THE T-CELL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE IS OFTEN DEFICIENT IN ANTIBODY-RESPONDERS, AND AUGMENTED BY ANTI-TNF THERAPY

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 immunemodifying 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, and was preserved by nonanti- TNF biologic therapies;augmented clonal depth was associated with anti-TNF treatment (Figure). 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 (Figure). 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. (Table Presented)

SARS-COV-2 VACCINATION INDUCES A PREDOMINENTLY CLASS II (CYTOKINE EFFECTOR) T CELL RESPONSE, BUT THE CLASS I RESPONSE IS AUGMENTED BY ANTI-TNF THERAPY AND VACCINE TYPE

BACKGROUND: In response to COVID-19 vaccination, cytotoxic and cytokine effector T cell immune responses are elicited in the T-cell compartment, based on recognition of epitopes presented by Class I or Class II MHC molecules, respectively. The levels of these distinct T-cell responses may have significant implications for immunization strategies and risk assessment. Knowledge of these two responses after vaccination is still largely unknown, especially in the context of immunomodulatory treatment regimens. METHODS: We performed T-cell receptor (TCR) immunosequencing (Adaptive Biotechnologies, Seattle WA) of IBD patients (N=303) and health care worker controls (HCW, N=224) at up to four time points (prior to dose 1, prior to dose 2, 2 weeks after dose 2, 8 weeks after dose 2). Two metrics of TCR response, breadth (# of unique antigen-specific sequences) and depth (expansion of antigen-specific sequences), were calculated for all sequences and Class I- and Class II-specific sequences, and compared to demographics, IBD treatment, and vaccine type. Subjects with exceptional Class I or Class II responses were calculated as significant residuals relative to the Class I vs. Class II regression line. Similar associations were observed for both breadth and depth: breadth is presented here for brevity. RESULTS: Both Class I- and Class II-specific T-cell responses peaked 2 weeks after dose 2, and significantly correlated with lower age, female gender, and mRNA vaccine type (mRNA-1273/Moderna and BNT262b/Pfizer, versus vector vaccine AD26CoV2/J&J) (FIGURE). Class II responses comprised ~85% of detected TCR response in both IBD and HCW subjects. Among IBD patients, there was a significant elevation of the class I response with anti-TNF treatment (p=0.04). This effect was most pronounced at later timepoints, suggesting that anti-TNF permitted a more persistent Class I-specific response. Among patients with exceptionally high or low Class I TCR response, there were significant differences in TCR metrics across vaccine types (p=0.0035). 21% of AD26CoV2 patients were highly Class I-biased (Zscore>1, 9.4% and 7.3% for BNT162 and mRNA-1273, respectively), and this was correlated with lower anti-spike serology 2 and 8 weeks after vaccination (p<1E-10). Conversely, mRNA- 1273 patients were Class I-deficient, representing 25.3% of patients but 44.1% of highly Class I-deficient patients (Zscore<1, 0% for AD26CoV2). CONCLUSION: The T-cell clonal response to SARS-CoV-2 vaccine is Class II-predominant, but the Class I-response is augmented by anti-TNF therapy and vector vaccine type. These factors may help guide reimmunization vaccine strategy in immune-impaired populations, and warrant further study of the effects of anti-TNF therapies on vaccine efficacy.(Figure Presented)Figure: TCR response time course (left);effect of anti-TNF (middle);effect of vaccine type (right). Breadth was predominantly Class II for most patients, with maximum response at 2 weeks after full vaccination (left). The balance of Class I vs. Class II response was significantly biased towards Class I at 8 weeks after full vaccination for patients receiving anti-TNF treatment for IBD (asterisk, p=0.036). Patients receiving AD26CoV2 vaccines were significantly increased in Class I responses, while patients receiving mRNA-1273 vaccines were significantly reduced for Class I responses (t-tests: p=0.0036 at 8 weeks [asterisk], p=0.051 at 2 weeks).

