The T-cell clonal response to SARS-CoV-2 vaccination in inflammatory bowel disease patients is augmented by anti-TNF therapy and often deficient in antibody-responders

Abstract

Background: Vaccination against SARS-CoV-2 is a highly effective strategy to protect against infection, which is predominantly mediated by vaccine-induced antibodies. Postvaccination antibodies are robustly produced by those with inflammatory bowel disease (IBD) even on immune-modifying therapies but are blunted by anti-TNF therapy. In contrast, T-cell response which primarily determines long-term efficacy against disease progression, , is less well understood. We aimed to assess the post-vaccination T-cell response and its relationship to antibody responses in patients with inflammatory bowel disease (IBD) on immune-modifying therapies. Methods: We evaluated IBD patients who completed SARS-CoV-2 vaccination using samples collected at four time points (dose 1, dose 2, 2 weeks after dose 2, 8 weeks after dose 2). T-cell clonal analysis was performed by T-cell Receptor (TCR) immunosequencing. The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets and were compared to antibody responses. Results: Overall, 303 subjects were included (55% female; 5% with prior COVID) (Table). 53% received BNT262b (Pfizer), 42% mRNA-1273 (Moderna) and 5% Ad26CoV2 (J&J). The Spike-specific clonal response peaked 2 weeks after completion of the vaccine regimen (3- and 5-fold for breadth and depth, respectively); no changes were seen for non-Spike clones, suggesting vaccine specificity. Reduced T-cell clonal depth was associated with chronologic age, male sex, and immunomodulator treatment. It was preserved by non-anti-TNF biologic therapies, and augmented clonal depth was associated with anti-TNF treatment. TCR depth and breadth were associated with vaccine type; after adjusting for age and gender, Ad26CoV2 (J&J) exhibited weaker metrics than mRNA-1273 (Moderna) (p=0.01 for each) or BNT262b (Pfizer) (p=0.056 for depth). Antibody and T-cell responses were only modestly correlated. While those with robust humoral responses also had robust TCR clonal expansion, a substantial fraction of patients with high antibody levels had only a minimal T-cell clonal response.. Conclusion: Age, sex and select immunotherapies are associated with the T-cell clonal response to SARS-CoV-2 vaccines, and T-cell responses are low in many patients despite high antibody levels. These factors, as well as differences seen by vaccine type may help guide reimmunization vaccine strategy in immune-impaired populations. Further study of the effects of anti-TNF therapy on vaccine responses are warranted.

Impaired Humoral Immunity with Concomitant Preserved T Cell Reactivity in IBD Patients on Treatment with Infliximab 6 Month after Vaccination with the SARS-CoV-2 mRNA Vaccine BNT162b2: A Pilot Study

“…Reuken et al (2021) have demonstrated T-cellular reactivity comparable to healthy controls after the first COVID-19 vaccination in IBD patients independent of existing immunosuppressive therapy [ 25 ]. In the study recently published by Li et al, robust T-cell reactivity was demonstrated in IBD patients on anti-TNF therapy 8 weeks after vaccination [ 48 ]. According to X et al, T-cellular reactivity was detected in approximately 80% of IBD patients receiving therapy with anti-TNF or vedolizumab at 8 to 10 weeks after COVID-19 secondary inoculation [ 42 ].…”

Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review

“…Interestingly, preliminary data from a study analyzing the T-cell clonal response in 303 IBD patients found that antibody and T-cell clonal responses were only modestly correlated, with low T-cell clonal response observed in patients with high antibody levels. The T-cell clonal response was preserved with ustekinumab and vedolizumab and paradoxically augmented by TNF inhibitors [179]. In PsO patients, a lower proportion of patients receiving MTX or biologic therapy showed detectable T-cell response compared with the control group (62 and 71% vs. 100%, respectively) [168].…”

Recent advances in clinical practice: management of inflammatory bowel disease during the COVID-19 pandemic

“…CORALE-IBD found a poor correlation between anti-S RBD antibody concentration and T cell clonal response to SARS-CoV-2 vaccines from 303 patients with IBD who were on a range of therapies, although they found that patients with IBD treated with anti-TNF therapy had an augmented T cell clonal depth compared with patients receiving no treatment. 152 The CLARITY IBD study, a UK-wide prospective cohort study of patients with IBD investigating the impact of infliximab and vedolizumab, and/or concomitant immunomodulators, on SARS-CoV-2 acquisition, illness and immunity in patients with IBD, reported an uncoupling of anti-S RBD antibodies and anti-spike T cell responses, however, similar T cell responses were observed between infliximab-treated compared with vedolizumab-treated patients after one or two doses of either vaccine. 146 Further studies are required to confirm these findings, and to determine the relative contributions of T cell vaccine responses to SARS-CoV-2 immunity in patient with IBD.…”