key: cord-0801053-unbx6od5 authors: Kennedy, N. A.; Lin, S.; Goodhand, J. R.; Chanchlani, N.; CLARITY IBD Contributors,; Powell, N.; Ahmad, T. title: Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines date: 2021-03-28 journal: nan DOI: 10.1101/2021.03.25.21254335 sha: bdde86695f40b289a32c7c09d0bcfebf1ca9118b doc_id: 801053 cord_uid: unbx6od5 Background 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. Methods Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared to a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin a4B7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations 3-10 weeks after vaccination in patients without evidence of prior infection. Secondary outcomes were seroconversion rates, and antibody responses following past infection or a second dose of the BNT162b2 vaccine. Findings 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- compared to vedolizumab-treated patients who received the BNT162b2 (fold change [FC] 0.29 [95% CI 0.21, 0.40], p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 [95% CI 0.30, 0.51], p<0.0001) vaccines. In both models, age > 59 years, immunomodulator use, Crohn's disease, and smoking were associated with lower, whilst 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. Interpretation 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. Funding Royal Devon and Exeter and Hull University Hospital Foundation NHS Trusts. Unrestricted educational grants: F. Hoffmann-La Roche AG (Switzerland), Biogen GmbH (Switzerland), Celltrion Healthcare (South Korea) and Galapagos NV (Belgium). 2 Evidence before this study 3 Faced with further surges of SARS-CoV-2 infection, a growing number of countries, including the UK, 4 have opted to delay second vaccine doses for all people. This strategy trades maximal effectiveness 5 against a lower level of protective immunity across more of the at-risk population. 6 We have previously shown that seroprevalence, seroconversion in PCR-confirmed cases, and the 7 magnitude of anti-SARS-CoV-2 antibodies following SARS-CoV-2 infection are reduced in infliximab-8 compared with vedolizumab-treated patients. Whether single-doses of vaccines are effective in 9 patients treated with anti-TNF therapies is unknown. 10 We searched PubMed from 25 November 2019 to 23 March 2021 with the terms "anti-tumour 11 necrosis factor" or "anti-integrin" or "infliximab" or "adalimumab" or "vedolizumab" or "biological 12 therapy" or "biologic therapy" AND "SARS-CoV-2" or "coronavirus" or "COVID-19" or AND 13 "seroprevalence" or "seroconversion" or "antibody" or "antibody response" or "magnitude" or 14 "immunogenicity" AND "vaccine" or "vaccination" or "immunisation" or "immunization" or 15 "ChAdOx1 nCoV-19" or "BNT162b2" or "mRNA-1273", without restriction on language. 16 Serological responses to SARS-CoV-2 vaccines have been reported in registration trials and small 17 observational cohorts of healthy volunteers. Two small studies, including one unpublished preprint, 18 found that COVID-19 vaccine immunogenicity rates were lower in transplant recipients and patients 19 with malignancy receiving immunosuppressive therapy, and fewer patients treated with potent 20 immunosuppressants seroconverted than healthy controls. No studies have assessed the effect of 21 anti-TNF therapy on immunogenicity following SARS-CoV-2 vaccination. 22 23 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Infliximab and immunomodulators reduce immunogenicity of a single-dose of SARS-CoV-2 vaccines To test if anti-TNF drugs attenuate serological responses to primary SARS-CoV-2 vaccines, we 25 analysed anti-SARS-CoV-2 spike (S) antibody concentrations and seroconversion rates in 1293 26 patients with inflammatory bowel disease who received primary vaccinations with either the 27 ChAdOx1 nCoV-19 or BNT162b2 vaccines. 865 were treated with the anti-TNF drug infliximab and 28 outcomes were compared to a reference cohort of 428 patients treated with vedolizumab, a gut 29 selective anti-integrin α4β7 monoclonal antibody that is not associated with impaired systemic 30 immune responses. 31 Anti-SARS-CoV-2 antibody levels and rates of seroconversion were lower following primary 32 vaccination with both the BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD treated 33 with infliximab compared to vedolizumab. Older age, immunomodulator use, Crohn's disease 34 (versus ulcerative colitis or inflammatory bowel disease unclassified), and current smoking were 35 associated with lower anti-SARS-CoV-2 antibody concentrations, irrespective of vaccine type. Non-36 white ethnicity was associated with higher anti-SARS-CoV-2 (S) antibody concentrations following 37 primary vaccination with both vaccines. Antibody concentrations and seroconversion rates were 38 higher in patients with past SARS-CoV-2 infection prior to a single-dose of either vaccine, and after 2 39 doses of the BNT162b2 vaccine. 