Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD

  1. Nicholas A Kennedy
  2. Simeng Lin
  3. James R Goodhand
  4. Neil Chanchlani
  5. Benjamin Hamilton
  6. Claire Bewshea
  7. Rachel Nice
  8. Desmond Chee
  9. JR Fraser Cummings
  10. Aileen Fraser
  11. Peter M Irving
  12. Nikolaos Kamperidis
  13. Klaartje B Kok
  14. Christopher Andrew Lamb
  15. Jonathan Macdonald
  16. Shameer Mehta
  17. Richard CG Pollok
  18. Tim Raine
  19. Philip J Smith
  20. Ajay Mark Verma
  21. Simon Jochum
  22. Timothy J McDonald
  23. Shaji Sebastian
  24. Charlie W Lees
  25. Nick Powell
  26. Tariq Ahmad

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Abstract

Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.

Design

Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3–10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.

Results

Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn’s disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine.

Conclusion

Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.

Trial registration number

ISRCTN45176516 .

Article activity feed

  1. Version published to 10.1136/gutjnl-2021-324789
  2. ScreenIT

    SciScore for 10.1101/2021.03.25.21254335: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The Surrey Borders Research Ethics committee approved the study (REC reference: 20/HRA/3114) in September 2020.
    Consent: Patients were included after providing informed, written consent.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    To determine antibody responses specific to vaccination we used the Roche Elecsys Anti-SARS-CoV-2 spike (S) immunoassay13 alongside the nucleocapsid (N) immunoassay.14 This double sandwich electrochemiluminescence immunoassay uses a recombinant protein of the receptor binding domain on the spike protein as an antigen for the determination of antibodies against SARS-CoV-2.
    Anti-SARS-CoV-2
    suggested: None
    Outcomes: Our primary outcome was anti-SARS-CoV-2 anti-spike (S) protein receptor-binding protein antibodies three to ten weeks after primary vaccination.
    anti-SARS-CoV-2 anti-spike ( S ) protein receptor-binding protein
    suggested: None
    anti-spike
    suggested: None
    Anti-S antibody concentrations are reported as geometric means and standard deviations.
    Anti-S
    suggested: None
    For age, a cut-off was chosen based on graphical inspection of the relationship between age and anti-SARS-CoV-2 (S) antibody concentrations.
    anti-SARS-CoV-2 ( S )
    suggested: None
    Software and Algorithms
    SentencesResources
    Data were entered electronically into a purpose-designed REDCap database hosted at the Royal Devon and Exeter NHS Foundation Trust.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    ), Celltrion Healthcare (South Korea) and Galapagos NV (Belgium).
    Celltrion Healthcare
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Whilst our data are biologically plausible, we acknowledge the following limitations of our study. We have used an electrochemiluminescence immunoassay to measure antibody concentrations rather than using a neutralising assay. Although neutralisation assays are considered more biologically relevant, it is now established that anti receptor-binding domain antibodies, which target the spike protein component that engages host cells through ligation of angiotensin-converting enzyme 2, closely correlate with neutralisation assays.29,30 Second, we only assessed humoral responses to infection, and it is likely that protective immunity additionally requires induction of memory T cell responses. Finally, we investigated one anti-TNF drug, infliximab, only. However, we suspect that our key findings will apply to other anti-TNF biologics used to treat IMIDs, including adalimumab, certolizumab, golimumab, and etanercept. Further observational data will be required to elucidate the impact of other classes of therapies for IMIDs on SARS-CoV-2 vaccine immunogenicity. Our findings have important implications for patients treated with anti-TNF drugs particularly those also treated with an immunomodulator. Poor antibody responses to a single-dose of vaccine unnecessarily exposes infliximab-treated patients to SARS-CoV-2 infection. However, because we observed higher rates of seroconversion in patients with two exposures to SARS-CoV-2 antigen, even in the presence of TNF blockade, these patien...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    ISRCTN45176516NANA

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2021.03.25.21254335v2 on medRxiv
  4. Version published to 10.1101/2021.03.25.21254335v1 on medRxiv