAU/ml) were found in 449 (41%) patients, and 6 (5%) controls (p<0.001). The change was - 83% in patients and - 66% in controls (p<0.001). Patients had a greater estimated 30 days percent reduction in anti-RBD levels compared to controls - 4.9 (95% CI - 7.4 to - 2.4), (p<0.05). Among therapies, mono- or combination treatment with tumor necrosis factor inhibitors was associated with the greatest decline. Conclusions Within 4 months after vaccination, antibody levels declined considerably in both IMID patients and controls. Patients had lower initial antibody levels and a more pronounced decline compared to healthy controls and were therefore more likely to decline to low antibody levels. These results support that IMID patients need additional vaccine doses at an earlier stage than healthy individuals.

Objectives To estimate the incidence of serious infections (SIs) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with tumour necrosis factor inhibitor (TNFi), and compare risk of SIs between patients with RA and PsA. Methods We included patients with RA and PsA from the NORwegian-Disease Modifying Anti-Rheumatic Drug registry starting TNFi treatment. Crude incidence rates (IRs) and IR ratio for SIs were calculated. The risk of SIs in patients with RA and PsA was compared using adjusted Cox-regression models. Results A total of 3169 TNFi treatment courses (RA/PsA: 1778/1391) were identified in 2359 patients. Patients with RA were significantly older with more extensive use of co-medication. The crude IRs for SIs were 4.17 (95% CI 3.52 to 4.95) in patients with RA and 2.16 (95% CI 1.66 to 2.81) in patients with PsA. Compared with the patients with RA, patients with PsA had a lower risk of SIs (HR 0.59, 95% CI 0.41 to 0.85, p=0.004) in complete set analysis. The reduced risk in PsA versus RA remained significant after multiple adjustments and consistent across strata based on age, gender and disease status. Conclusions Compared with patients with RA, the risk of SIs was significantly lower in patients with PsA during TNFi exposure.

Background Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy. Methods This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lorenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2-4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625. Findings Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2-4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2-4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45-65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878-11 243]) than after the third dose (median 5087 BAU/ml [1250-9081]; p< 0middot0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916-12 001]; p<0middot0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440-35 935]) than in the vaccine group (p<0middot0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses. Interpretation Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group. Copyright (c) 2022 Elsevier Ltd. All rights reserved.