COVID-19 Vaccine-Induced Antibody Responses are Impaired in IBD Patients Treated with Infliximab or Tofacitinib, but not Thiopurines, Ustekinumab or Vedolizumab

Abstract

Background: We sought to determine whether COVID-19 vaccine-induced antibody responses were impacted by commonly used immunosuppressive drugs in IBD. 

Methods: We prospectively recruited 483 adults (121 healthy controls and 362 IBD) following two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines (doses delivered between six to twelve weeks apart according to scheduling adopted in the United Kingdom). IBD medications studied comprised thiopurines (n=78), infliximab (n=63), thiopurine/infliximab combination therapy (n=72), ustekinumab (n=57), vedolizumab (n=62) or tofacitinib (n=30). The primary outcome was anti-SARS-CoV-2 spike (anti-S1 RBD) antibody concentrations, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age and vaccine type.  

Findings: Geometric mean [geometric SD] anti-S1 RBD antibody concentrations were significantly lower in patients treated with infliximab (157U/mL [5.7]; P<0.0001), infliximab and thiopurine combination (111U/mL [5.7]; P<0.0001) and tofacitinib (430 U/mL [3.1]; P=0.0012) compared to controls (1578U/ml [3.7]). There were no significant differences in anti-S1 RBD antibody concentrations between control subjects and thiopurine (1020U/mL [4.3]; P=0.74), nor ustekinumab (582U/mL [4.6]; P=0.11), nor vedolizumab treated patients (954U/mL [4.1]; P=0.50). In multivariable modelling, lower anti-S1 RBD antibody concentrations were independently associated with infliximab (FC 0.12, 95% CI 0.08-0.17, P<0.0001) and tofacitinib (0.43, 95% CI 0.22-0.81, P=0.009), but not with ustekinumab (0.69, 95% CI 0.41-1.19, P=0.18), thiopurine (0.89, 95% CI [0.64-1.24], P=0.50) or vedolizumab (1.16, 95% CI 0.74-1.83, P=0.51). mRNA vaccines (3.68 [95% CI 2.80-4.84], P<0.0001) and older age (0.79 [95% CI 0.72-0.87], P<0.0001) were independently associated with higher and lower anti-S1 antibody concentrations respectively. 

Interpretation: In IBD patients the immunogenicity of COVID-19 vaccines is differentially impacted by immunosuppressive drugs. Scheduling of third primary, or booster dosing could be personalized based on an individual’s treatment, and patients taking anti-TNF and tofacitinib should be prioritized. 

Funding: Financial support was provided as a Research Grant by Pfizer Ltd.

Declaration of Interest: Dr. Kennedy 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; grants and nonfinancial support from AbbVie, grants and personal fees from Celltrion, personal fees and non-financial support from Janssen, personal fees from Takeda, personal fees and non-financial support from Dr Falk, outside the submitted work. Dr Saifuddin has received travel expense support from Dr Falk Pharma. Prof. Sebastian reports grants from Takeda, Abbvie, AMGEN, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Falk Pharma, Tillots pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. Dr Alexander reports sponsorship from Vifor Pharma for accommodation/travel to BSG 2019, outside the submitted work. Dr Hart reports personal fees from Abbvie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Falk, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from Astra Zeneca, outside the submitted work. Dr Irving reports grants and personal fees from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, personal fees from Gilead, personal fees from Abbvie, personal fees from Janssen, personal fees from Boehringer Ingelheim, personal fees from Topivert, personal fees from VH2, personal fees from Celgene, personal fees from Arena, personal fees from Samsung Bioepis, personal fees from Sandoz, personal fees from Procise, personal fees from Prometheus, outside the submitted work. Dr Parkes receives unrestricted educational grants from Pfizer for genetic analyses to support the IBD BioResource. Dr Jones has received speaker fees from Takeda, Ferring and Janssen. Dr. Kok reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. Prof. Lees reports personal fees from Abbvie, personal fees from Janssen, personal fees from Pfizer, personal fees from Takeda, grants from Gilead, personal fees from Gilead, personal fees from Galapagos, personal fees from Iterative Scopes, personal fees from Trellus Health, personal fees from Celltion, personal fees from Ferring, personal fees from BMS, during the conduct of the study. 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, nonfinancial support from Immundiagnostik, during the conduct of the study. Dr. Powell reports personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Abbvie, personal fees from Roche, personal fees from Lilly, personal fees from Allergan, personal fees from Celgene, outside the submitted work; and 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. Prof. Ahmad reports grants and non-financial support 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; personal fees from Biogen inc, grants and personal fees from Celltrion Healthcare, personal fees and non-financial support from Immundiagnostik, personal fees from Takeda, personal fees from ARENA, personal fees from Gilead, personal fees from Adcock Ingram Healthcare, personal fees from Pfizer, personal fees from Genentech, non-financial support from Tillotts, outside the submitted work. The following authors nothing to declare: Dr Castro Seoane, Claire Bewshea, Rachel Nice, Laura Constable Dr Ibraheim, Dr Anandabaskaran, Dr Saifuddin, Z. Liu, Andrea D'Mello, Dr Balarajah, Dr Fiorentino, Dr Hicks, Dr Williams, Dr Kent, Rachel Linger, Rebecca King, Dr Patel and Professor Teare

Ethical Approval: The protocol is available online at https://www.vipstudy.uk. The study was registered with the ISRCTN registry. The Wales Research Ethics Committee 5 approved the study (REC reference: 21/WA/0105) in March 2021.

Keywords: SARS-CoV-2, immune-mediated inflammatory diseases, Inflammatory bowel disease, thiopurine, azathioprine, anti-TNF therapy, infliximab, vedolizumab, ustekinumab, tofacitinib, immunosuppressant, vaccine, ChAdOx1 nCoV-19, BNT162b2