POST-VACCINATION SYMPTOMS AFTER A THIRD DOSE OF SARS-COV-2 MRNA VACCINATION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Background:Symptoms after SARS-CoV-2 primary vaccination among patients with inflammatory bowel disease (IBD) are generally similar to the general population,although symptoms after the second dose are more frequent and severe than after the first dose.Postvaccination symptoms after a 3rd mRNA vaccine dose in the predominantly immune-compromised IBD population is unknown.Methods:Adults with IBD participating in the prospective Coronavirus Risk Associations and Longitudinal Evaluation in IBD (CORALE-IBD) vaccine registry who received a 3rd mRNA vaccine dose were asked to complete a detailed symptom survey 1 week after vaccination.Symptoms were assessed across 11 organ systems,and graded as mild,moderate,or severe,or requiring hospitalization.“Severe+” referred to those with severe symptoms or who required hospitalization.We stratified by age (<or> 50 years) given prior distinct symptom profiles after dose 2 (D2).We also evaluated whether severe+ symptoms after D2 predicted severe+ symptoms after dose 3 (D3).Results:We included 524 participants (70% female, mean age 45 years) who received a 3rd mRNA vaccine through October 11, 2021.Most had Crohn's disease (71%), and 89% were on biologic therapies.Most (58%) had received primary vaccination with BNT562b2,and only 3.5% reported prior COVID infection at the time of initial vaccination.Overall, 97% of subjects received a 3rd dose with the same mRNA vaccine as in their initial series with the remainder receiving the other mRNA vaccine type.No participants received a 3rd dose with the Ad26.CoV.2 (J&J) vaccine. Overall, 41% reported symptoms after a 3rd dose,with symptoms generally more frequent and severe among those <55 years (Table).The most frequent postvaccination symptom was injection site pain (39%).Common systemic symptoms included fatigue/malaise (34%),headache (23%),and muscle, bone or joint symptoms (13%).These were all less frequent after D3 than after D2 (Figure).Gastrointestinal symptoms were reported by 8.8%, which was slightly more frequent than after D2 (7.8%).Among those with postvaccination symptoms, the proportion with severe symptoms after D3 was lower than D2 for fatigue/ malaise, headache, dizziness and lightheadedness, fever/chills, and rheumatologic symptoms, but was slightly higher than D2 for gastrointestinal symptoms.Severe+ symptoms were seen in 17% after D2 and in 14% after D3. Of those with severe+ symptoms after D2, 34% had severe+ symptoms after D3.In contrast, about 22% had severe+ symptoms after D3 but did not report severe+ symptoms after D2.Conclusion:The frequency and severity of symptoms after a 3rd mRNA vaccine dose are generally similar or lower than those after a second dose.Furthermore, prior severe+ symptoms after D2 do not necessarily predict severe+ symptoms after D3. Further evaluation of postvaccination gastrointestinal symptoms in this population is warranted. (Figure Presented) (Table Presented)

PATIENTS WITH INFLAMMATORY BOWEL DISEASE HAVE IMPAIRED HUMORAL BUT PRESERVED CELLULAR RESPONSES TO SARS-COV-2 MRNA VACCINATION

Background: Vaccine-induced protection against SARS-CoV-2 infection is predominantly mediated by humoral immunity;protection against disease progression is primarily determined by cellular immunity. Patients with inflammatory bowel disease (IBD) have high rates of post-vaccination anti-Spike IgG [IgG(S)] seroconversion, but postvaccination immune responses relative to non-IBD controls have not been well described. We aimed to assess post-vaccination humoral (antibody) and cellular (T-cell) responses in IBD relative to healthcare worker (HCW) controls. Methods: We evaluated IBD patients enrolled in a US registry referred from 26 centers at 2, 8, and 16 weeks after completing 2 doses of SARSCoV- 2 mRNA vaccination and compared results to non-IBD non-immunosuppressed HCW participating in a parallel study. We analyzed plasma antibodies to the receptor binding domain of the viral spike protein using the SARS-CoV-2 IgG-II assay (Abbott Labs, Abbott Park, IL);IgG(S) > 50 AU/mL was defined as positive. Those with prior COVID were excluded. We also performed T-cell clonal analysis by T-cell receptor (TCR) immunosequencing at 8 weeks (Adaptive Biotechnologies, Seattle, WA). 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. Analyses were adjusted for age, sex and vaccine type. Results: Overall, 1805 subjects were included (IBD n=1074 (65% Crohn's disease, 35% ulcerative colitis);HCW n=731). Age and sex were similar between both cohorts;Hispanic ethnicity and Asian race were less common among IBD than HCW (Table). Vaccine type included BNT162b2 (Pfizer) (75% of IBD, 98% of HCW) and the remainder mRNA-1274 (Moderna). IBD treatments included anti- TNF (46%), other biologics (33%), other immune suppressing therapy (9%), and no immune suppression (12%). Postvaccination antibody levels were lower among IBD than HCW both before and after adjusting for vaccine type (p<0.0001 each timepoint;Figure). After further restricting the IBD cohort to those on no immune-suppressive therapies, antibodies remained lower in IBD vs HCW at 2w (p=0.008) and 8w (p<0.0001), but not 16w (p=0.07). Among 321 subjects with available whole cell samples at 8 weeks (IBD n=163, HCW =158), Spikespecific TCR responses were similar between IBD and HCW for both clonal breadth and depth in both unadjusted and adjusted analyses;sub-analyses of those on biologics yielded similar results. Conclusion: Patients with IBD have dampened humoral responses, but similar cellular responses, after SARS-CoV-2 mRNA vaccination relative to HCW. These findings suggest a potentially greater risk of infection, but not of disease progression, among those with IBD, and should be considered to help guide booster dosing strategies for the IBD population. (Figure Presented) (Figure Presented) Figure: Post-vaccination immune responses: (A) Antibody responses are lower in IBD relative to non-IBD healthcare workers at 2, 8, and 16 weeks (p<0.0001 at each timepoint). In contrast, post-vaccination Spike-specific T-cell receptor clonal breadth (B1) and clonal depth (B2) at 8 weeks are similar in IBD compared to healthcare workers.

