Op0085 longitudinal T Cell Responses to a Series of Four Sars-Cov-2 Vaccine Doses or Covid-19 in Patients on TNF Inhibitors

Abstract

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.