40 41 Our findings have important implications for patients treated with anti-TNF therapy, particularly for 42 those also treated with an immunomodulator. Poor antibody responses to a single-dose of vaccine 43 exposes these patients to a potential increased risk of SARS-CoV-2 infection. However, higher rates 44 of seroconversion in patients with two exposures to SARS-CoV-2 antigen, even in the presence of 45 TNF blockade, suggest that all patients receiving these drugs should be prioritized for optimally 46 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. ; https://doi.org/10.1101/2021.03.25.21254335 doi: medRxiv preprint timed second doses. Until patients receive a second vaccine dose, they should consider that they are 47 not protected from SARS-CoV-2 infection and continue to practice enhanced physical distancing and 48 shielding if appropriate. Even after two antigen exposures, a small subset of patients failed to mount 49 an antibody response. Antibody testing and adapted vaccine schedules should be considered to 50 protect these at-risk patients. 51 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Treatment typically requires immunosuppression with immunomodulators (azathioprine, 97 mercaptopurine, and methotrexate) and/or biological therapies that target disease relevant 98 cytokines or the immune cells that produce them. Anti-tumour necrosis factor (TNF) drugs, such as 99 infliximab and adalimumab, are the most frequently prescribed biopharmaceuticals used in the 100 treatment of IMIDs. These drugs impair immunogenicity following pneumococcal, 6 influenza, 7 and 101 hepatitis B 8 vaccinations and increase the risk of serious infection, most notably with respiratory 102 pathogens. 9 Conversely, vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody is not 103 associated with increased susceptibility to systemic infection or attenuated serological responses to 104 vaccination. 10 105 We have recently reported that seroprevalence, seroconversion in PCR-confirmed cases, and the 106 magnitude of anti-SARS-CoV-2 antibodies following SARS-CoV-2 infection are reduced in infliximab-107 compared with vedolizumab-treated patients. 11 We hypothesised that, following at least a single-108 dose with BNT162b2 or ChAdOx1 nCoV-19 vaccine, serological responses would be similarly 109 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint i) The intra-assay and inter-assay coefficient of variation were 1·3% and 5·6%, respectively 162 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. Table 231 1. 232 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. ; Whilst our data are biologically plausible, we acknowledge the following limitations of our study. We 324 have used an electrochemiluminescence immunoassay to measure antibody concentrations rather 325 than using a neutralising assay. Although neutralisation assays are considered more biologically 326 relevant, it is now established that anti receptor-binding domain antibodies, which target the spike 327 protein component that engages host cells through ligation of angiotensin-converting enzyme 2, 328 closely correlate with neutralisation assays. 29,30 Second, we only assessed humoral responses to 329 infection, and it is likely that protective immunity additionally requires induction of memory T cell 330 responses. Finally, we investigated one anti-TNF drug, infliximab, only. However, we suspect that our 331 key findings will apply to other anti-TNF biologics used to treat IMIDs, including adalimumab, 332 certolizumab, golimumab, and etanercept. Further observational data will be required to elucidate 333 the impact of other classes of therapies for IMIDs on SARS-CoV-2 vaccine immunogenicity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. ; is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The study protocol including the statistical analysis plan is available at www.clarityibd.org. Individual 489 participant de-identified data that underlie the results reported in this article will be available 490 immediately after publication for a period of 5 years. The data will be made available to investigators 491 whose proposed use of the data has been approved by an independent review committee. Analyses 492 will be restricted to the aims in the approved proposal. Proposals should be directed to 493 tariq.ahmad1@nhs.net. To gain access data requestors will need to sign a data access agreement. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 28, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Anti-SARS-CoV-2 S U/mL Joint Committee on Vaccination and Immunisation. 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Dr. Lin reports 400 non-financial support from Pfizer, non-financial support from Ferring, outside the submitted work. 401Dr. Goodhand reports grants from F. Hoffmann-La Roche AG, grants from Biogen Inc, grants from 402 Celltrion Healthcare, grants from Galapagos NV, non-financial support from Immundiagnostik, during 403 the conduct of the study. Dr. Chee reports non-financial support from Ferring, personal fees and 404 non-financial support from Pfizer, outside the submitted work. Dr. Cummings reports grants and 405 personal fees from Samsung, Pfizer & Biogen; personal fees and non-financial support from Janssen 406 & Abbvie; grants, personal fees and non-financial support from Takeda; personal fees from MSD, 407Sandoz, Celltrion & NAPP, outside the submitted work. Dr. Irving reports grants and personal fees 408 from Takeda, grants from MSD, grants and personal fees from Pfizer, personal fees from Galapagos, 409