Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease

Abstract

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vβ gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

A Paratope-Enhanced Method to Determine Breadth and Depth TCR Clonal Metrics of the Private Human T-Cell Vaccine Response after SARS-CoV-2 Vaccination

“…The association between TCR metrics and subject age in the IBD and HCW cohorts is shown in Table 3 . Consistent with the trend in public vaccine-response TCR metrics in previous analyses [ 15 , 16 ], higher age is associated with lower depth but not with breadth in both IBD and HCW, e.g., for TCR2 depth, the association p -value is 5.51 × 10 −3 in IBD (estimate = −0.004) and 0.039 in HCW (estimate = −0.0038), with a combined p -value of 5.59 × 10 −4 (estimate = −0.0039) in all the subjects.…”

“…Detailed demographic information of the IBD and HCW cohorts has been previously reported [ 15 , 16 ], with the demographics of the two cohorts summarized in Table 1 . Individuals in these cohorts were studied at up to four time points in relation to SARS-CoV-2 mRNA vaccination.…”

“…We therefore produced breadth and depth metrics for the private TCR vaccine response of individuals using double-filtered TCRs (either TCR1 or TCR2) and compared them with the breadth and depth metrics produced by a targeted public TCR response method (Adaptive Biotechnologies) from the same subjects and TCR datasets [ 15 , 16 ]. The intra-individual correlations of the private and public TCR vaccine responses are shown in Figure 3 .…”

“…Unlike antibody immunity, T-cells cross-respond to Omicron, delta, and beta variants at comparable magnitudes [ 9 , 10 , 11 ]. Also, whereas antibody immunity is reduced by anti-TNF and preserved by mycophenolate immunosuppressant therapy, T-cell responses are augmented by anti-TNF and reduced by mycophenolate [ 11 , 12 , 13 , 14 , 15 , 16 ]. Thus, a more robust understanding of the dynamics and effectors of T-cell immunity, independent of antibody immunity, will be essential to mobilizing every aspect of adaptive immunity.…”

Progress in kidney transplantation: The role for systems immunology

“…This methodology has recently been expanded to diagnosis of other vector-borne disease and has the potential to be applied to innumerable viral pathogens (143). TCR repertoire has proved to be useful in evaluating response to vaccination, and may be a useful adjunct in screening patients for baseline protective immunity prior to transplantation to guide prophylaxis or duration of therapy (147,148).…”