Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.

Objective: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.
Design: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.
Results: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups.
Conclusions: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant.
Trial Registration Number: ISRCTN45176516.
Competing Interests: Competing interests: NAK reports grants from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study; grants and non-financial 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 Pharma, outside the submitted work. SL reports non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. LWH declares an interest in SENISCA as founder and Chief Scientific Officer. KBK reports personal fees from Janssen, personal fees from Takeda, personal fees from PredictImmune, personal fees from Amgen, outside the submitted work. CAL reports grants from Genentech, grants and personal fees from Janssen, grants and personal fees from Takeda, grants from AbbVie, personal fees from Ferring, grants from Eli Lilly, grants from Pfizer, grants from Roche, grants from UCB Biopharma, grants from Sanofi Aventis, grants from Biogen IDEC, grants from Orion OYJ, personal fees from Dr Falk Pharma, grants from AstraZeneca, outside the submitted work. PJS reports speaker fees and advisory board sponsorship from Janssen, Celltrion, AbbVie, Tillotts Pharma, Galapagos, Amgen, Dr Falk Pharma and Takeda outside the submitted work. AH reports personal fees from AbbVie, personal fees from Allergan, personal fees from BMS, personal fees from Celltrion, personal fees from Dr Falk Pharma, personal fees from GSK, personal fees from Takeda, personal fees from Pfizer, personal fees from Janssen, personal fees from Galapogos, personal fees from AstraZeneca, outside the submitted work. RCP reports acting as consultant, advisory board member, speaker or recipient of educational grant from Dr Falk Pharma, Ferring, Janssen, Pharmacosmos and Takeda, outside the submitted work. CWL 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. RB and DA are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. SS reports grants from Takeda, AbbVie, Amgen, Tillots Pharma, personal fees from Jaansen, Takeda, Galapagos, Celltrion, Dr Falk Pharma, Tillots Pharma, Cellgene, Pfizer, Pharmacocosmos, outside the submitted work. NP 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 NP has served as a speaker/advisory board member for AbbVie, Allergan, Bristol-Myers Squibb, Celgene, Dr Falk Pharma, Ferring, Janssen, Pfizer, Tillotts Pharma, Takeda and Vifor Pharma. JRG reports grants from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study. TA reports grants and non-financial support from F. Hoffmann-La Roche, grants from Biogen, grants from Celltrion Healthcare, grants from Galapagos, non-financial support from Immundiagnostik, during the conduct of the study; personal fees from Biogen, 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 Pharma, outside the submitted work.
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