ABSTRACT
Background : Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccineinduced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods: We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti- SARS-CoV-2 spike (S) Ab assay, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15 U/ml, which correlated with 20% viral neutralization). Results: Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/ml;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/ml;p<0.0001) and uste (561U/ml;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy-treated patients (1020U/ml;p=0.62), nor between controls and vedo-treated patients (944U/ml;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07-0.14], p<0.0001), tofa (0.36 [95% CI 0.19-0.69], p=0.002) and uste (0.56 [95% CI 0.31-1.00], p=0.049), but not with thiopurine (0.77 [95% CI 0.54-1.11], p=0.17) or vedo (1.01 [95% CI 0.61-1.68], p=0.96). mRNA vaccines (3.67 [95% CI 2.72-4.96], p<0.0001) and older age (0.82 [95% CI 0.73-0.91], p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. Conclusions : COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual's immunosuppressive treatment. (Figure Presented) (Figure Presented)
ABSTRACT
Background: Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody. Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. Methods: Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine. Results: Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/ mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1). Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 - 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumabtreated patients after one or two doses of either vaccine. Antibody half-life was shorter in infliximab- than vedolizumabtreated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 - 4.1] vs 7.2 weeks [95% CI 6.8 - 7.6]) and ChAdOx1 nCoV- 19 (5.3 weeks [95% CI 5.1 - 5.5] vs 9.3 weeks [95% CI 8.5 - 10.2], p value < 0.0001). Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3). Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 - 0.99], p = 0.035). Conclusion: Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.
ABSTRACT
Background: Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccine-induced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods: We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti- SARS-CoV-2 spike (S) Ab assay, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15 U/mL, which correlated with 20% viral neutralization). Results: Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/mL;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/mL;p<0.0001) and uste (561U/mL;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy- treated patients (1020U/mL;p=0.62), nor between controls and vedo-treated patients (944 U/mL;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07-0.14], p<0.0001), tofa (0.36 [95% CI 0.19-0.69], p=0.002) and uste (0.56 [95% CI 0.31-1.00], p=0.049), but not with thiopurine (0.77 [95% CI 0.54-1.11], p=0.17) or vedo (1.01 [95% CI 0.61-1.68], p=0.96). mRNA vaccines (3.67 [95% CI 2.72- 4.96], p<0.0001) and older age (0.82 [95% CI 0.73-0.91], p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. Conclusion: COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual's immunosuppressive treatment.
ABSTRACT
Introduction: A subcutaneous (SC) infliximab (IFX), CT-P13 SC, has received regulatory approval from the European Medicines Agency for indications including inflammatory bowel disease.1 In response to the coronavirus disease 2019 (COVID-19) pandemic, clinical guidance has recommended considering switching from intravenous (IV) treatment to SC alternatives to minimise hospital visits.2 Aims & Methods: In this analysis, data from the pivotal randomised controlled trial (NCT02883452) of CT-P13 SC in patients with active Crohn's disease (CD) and ulcerative colitis (UC) were analysed to investigate the clinical impact of switching from IV to SC IFX.3 Patients in the CT-P13 IV arm of the pivotal trial received CT-P13 5 mg/kg IV every 8 weeks from Week (W) 6 until W22. At W30, patients switched to receive CT-P13 SC every 2 weeks up to W54 (dose 120 mg or 240 mg for patients <80 kg or ≥80 kg, respectively).3 This post hoc analysis compared per-patient pairwise data at W30 (pre-switch) and W54 (post-switch) from the CT-P13 IV arm for the following outcomes: trough serum concentration (Ctrough;5 μg/mL was considered to be the target exposure level), clinical response (for CD patients, ≥100-point decrease in Crohn's Disease Activity Index score;for UC patients, ≥2-point decrease in partial Mayo score with accompanying ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1) and immunogenicity (anti-drug antibody [ADA] and neutralising antibody [NAb] positivity;as measured by a drug tolerant assay;ADA negative was regarded as NAb negative). For pairwise comparisons, patients with missing data at either W30 or W54 were excluded from the analysis. Statistical comparisons used Fisher's exact test. The differences are reported in a descriptive manner. Results: Overall, 65 patients (25 CD;40 UC) were included in the CT-P13 IV arm. The proportion of patients with a Ctrough level exceeding target exposure was significantly higher post-switch (36/41, 87.8%) than pre-switch (8/41, 19.5%;p<0.00001) (Table). Clinical response rates were comparable at both pre- and post-switch timepoints (40/49 [81.6%] vs 44/49 [89.8%], respectively;p=0.3873). Positive ADA and NAb rates at pre-switch and post-switch were also comparable, in which some changes were regarded from patients with marginal value (Table). Conclusion: Switching from IV to SC IFX did not detrimentally affect the clinical outcomes of patients with active CD or UC. Further, switching from IV to SC IFX might confer more favourable pharmacokinetic outcomes, although larger comparative studies are warranted. (Table Presented).