The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study

Timothy Tree

doi:10.1016/S2665-9913(21)00212-5

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study

Timothy Tree

Peter Gorer Department of Immunobiology

Research output: Contribution to journal › Article › peer-review

136 Citations (Scopus)

Abstract

Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. Methods: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. Findings: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. Interpretation: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. Funding: UK National Institute for Health Research.

Original language	English
Pages (from-to)	e627-e637
Journal	The Lancet Rheumatology
Volume	3
Issue number	9
DOIs	https://doi.org/10.1016/S2665-9913(21)00212-5
Publication status	Published - Sept 2021

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10.1016/S2665-9913(21)00212-5

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@article{1efea49934484c7b812d0dfe7251fb5b,

title = "The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study",

abstract = "Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. Methods: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. Findings: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. Interpretation: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. Funding: UK National Institute for Health Research.",

author = "Timothy Tree",

note = "Funding Information: This research was funded by the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. This work was supported by a grant from the Psoriasis Association to CHS; a King's Together Rapid COVID-19 Call award to MHM and KJD; Fondation Dormeur, Vaduz for funding equipment to KJD; a Huo Family Foundation Award to MHM and KJD; a grant from the Chronic Disease Research Foundation (CDRF-22/2020) to MAB, MHM, and KJD; part of the EDCTP2 programme supported by the European Union (RIA2020EF-3008 COVAB); UK Medical Research Council (MRC) through the Genotype-to-Phenotype UK National Virology Consortium (MR/W005611/1) to MHM and KJD; and a grant from Isaac Schapera Research Trust to AR. CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). SKM is funded by an MRC Clinical Academic Research Partnership award (MR/T02383X/1). Funding Information: This research was funded by the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. This work was supported by a grant from the Psoriasis Association to CHS; a King's Together Rapid COVID-19 Call award to MHM and KJD; Fondation Dormeur, Vaduz for funding equipment to KJD; a Huo Family Foundation Award to MHM and KJD; a grant from the Chronic Disease Research Foundation (CDRF-22/2020) to MAB, MHM, and KJD; part of the EDCTP2 programme supported by the European Union (RIA2020EF-3008 COVAB); UK Medical Research Council (MRC) through the Genotype-to-Phenotype UK National Virology Consortium (MR/W005611/1) to MHM and KJD; and a grant from Isaac Schapera Research Trust to AR. CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). SKM is funded by an MRC Clinical Academic Research Partnership award (MR/T02383X/1). Funding Information: CHS reports grants from AbbVie, Sanofi, Novartis, and Pfizer, outside the submitted work. JBG reports personal fees from AbbVie, Sanofi, Novartis, Pfizer, Janssen, and UCB, and grants from Eli Lilly, outside the submitted work. SKM reports departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sanofi, and UCB, outside the submitted work. MAB reports departmental income from Clementia, Eli Lilly, Ipsen, Novartis, Pathios Therapeutics, Regeneron, and UCB, outside the submitted work. JNB reports grants and personal fees from AbbVie, Novartis, Lilly, and J&J, outside the submitted work. SN reports personal fees from Pfizer and Janssen, outside of the submitted work. APC reports grants from Bristol Myers Squibb and Janssen, and speaker bureau and consultancy fees from AbbVie, Bristol Myers Squibb, and UCB. TIMT reports grants from GlaxoSmithKline, Sanofi, and Imcyse, and consultancy fees from GlaxoSmithKline, Novartis, UCB, and Quell Therapeutics, outside the submitted work. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "10.1016/S2665-9913(21)00212-5",

language = "English",

volume = "3",

pages = "e627--e637",

journal = "The Lancet Rheumatology",

issn = "2665-9913",

publisher = "Elsevier",

number = "9",

}

TY - JOUR

T1 - The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study

AU - Tree, Timothy

N1 - Funding Information: This research was funded by the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. This work was supported by a grant from the Psoriasis Association to CHS; a King's Together Rapid COVID-19 Call award to MHM and KJD; Fondation Dormeur, Vaduz for funding equipment to KJD; a Huo Family Foundation Award to MHM and KJD; a grant from the Chronic Disease Research Foundation (CDRF-22/2020) to MAB, MHM, and KJD; part of the EDCTP2 programme supported by the European Union (RIA2020EF-3008 COVAB); UK Medical Research Council (MRC) through the Genotype-to-Phenotype UK National Virology Consortium (MR/W005611/1) to MHM and KJD; and a grant from Isaac Schapera Research Trust to AR. CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). SKM is funded by an MRC Clinical Academic Research Partnership award (MR/T02383X/1). Funding Information: This research was funded by the UK National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the UK National Health Service, the NIHR, or the UK Department of Health. This work was supported by a grant from the Psoriasis Association to CHS; a King's Together Rapid COVID-19 Call award to MHM and KJD; Fondation Dormeur, Vaduz for funding equipment to KJD; a Huo Family Foundation Award to MHM and KJD; a grant from the Chronic Disease Research Foundation (CDRF-22/2020) to MAB, MHM, and KJD; part of the EDCTP2 programme supported by the European Union (RIA2020EF-3008 COVAB); UK Medical Research Council (MRC) through the Genotype-to-Phenotype UK National Virology Consortium (MR/W005611/1) to MHM and KJD; and a grant from Isaac Schapera Research Trust to AR. CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). SKM is funded by an MRC Clinical Academic Research Partnership award (MR/T02383X/1). Funding Information: CHS reports grants from AbbVie, Sanofi, Novartis, and Pfizer, outside the submitted work. JBG reports personal fees from AbbVie, Sanofi, Novartis, Pfizer, Janssen, and UCB, and grants from Eli Lilly, outside the submitted work. SKM reports departmental income from AbbVie, Celgene, Eli Lilly, Janssen-Cilag, Novartis, Sanofi, and UCB, outside the submitted work. MAB reports departmental income from Clementia, Eli Lilly, Ipsen, Novartis, Pathios Therapeutics, Regeneron, and UCB, outside the submitted work. JNB reports grants and personal fees from AbbVie, Novartis, Lilly, and J&J, outside the submitted work. SN reports personal fees from Pfizer and Janssen, outside of the submitted work. APC reports grants from Bristol Myers Squibb and Janssen, and speaker bureau and consultancy fees from AbbVie, Bristol Myers Squibb, and UCB. TIMT reports grants from GlaxoSmithKline, Sanofi, and Imcyse, and consultancy fees from GlaxoSmithKline, Novartis, UCB, and Quell Therapeutics, outside the submitted work. All other authors declare no competing interests. Publisher Copyright: © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. Methods: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. Findings: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. Interpretation: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. Funding: UK National Institute for Health Research.

AB - Background: Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. Methods: In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. Findings: Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. Interpretation: Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. Funding: UK National Institute for Health Research.

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DO - 10.1016/S2665-9913(21)00212-5

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JO - The Lancet Rheumatology

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The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study

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