Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study

Luuk Wieske; Koos P J van Dam; Maurice Steenhuis; Eileen W Stalman; Laura Y L Kummer; Zoé L E van Kempen; Joep Killestein; Adriaan G Volkers; Sander W Tas; Laura Boekel; Gerrit J Wolbink; Anneke J van der Kooi; Joost Raaphorst; Mark Löwenberg; R Bart Takkenberg; Geert R A M D'Haens; Phyllis I Spuls; Marcel W Bekkenk; Annelie H Musters; Nicoline F Post; Angela L Bosma; Marc L Hilhorst; Yosta Vegting; Frederike J Bemelman; Alexandre E Voskuyl; Bo Broens; Agner Parra Sanchez; Cécile A C M van Els; Jelle de Wit; Abraham Rutgers; Karina de Leeuw; Barbara Horváth; Jan J G M Verschuuren; Annabel M Ruiter; Lotte van Ouwerkerk; Diane van der Woude; Renée C F Allaart; Y K Onno Teng; Pieter van Paassen; Matthias H Busch; Papay B P Jallah; Esther Brusse; Pieter A van Doorn; Adája E Baars; Dirk Jan Hijnen; Corine R G Schreurs; W Ludo van der Pol; H Stephan Goedee; Sofie Keijzer; Jim B D Keijser; T2B! immunity against SARS-CoV-2 study group

doi:10.1016/S2665-9913(22)00034-0

Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study

Luuk Wieske^*, Koos P J van Dam, Maurice Steenhuis, Eileen W Stalman, Laura Y L Kummer, Zoé L E van Kempen, Joep Killestein, Adriaan G Volkers, Sander W Tas, Laura Boekel, Gerrit J Wolbink, Anneke J van der Kooi, Joost Raaphorst, Mark Löwenberg, R Bart Takkenberg, Geert R A M D'Haens, Phyllis I Spuls, Marcel W Bekkenk, Annelie H Musters, Nicoline F PostAngela L Bosma, Marc L Hilhorst, Yosta Vegting, Frederike J Bemelman, Alexandre E Voskuyl, Bo Broens, Agner Parra Sanchez, Cécile A C M van Els, Jelle de Wit, Abraham Rutgers, Karina de Leeuw, Barbara Horváth, Jan J G M Verschuuren, Annabel M Ruiter, Lotte van Ouwerkerk, Diane van der Woude, Renée C F Allaart, Y K Onno Teng, Pieter van Paassen, Matthias H Busch, Papay B P Jallah, Esther Brusse, Pieter A van Doorn, Adája E Baars, Dirk Jan Hijnen, Corine R G Schreurs, W Ludo van der Pol, H Stephan Goedee, Sofie Keijzer, Jim B D Keijser, T2B! immunity against SARS-CoV-2 study group

^*Corresponding author for this work

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

Abstract

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.

Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.

Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.

Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.

Funding: ZonMw (The Netherlands Organization for Health Research and Development).

Original language	English
Pages (from-to)	E338-E350
Number of pages	13
Journal	The Lancet Rheumatology
Volume	4
Issue number	5
Early online date	17 Mar 2022
DOIs	https://doi.org/10.1016/S2665-9913(22)00034-0
Publication status	Published - May 2022

Keywords

BNT162B2
DISEASE

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https://europepmc.org/articles/pmc8930018?pdf=renderLicence: Free access - publisher

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Wieske, L., van Dam, K. P. J., Steenhuis, M., Stalman, E. W., Kummer, L. Y. L., van Kempen, Z. L. E., Killestein, J., Volkers, A. G., Tas, S. W., Boekel, L., Wolbink, G. J., van der Kooi, A. J., Raaphorst, J., Löwenberg, M., Takkenberg, R. B., D'Haens, G. R. A. M., Spuls, P. I., Bekkenk, M. W., Musters, A. H., ... T2B! immunity against SARS-CoV-2 study group (2022). Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study. The Lancet Rheumatology, 4(5), E338-E350. https://doi.org/10.1016/S2665-9913(22)00034-0

@article{e2d0450e0209493b9d937c80a39135ed,

title = "Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study",

abstract = "Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.Funding: ZonMw (The Netherlands Organization for Health Research and Development).",

