BackgroundT 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.ObjectivesTo examine longitudinal T cell responses across diagnoses, following vaccine series and COVID-19 in patients on tumor necrosis factor inhibitors (TNFi).MethodsThe 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).ResultsBetween 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 4thvaccine 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 3rdand 4thdose 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 3rddose; 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 4thvaccine 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 3rddose (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 4thdose (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).ConclusionPatients 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 4thdose. These results support giving a 4thvaccine 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. 2022Table 1.Number 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 1.CD4 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+).AcknowledgementsWe 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 InterestsHilde 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.
BackgroundPatients 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.ObjectivesTo examine whether post-vaccination anti-Spike antibody levels were predictive of breakthrough infection and the clinical outcome of COVID-19.MethodsThe 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 3rdvaccine dose until COVID-19 or a 4thvaccine dose, adjusting for age, sex, diagnosis, medication and comorbidity, with calendar month as a time varying covariate.ResultsA 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 7th2021 to December 14th2022. Patients had received either BNT162b2 (61%) or mRNA-1273 (39%) as a 3rddose. 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 3rdvaccine dose. In total, 24 patients had COVID-19 before the Omicron variant became predominant in Norway (1stJanuary 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.ConclusionPatients 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. 2022Figure 1.Cumulative 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.AcknowledgementsWe 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 InterestsHilde 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.
BackgroundSafety 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.ObjectivesTo 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.MethodsThe 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.ResultsBetween 7thof July 2021 and 6thof 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.ConclusionThere 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 2022Table 1.Demographic characteristics and immunosuppressive medication in patients receiving a 1stmonovalent and a 2ndbivalent 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.Figure 1.Adverse events after bivalent vaccine as a 2ndbooster dose compared to a monovalent vaccine as a 1stbooster dose.AcknowledgementsWe 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 InterestsHilde 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.
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