Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
The effect of immunomodulator and biological therapy for IBD on the immune response to SARS-CoV-2 is of substantial interest to patients and clinicians worldwide. The CLARITY IBD study recently reported attenuated serological responses in patients with IBD treated with infliximab in comparison with vedolizumab,1 with the effect greatest in those on infliximab/thiopurine combination therapy. Independently, the global SECURE-IBD registry highlighted that infliximab/thiopurine combination therapy, but not infliximab or vedolizumab monotherapies, was associated with more severe clinical outcomes upon SARS-CoV-2 infection.2 3
However, these studies have not addressed treatment effects on neutralising antibody responses, which are associated with protection to SARS-CoV-2; nor have they analysed the range of serological signatures that may influence clinical outcomes.4 5
To answer these questions, we performed an extended analysis of serological responses to SARS-CoV-2 infection in patients with seropositive IBD treated with either infliximab or vedolizumab monotherapy, or infliximab/thiopurine combination therapy (figures 1 and 2; online supplemental material). Blood samples were collected from consenting patients attending infusion centres in Oxford and London between May and December 2020. Sera were initially screened by Abbott assay for SARS-CoV-2 antibody responses.6 Serological reactivity profiles in positive samples were compared with those from healthy adult controls seropositive in the same assay7 (online supplemental table 1).
Antibody reactivity to the receptor-binding domain (RBD) of the SARS-CoV-2 spike, full-length spike (S) and the nucleocapsid (N) was assayed by IgG/IgA standard ELISAs and IgG high-throughput MSD V-PLEX assay. An ACE2-SARS-CoV-2 RBD inhibition assay was used to detect neutralising antibodies.5 8
All treatments were associated with significantly reduced IgG antibody responses compared with healthy controls for all SARS-CoV-2 antigens, using an MSD V-PLEX assay (figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with infliximab/thiopurine combination therapy (figure 2A; p=0.00019). Furthermore, IgA responses were significantly reduced in individuals treated with infliximab/thiopurine combination therapy compared with healthy controls (figure 2B; p=0.009), but not in patients with IBD treated with infliximab or vedolizumab monotherapy.
Next, we used an ELISA-based inhibition assay to determine the ability of serum to neutralise the SARS-CoV-2 RBD–ACE2 interaction (figure 2C). Individuals treated with vedolizumab or infliximab monotherapy did not show a significant difference in neutralising antibody responses compared with healthy individuals (figure 2C). However, individuals treated with infliximab/thiopurine combination therapy showed a significantly reduced response compared with either monotherapy groups, and to the healthy control group (figure 2C, p=0.0054, p=0.0022 and p=0.0092).
Our data are novel, first in demonstrating that infliximab/thiopurine combination therapy is associated with significantly lower IgA as well as a range of IgG responses, and most importantly, with impaired functional neutralising antibody responses, compared with responses in healthy individuals. Second, we show that while IgG responses were significantly reduced in individuals with IBD treated with infliximab or vedolizumab monotherapy compared with healthy controls, this was not the case for IgA and neutralising antibody responses. As neutralising antibody responses are associated with protection,9 10 this observation may provide the mechanistic explanation for the observation reported by the SECURE-IBD study that individuals with combination therapy were at greater risk of severe COVID-19 outcomes than patients on monotherapy.9 10
The interpretation of these data requires circumspection in view of the relatively modest size of the study, notwithstanding the significant differences between treatment groups. In this context, we present these data as an important basis to direct further research in this field rather than to alter clinical practice.
In demonstrating that these therapeutic interventions are selectively associated with a pattern of attenuated antibody responses to SARS-CoV-2 infection compared with healthy controls, we believe these data extend current understanding in this important area, and have potentially important implications for patient care and vaccination strategies.
Patient consent for publication
This study involves human participants. Samples from Oxford IBD patients were collected as a project (ref: ORB 20/A054) under the ethical approval of the Oxford Radcliffe Biobank, a research tissue bank that has a favourable opinion from the Oxford C South Central REC (ref:19/ SC/0173). Samples from London IBD patients were collected as a project under the ethical approval of the Digestive Disease Bioresource, Barts Health NHS Trust, a research tissue bank that has a favourable opinion from the Bromley REC (ref: 15/LO/2127). Asymptomatic staff sample and data collection (N=36) were part of enhanced hospital infection prevention and control measures instituted by the UK Department of Health and Social Care. Deidentified data from staff testing and patients were obtained from the Infections in Oxfordshire Research Database (IORD) which has generic Research Ethics Committee, Health Research Authority and Confidentiality Advisory Group approvals (19/SC/0403, ECC5-017(A)/2009). Healthy control participants were recruited under the GI Biobank Study 16/YH/0247, approved by the research ethics committee (REC) at Yorkshire & The Humber - Sheffield Research Ethics Committee on 29 July 2016, which has been amended for this purpose on 8 June 2020. Participants gave informed consent to participate in the study before taking part.
JW and ME contributed equally.
Contributors ME, JW ran experiments. ME, JW, UO, CPT, JS S-YW, J-FC, PK, SD, EB, DE, DS, JL analysed data. ME, JW, CPT, JS, PS, LJ, MT, PK, CM, SD wrote paper. SD, PK, CGM, CPT, JS designed the study.
Funding This study was funded by Leona M. and Harry B. Helmsley Charitable Trust (2107–04731), National Institute for Health Research (COV19-RECPLAS).
Competing interests JS has received lecture fees from Takeda and from the Falk Foundation.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.