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.

Keywords: SARS-CoV-2 (COVID-19); T-cell repertoire; immunodeficiency; inflammatory bowel disease; mRNA vaccine.

Figure 1

Breadth and depth metrics after COVID-19 vaccination. (A, B) Breadth and depth increases over time, peaking at 2 weeks after vaccine dose 2 in IBD. This increase was observed for both IBD and HCW cohorts. (C, D) Depth, but not breadth, was dependent on age. Younger patients have greater depth and more clonal expansion, with a similar number of unique clones detected. (E, F) Female patients only exhibited increased depth at dose 2 but were also younger. (G, H) Ad26.COV2.S vaccination resulted in lower depth. mRNA-1273 vaccination resulted in slightly higher breadth only at 8 weeks after dose 2. (I, J) Prior covid infection resulted in higher breadth and depth, except at 2 weeks after vaccination (*p<0.05). N.S., not-significant

Figure 2

Class-I and Class-II TCR metrics. (A, B) Class-I-specific breadth was consistently lower than Class-II-specific breadth. The residual metric was used to describe how much Class-I-specific breadth was observed relative to expected. (C, D) The Class-I/II residual was replicated for depth. (E) Z-scores for female patients were higher. (F) Z-scores for mRNA-1273 patients were significantly lower. Ad26.COV2.S differences were not statistically significant with the small sample size, but trended higher. (G, H) Anti-TNF treatment by adalimumab but not infliximab increased depth z-scores, and anti-IL23 decreased breadth z-scores. (I) Prior covid infection was significantly associated with higher z-scores (*p<0.05).

Figure 3

Class-I/II patient extremes. (A) Age groups of patients with breadth z-scores <-1, >1, and between -1 and 1 are shown with the number of samples in each group. Class-I-biased patients were more likely to be younger, while Class-I-deficient patients were more likely to be older. Ad26.COV2.S vaccines resulted in a higher proportion of Class-I-biased patients. (B) Similar trends were observed using depth z-scores. (C) Spike-specific antibody serology was correlated with both breadth and depth. (D) Prior covid infection was strongly associated with antibody counts. mRNA-1273 vaccination resulted in higher antibody counts and Ad26.COV2.S vaccination resulted in lower counts (*p<0.05).