Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab

Abstract

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

Fig. 1. Anti-S RBD antibody concentration stratified by biologic therapy (infliximab vs vedolizumab), type of vaccine, vaccine dose and history of prior SARS-CoV-2 infection.

The wider bar represents the geometric mean, while the narrower bars are drawn one geometric standard deviation on either side of the geometric mean. Based on published data using neutralisation assays threshold shown of 15 U/mL was used to determine seroconversion. The biologic treatment infliximab is shown in green and vedolizumab in orange. The number of individuals tested for each group are shown in black at the top of each panel. Source data are provided as a Source Data file.

Fig. 2. Exponentiated coefficients of linear regression models of log anti-S RBD antibody concentration.

Exponentiated coefficients of the linear regression model of log anti-S RBD antibody concentration in participants who received a BNT162b2 vaccine. b ChAdOx1 nCoV-19 vaccine. c either the BNT162b2 or ChAdOx1 nCoV-19 vaccine. The resultant values represent the fold change of antibody concentration associated with each variable (black square). The horizontal solid line through each square represents the 95% confidence interval. Each vaccine was modelled separately, and then a further model was created using all available data. The vertical dotted line represents a fold change of 1. Tests were two-tailed. p values were derived from linear regression using the t-test statistic and reported without correction for multiple testing. Source data are provided as a Source Data file. UC ulcerative colitis, IBDU IBD unclassified.

Fig. 3. Anti-SARS-CoV-2 spike T cell responses stratified by vaccine platform (BNT162b2 vs ChAdOx1 nCoV-19), biologic therapy (infliximab vs vedolizumab) and vaccine dose (one vs two).

a Spike MEP T cell responses SFC per 10⁶ PBMC stratified by vaccine platform, biologic therapy (infliximab vs vedolizumab) and the number of vaccine doses. The horizontal bar represents the geometric mean and the narrow bars represent one geometric standard deviation on either side of the geometric mean. The number of T cell responders / total number of individuals tested are shown in black at the top of each panel. b Scatterplot demonstrating the correlation between T cell responses against spike MEP pool (SFC per 10⁶ PBMC) and anti-SARS-CoV-2 spike antibody concentration after the first (LHS) and second (RHS) dose of BNT162B2 (top) and ChAdOx1 nCoV-19 (bottom) vaccine. The number of non-T cell responders/total number of individuals tested is shown in blue on the bottom RHS of each panel. The shaded grey band represents the 95% confidence interval. The horizontal dotted line in b represents a threshold of 15 U/mL of anti-S1 SARS-CoV-2 antibody. The tests were two-tailed and p values were reported without correction for multiple testing. The biologic infliximab is shown in green and vedolizumab is shown in orange. Source data are provided as a Source Data file. MEP mapped epitope peptide, SFC spot forming cells, PBMC peripheral blood mononuclear cell, LHS left-hand side, RHS right-hand side, R Spearman’s rank correlation.

Fig. 4. Anti-spike T cell responses ordered by the cumulative magnitude of anti-S RBD following two doses of the BNT162b2 or ChAdOx1 nCoV-19 vaccine show uncoupling of the T cell and antibody responses.

Top panel shows T cell responses to spike, and the bottom panel shows anti-S RBD responses plotted for individual study participants ordered by increasing magnitude of anti-S RBD antibody concentration (U/mL). The vertical dark grey bars at the LHS of the panels indicate individuals with no anti-S RBD response. The vertical light grey bars in the panels indicate individuals with no T cell response. The horizontal dotted line represents a threshold shown of 15 U/mL of anti-S RBD. Source data are provided as a Source Data file. LHS left-hand side, MEP mapped epitope peptide, SFC spot forming cells.

Fig. 5. Rolling geometric mean antibody concentration over time from the date of the second dose of the SARS-CoV-2 vaccine (week 0) stratified by biologic therapy (infliximab vs vedolizumab), vaccine and history of prior SARS-CoV-2 infection.

Geometric means are calculated using a rolling 15-day window (i.e. 7 days on either side of the day indicated). The shaded areas represent the 95% confidence intervals of the geometric means. The horizontal blue line represents the seroconversion threshold (15 U/mL). The number of participants included at each time point is presented in Supplementary Fig. 2. Overall, data from 4474 participants with no history of prior infection (3029 on infliximab and 1445 on vedolizumab) and 1179 participants with a history of prior infection (833 on infliximab and 346 on vedolizumab) were included in this graph between 22 weeks before and 29 weeks after the second vaccine dose. The biologic treatment infliximab is shown in green and vedolizumab is shown in orange. Source data are provided as a Source Data file.

Fig. 6. Kaplan–Meier graphs comparing the time to PCR-confirmed SARS-CoV-2 infection stratified by biologic therapy (infliximab vs vedolizumab) in participants before vaccination and after receiving two doses of vaccine.

a The time to PCR-confirmed SARS-CoV-2 infection in participants who have not received any dose of either vaccine stratified by biologic therapy (infliximab vs vedolizumab). b The time to a PCR-confirmed SARS-CoV-2 breakthrough infection in participants following two doses of either vaccine stratified by biologic therapy. The biologic treatment infliximab is shown in green and vedolizumab in orange. The number of participants at each time point are displayed in black at the bottom of each figure. P values are calculated using the log-rank test. Source data are provided as a Source Data file.