keywords = "BNT162B2, DISEASE",

author = "Luuk Wieske and {van Dam}, {Koos P J} and Maurice Steenhuis and Stalman, {Eileen W} and Kummer, {Laura Y L} and {van Kempen}, {Zo{\'e} L E} and Joep Killestein and Volkers, {Adriaan G} and Tas, {Sander W} and Laura Boekel and Wolbink, {Gerrit J} and {van der Kooi}, {Anneke J} and Joost Raaphorst and Mark L{\"o}wenberg and Takkenberg, {R Bart} and D'Haens, {Geert R A M} and Spuls, {Phyllis I} and Bekkenk, {Marcel W} and Musters, {Annelie H} and Post, {Nicoline F} and Bosma, {Angela L} and Hilhorst, {Marc L} and Yosta Vegting and Bemelman, {Frederike J} and Voskuyl, {Alexandre E} and Bo Broens and Sanchez, {Agner Parra} and {van Els}, {C{\'e}cile A C M} and {de Wit}, Jelle and Abraham Rutgers and {de Leeuw}, Karina and Barbara Horv{\'a}th and Verschuuren, {Jan J G M} and Ruiter, {Annabel M} and {van Ouwerkerk}, Lotte and {van der Woude}, Diane and Allaart, {Ren{\'e}e C F} and Teng, {Y K Onno} and {van Paassen}, Pieter and Busch, {Matthias H} and Jallah, {Papay B P} and Esther Brusse and {van Doorn}, {Pieter A} and Baars, {Ad{\'a}ja E} and Hijnen, {Dirk Jan} and Schreurs, {Corine R G} and {van der Pol}, {W Ludo} and Goedee, {H Stephan} and Sofie Keijzer and Keijser, {Jim B D} and {T2B! immunity against SARS-CoV-2 study group}",

year = "2022",

month = may,

doi = "10.1016/S2665-9913(22)00034-0",

language = "English",

volume = "4",

pages = "E338--E350",

journal = "The Lancet Rheumatology",

issn = "2665-9913",

publisher = "Lancet Publishing Group",

number = "5",

}

Wieske, L, van Dam, KPJ, Steenhuis, M, Stalman, EW, Kummer, LYL, van Kempen, ZLE, Killestein, J, Volkers, AG, Tas, SW, Boekel, L, Wolbink, GJ, van der Kooi, AJ, Raaphorst, J, Löwenberg, M, Takkenberg, RB, D'Haens, GRAM, Spuls, PI, Bekkenk, MW, Musters, AH, Post, NF, Bosma, AL, Hilhorst, ML, Vegting, Y, Bemelman, FJ, Voskuyl, AE, Broens, B, Sanchez, AP, van Els, CACM, de Wit, J, Rutgers, A, de Leeuw, K, Horváth, B, Verschuuren, JJGM, Ruiter, AM, van Ouwerkerk, L, van der Woude, D, Allaart, RCF, Teng, YKO, van Paassen, P, Busch, MH, Jallah, PBP, Brusse, E, van Doorn, PA, Baars, AE, Hijnen, DJ, Schreurs, CRG, van der Pol, WL, Goedee, HS, Keijzer, S, Keijser, JBD & T2B! immunity against SARS-CoV-2 study group 2022, 'Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study', The Lancet Rheumatology, vol. 4, no. 5, pp. E338-E350. https://doi.org/10.1016/S2665-9913(22)00034-0

TY - JOUR

T1 - Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants

T2 - a cohort study

AU - Wieske, Luuk

AU - van Dam, Koos P J

AU - Steenhuis, Maurice

AU - Stalman, Eileen W

AU - Kummer, Laura Y L

AU - van Kempen, Zoé L E

AU - Killestein, Joep

AU - Volkers, Adriaan G

AU - Tas, Sander W

AU - Boekel, Laura

AU - Wolbink, Gerrit J

AU - van der Kooi, Anneke J

AU - Raaphorst, Joost

AU - Löwenberg, Mark

AU - Takkenberg, R Bart

AU - D'Haens, Geert R A M

AU - Spuls, Phyllis I

AU - Bekkenk, Marcel W

AU - Musters, Annelie H

AU - Post, Nicoline F

AU - Bosma, Angela L

AU - Hilhorst, Marc L

AU - Vegting, Yosta

AU - Bemelman, Frederike J

AU - Voskuyl, Alexandre E

AU - Broens, Bo

AU - Sanchez, Agner Parra

AU - van Els, Cécile A C M

AU - de Wit, Jelle

AU - Rutgers, Abraham

AU - de Leeuw, Karina

AU - Horváth, Barbara

AU - Verschuuren, Jan J G M

AU - Ruiter, Annabel M

AU - van Ouwerkerk, Lotte

AU - van der Woude, Diane

AU - Allaart, Renée C F

AU - Teng, Y K Onno

AU - van Paassen, Pieter

AU - Busch, Matthias H

AU - Jallah, Papay B P

AU - Brusse, Esther

AU - van Doorn, Pieter A

AU - Baars, Adája E

AU - Hijnen, Dirk Jan

AU - Schreurs, Corine R G

AU - van der Pol, W Ludo

AU - Goedee, H Stephan

AU - Keijzer, Sofie

AU - Keijser, Jim B D

AU - T2B! immunity against SARS-CoV-2 study group

PY - 2022/5

Y1 - 2022/5

N2 - Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.Funding: ZonMw (The Netherlands Organization for Health Research and Development).

AB - Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders.Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses.Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment.Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited.Funding: ZonMw (The Netherlands Organization for Health Research and Development).

KW - BNT162B2

KW - DISEASE

U2 - 10.1016/S2665-9913(22)00034-0

DO - 10.1016/S2665-9913(22)00034-0

M3 - Article

C2 - 35317410

SN - 2665-9913

VL - 4

SP - E338-E350

JO - The Lancet Rheumatology

JF - The Lancet Rheumatology

IS - 5

ER -

Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study

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Keywords

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