COVID-19 Vaccine-Induced Antibody and T Cell Responses in Immunosuppressed Patients with Inflammatory Bowel Disease After the Third Vaccine Dose

Background: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking infliximab or tofacitinib after two vaccine doses. We sought to determine whether immunosuppressive treatments were associated with reduced antibody and T cell responses after a third vaccine dose. Methods: 352 adults (72 healthy controls and 280 IBD) from the prospectively recruited study cohort were sampled 28-49 days after a third dose of SARS-CoV-2 vaccine. IBD medications studied included thiopurines (n=65), infliximab (n=46), thiopurine/infliximab combination therapy (n=49), ustekinumab (n=44), vedolizumab (n=50) or tofacitinib (n=26). SARS-CoV-2 spike antibody binding and T cell responses were measured. Findings: Geometric mean [geometric SD] anti-S1 RBD antibody concentrations increased in all study groups following a third dose of vaccine, but were significantly lower in patients treated with infliximab (2736.8 U/mL [4.3]; P<0.0001), infliximab and thiopurine combination (1818.3 U/mL [6.7]; P<0.0001) and tofacitinib (8071.5 U/mL [3.1]; P=0.0018) compared to controls (16774.2 U/ml [2.6]). There were no significant differences in anti-S1 RBD antibody concentrations between control subjects and thiopurine (12019.7 U/mL [2.2]; P=0.099), ustekinumab (11089.3 U/mL [2.8]; P=0.060), nor vedolizumab treated patients (13564.9 U/mL [2.4]; P=0.27). In multivariable modelling, lower anti-S1 RBD antibody concentrations were independently associated with infliximab (Geometric mean ratio 0.15, 95% CI 0.11-0.21, P<0.0001), tofacitinib (0.52, 95% CI 0.31-0.87, P=0.012) and thiopurine (0.69, 95% CI 0.51-0.95, P=0.021), but not with ustekinumab (0.64, 95% CI 0.39-1.06, P=0.083), or vedolizumab (0.84, 95% CI 0.54-1.30, P=0.43). Previous SARS-CoV-2 infection (1.58, 95% CI 1.22-2.05, P=0.00056) and older age (0.88, 95% CI 0.80-0.97, P=0.0073) were independently associated with higher and lower anti-S1 antibody concentrations respectively. However, antigen specific T cell responses were similar in IBD patients in all treatment groups studied, except for recipients of tofacitinib without evidence of previous infection, where T cell responses were significantly reduced relative to healthy controls (p=0.021). Interpretation: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab/thiopurine combination and tofacitinib therapy. Tofacitinib was also associated with reduced T cell responses. These findings support continued prioritisation of immunosuppressed groups for further booster dosing, particularly those on Janus Kinase (JAK) inhibitors who have attenuation of both serological and cell-mediated vaccine-induced immunity. Funding: Financial support was provided as a Research Grant by Pfizer Ltd.Declaration of Interest: Dr Alexander reports sponsorship from Vifor Pharma for accommodation/travel to BSG 2019, outside the submitted work. Dr. Kennedy reports grants from AbbVie, Biogen, Celgene, Celtrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche and Takeda, consulting fees from Amgen, Bristol-Myers Squibb, Falk, Janssen, Mylan, Pharmacosmos, Galapagos, Takeda and Tillotts, personal fees from Allergan, Celltrion, Falk, Ferring, Janssen, Pharmacosmos, Takeda, Tilllotts, Galapagos, and support for attending meetings from AbbVie, Falk and Janssen outside the submitted work. Dr Saifuddin has received travel expense support from Janssen. Prof. Sebastian reports grants from Takeda, Abbvie, Tillots Pharma, Janssen, Pfizer, Biogen and personal fees from Takeda, Abbvie, Janssen, Pharmacocosmos, Biogen, Pfizer, Tillots Pharma and Falk Pharma, outside the submitted work. Dr Hart reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, AZ, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Galapogos, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda and Global Steering Committee for Genentech, support for attending meetings from Abbvie, Takeda and Janssen, and Participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AZ, Atlantic, Bristol-Myers Squibb, Galapogos, Janssen, Pfizer and Takeda. Dr Irving reports grants and personal fees from Celltrion, grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, grants and personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from BMS, personal fees from Lilly, personal fees from Arena, outside the submitted work. Dr Parkes receives unrestricted educational grants from Pfizer for genetic analyses to support the IBD BioResource and speaker fees from Janssen. Dr Jones has received grants from Wellcome Trust and ECCO, speaker fees from Takeda, Ferring and Janssen and support for attending meetings and/or travel from Ferring. Dr. Kok reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen and Ferring, support for attending meetings and/or travel Janssen and Takeda and Participation on a Data Safety Monitoring Board or Advisory Board from Janssen and Predict Immune. Dr Patel reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, DrFalk, Janssen, PreddictImmune, Takeda, support for attending meetings and/or travel from Abbvie, Ferring, Janssen, Tillots and Participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, Galapagos and Janssen. Dr Kent reports consulting fees from Janssen, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer and Takeda, support for attending meetings and/or travel from Janssen, Tillots and Norgine, Participation on a Data Safety Monitoring Board or Advisory Board from Abbvie. Dr Hicks reports support for attending meetings and/or travel from Abbvie. Prof. Lees reports a Future Leaders Fellow award from UKRI, personal consulting fees from Galapagos, Abbvie, Takeda, Pfizer, Janssen, Iterative Scopes and institutional consulting fees from Trellus Health, personal fees from Galapagos, Abbvie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresnius Kabi, Ferring and Dr Falk, and support for attending meetings from Galapagos, Abbvie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresnius Kabi, Ferring and Dr Falk. Prof Boyton and Prof Altmann are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. Dr. Goodhand reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during the conduct of the study. Prof. Ahmad reports grant funding from Pfizer to his institution to deliver this study, grants from Celltrion, Roche, Takeda, Biogen and Galapagos and honoraria for lectures from Takeda and Roche, outside the submitted work. Financial support for the VIP study was provided as a Research Grant by Pfizer Ltd and Dr Powell is the PI on this grant. Dr Powell has received research grant(s) from Bristol Myers Squibb outside the submitted work. Dr. Powell reports personal fees from Takeda, Janssen, Pfizer, Bristol-Myers Squibb, Abbvie, Roche, Lilly, Allergan, and Celgene, outside the submitted work; Dr. Powell has served as a speaker/advisory board member for Abbvie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda and Vifor Pharma. All other authors have nothing to declare. Ethical Approval: The Wales Research Ethics Committee 5 approved the study (REC reference: 21/WA/0105) in March 2021.