lancet-header

Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.

SARS-CoV-2 Delta Breakthrough Infections in Vaccinated Patients with Immune-Mediated Inflammatory Diseases Using Immunosuppressants – Data from Two Controlled Prospective Cohort Studies

26 Pages Posted: 16 Mar 2022

See all articles by Laura Boekel

Laura Boekel

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre, Location Reade

Eileen Stalman

Amsterdam UMC - Department of Neurology and Neurophysiology

Luuk Wieske

Amsterdam UMC - Department of Neurology and Neurophysiology

Femke Hooijberg

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

P.J. van Dam

Amsterdam UMC - Department of Neurology and Neurophysiology

Yaëlle Besten

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre, Location Reade

Laura Kummer

Amsterdam UMC - Department of Neurology and Neurophysiology

Maurice Steenhuis

Sanquin Research - Department of Immunopathology

Zoé van Kempen

Amsterdam UMC, Vrije Universiteit - Department of Neurology

Joep Killestein

Amsterdam UMC, Vrije Universiteit - Department of Neurology

Adriaan G. Volkers

University of Amsterdam - Department of Gastroenterology and Hepatology

Sander Tas

University of Amsterdam - Department of Rheumatology and Clinical Immunology

Anneke J. van der Kooi

University of Amsterdam - Department of Neurology

Joost Raaphorst

University of Amsterdam - Department of Neurology

Mark Löwenberg

affiliation not provided to SSRN

R. Bart Takkenberg

University of Amsterdam - Department of Gastroenterology and Hepatology

Geert R.A.M. D'Haens

University of Amsterdam - University Medical Center; VU University Amsterdam - Department of Epidemiology & Data Science

Phyllis I. Spuls

University of Amsterdam - Department of Dermatology

Marcel W. Bekkenk

University of Amsterdam - Department of Dermatology

Annelie H. Musters

University of Amsterdam - Department of Dermatology

Nicoline F. Post

University of Amsterdam - Department of Dermatology

Angela L. Bosma

University of Amsterdam - Department of Dermatology

Marc L. Hilhorst

University of Amsterdam - Department of Internal Medicine

Yosta Vegting

University of Amsterdam - Department of Internal Medicine

Frederike J. Bemelman

University of Amsterdam - Department of Internal Medicine

Alexandre Voskuyl

VU University Medical Center - Amsterdam Rheumatology and Immunology Center

Bo Broens

University of Amsterdam - Department of Clinical Immunology and Rheumatology

Agner Parra Sanchez

University of Amsterdam - Department of Clinical Immunology and Rheumatology

Cecile van Els

National Institute for Public Health and the Environment (RIVM) - Centre for Infectious Disease Control

Jelle de Wit

National Institute for Public Health and the Environment (RIVM) - Centre for Infectious Disease Control

Abraham Rutgers

University of Groningen - University Medical Center Groningen (UMCG)

Karina de Leeuw

University of Groningen - Department of Rheumatology and Clinical Immunology

Barbara Horváth

University of Groningen - Department of Dermatology

Jan J.G.M. Verschuuren

Leiden University - Department of Neurology

Annabel M. Ruiter

Leiden University - Department of Neurology

Lotte van Ouwerkerk

Leiden University - Department of Rheumatology

Diane van der Woude

Leiden University - Department of Rheumatology

Cornelia F. Allaart

Leiden University - Department of Rheumatology

Onno YK Teng

Leiden University - Department of Nephrology

Pieter van Paassen

Maastricht University - Division of Nephrology and Clinical Immunology

Matthias Busch

Department of Immunology, Maastricht UMC+

Papay B.P. Jallah

affiliation not provided to SSRN

Esther Brusse

Erasmus University Rotterdam (EUR) - Department of Neurology

Pieter van Doorn

Erasmus University Rotterdam (EUR) - Department of Neurology

Adája E. Baars

Erasmus University Rotterdam (EUR) - Department of Neurology

Dirk Jan Hijnen

Erasmus University Rotterdam (EUR) - Department of Dermatology

Corine R.G. Schreurs

Erasmus University Rotterdam (EUR) - Department of Dermatology

Ludo van der Pol

Utrecht University - Brain Center Rudolf Magnus

H. Stephan Goedee

Utrecht University - University Medical Center (Utrecht)

Erik Vogelzang

University of Amsterdam - Department of Medical Microbiology and Infection Control