Gastrointestinal symptoms in patients with inflammatory bowel disease after SARS-CoV-2 mRNA vaccination

Introduction: In the SARS-CoV2 mRNA vaccine trials, post-vaccination gastrointestinal (GI) symptoms were reported in 10-20% of participants. These symptoms could be perceived as inflammatory bowel disease (IBD) flare which could lead to patient anxiety, and unnecessary tests or treatment. We aimed to assess GI symptoms after SARS-CoV2 mRNA vaccination in patients with IBD relative to non-IBD healthcare workers (HCW). Methods: We assessed GI symptoms in adults with IBD and HCW at baseline and after each dose of a SARS-CoV-2 mRNA vaccine. We analyzed patient-reported IBD-specific disease activity (PRO2) after each dose (stool frequency (SF) and rectal bleeding for ulcerative colitis (UC), SF and abdominal pain for Crohn's disease (CD)). We also compared the frequency, severity, and duration of postvaccination GI symptoms in IBD patients compared to HCW. Severity was defined by impact on daily activities (mild, did not interfere;moderate, some interference;severe, prevented routine activity;extreme, required hospitalization). Severe and extreme were combined and designated as severe+. Duration was classified as<2 days, 2-7 days, or>7 days. Results: Post-vaccination GI symptoms were assessed after dose 1 (D1) (1391 IBD, 933 HCW) and dose 2 (D2) (1271 IBD, 884 HCW) (Table). About 60% of IBD and>99% of HCW received the BNT162b vaccine (Pfizer);the remainder received mRNA-1273 (Moderna). New GI symptoms after D1 were more frequent among IBD than HCW (6.0% vs 2.9%, p=0.001) but not after D2 (12.1% vs 12.7%, p=NS). Relative to HCW, IBD patients reported more diarrhea (3.8% vs. 1% (p<0.001) after D1 and 7.5% vs 4.2% (p=0.003) after D2) and abdominal pain (2.2% vs. 0.4% (p=0.001) after D1 and 6.2% vs 3% (p=0.002) after D2). Severe1 symptoms were noted in 1.5% IBD and 0.3% HCW (p=NS) after D1 and in 3.3% IBD and 0.1% HCW (p<0.001) after D2 (Figure 1). Longer GI symptom duration was more common in IBD than HCW after D1 (2.1% vs 0.5%, p=0.002) and D2 (5.4% vs. 2.1%, p<0.001). Among 423 CD and 300 UC patients with PRO2 data, 71%, 68%, and 65% of CD and 86%, 86%, and 83% of UC were in clinical remission at baseline, after D1, and after D2, respectively. Conclusion: The frequency of GI symptoms in IBD was greater than HCW after D1, but similar after D2. More severe and longer duration of GI symptoms were noted in a small number of IBD patients. Reassuringly, the mRNA vaccines do not seem to increase the risk of a disease flare in the vast majority of IBD patients.