Maureen Leeuw

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Sadaf Atiqi

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Ronald van Vollenhoven

University of Amsterdam - Department of Rheumatology and Clinical Immunology

Martijn Gerritsen

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Irene E. van der Horst-Bruinsma

affiliation not provided to SSRN

Willem F. Lems

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Michael Nurmohamed

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Maarten Boers

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Sofie Keijzer

Sanquin Research - Department of Immunopathology

Jim Keijser

Sanquin Research - Department of Immunopathology

Arend Boogaard

Sanquin Research

Olvi Cristianawati

Sanquin Research - Department of Immunopathology

Anja ten Brinke

Sanquin Research

Niels Verstegen

Sanquin Research

Aeilko H. Zwinderman

University of Amsterdam - University Medical Center

Marieke van Ham

Sanquin Research - Department of Immunopathology

Theo Rispens

Sanquin Research - Department of Immunopathology

Taco Kuijpers

University of Amsterdam - Department of Pediatric Immunology, Rheumatology and Infectious Disease

Gertjan Wolbink

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Filip Eftimov

Amsterdam UMC - Department of Neurology and Neurophysiology

More...

Abstract

Background: The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between vaccinated patients with immune-mediated inflammatory diseases (IMIDs) using immunosuppressants, and controls (IMID patients without immunosuppressants and healthy controls). The secondary objective was to explore determinants of breakthrough infections, including humoral immune responses after vaccination.

Methods: In this study we pooled data collected in two large ongoing prospective multi-center cohort studies (Target to-B! [T2B!] study and Amsterdam Rheumatology Center [ARC] study). Clinical data were collected from standardized electronic case record forms, digital questionnaires and medical files. Data were collected before the omicron variant of SARS-CoV-2 became dominant in the Netherlands (February-December 2021). A SARS-CoV-2 breakthrough infection with the SARS-CoV-2 delta variant was defined as a PCR or antigen confirmed SARS-CoV-2infection that occurred at least 14 days after vaccination, and was detected between July 1 and December 14, 2021. Post-vaccination serum samples were analyzed for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC study only). Multivariable logistic regression analyses were used to explore potential clinical and humoral determinants associated with the incidence of breakthrough infections.

Results: We included 3207 IMID patients with immunosuppressants and simultaneously enrolled 1807 controls (985 IMID patients without immunosuppressants and 822 healthy controls). The incidence of PCR/antigen test confirmed SARS-CoV-2 breakthrough infections was similar in patients with immunosuppressants (148/3207; 4.6%, 95% CI: 3.9 – 5.4) and controls (86/1807; 4.7%, 95% CI: 3.8 – 5.8). In the ARC-COVID cohort, the proportion of asymptomatic COVID-19 cases identified serologically was also similar (55/628; 8.8% vs 56/571; 9.8%). Seroconversion after vaccination and SARS-CoV-2 infection prior to vaccination were associated with a lower incidence of breakthrough infections. Hospitalization was required in 8 (5.4%, 95% CI: 2.4 – 10.3) of 148 IMID patients with immunosuppressants and 5 (5.8%, 95% CI: 1.9 – 13.0) of 86 controls with a SARS-CoV-2 breakthrough infection. Hospitalized COVID-19 breakthrough cases were older, and had more comorbidities compared with non-hospitalized cases. Hospitalization rates were higher in IMID patients treated with anti-CD20 therapy (3 [19%] of 16 patients) compared to IMID patients using other immunosuppressants (5 [4%] of 132 patients; P 0.04).

Conclusion: The incidence of SARS-CoV-2 breakthrough infections in IMID patients with immunosuppressants was similar to controls. SARS-CoV-2 infection prior to vaccination and the presence of a humoral response after SARS-CoV-2 vaccination were associated with fewer breakthrough infections. Breakthrough infections were mostly mild and severe disease was primarily seen in people with traditional risk factors and those on anti-CD20 therapy.

Funding Information: The T2B study was supported by ZonMw (the Netherlands Organization for Health Research and Development; project number 10430012010009). The ARC-was supported by ZonMw (project number: 10430022010020) and Reade foundation.

Declaration of Interests: None to declare.

Ethics Approval Statement: The research protocol of this study was approved by the medical ethical committee of the Amsterdam UMC (T2B-COVID study: 2020.194). All participants provided written informed consent.

Keywords: Breakthrough infectionsCOVID-19SARS-CoV-2Immune mediated inflammatory diseasesAnti-CD20 therapyImmunosuppressantsEpidemiologyIncidenceDisease severityHumoral immunity

Suggested Citation

Boekel, Laura and Stalman, Eileen and Wieske, Luuk and Hooijberg, Femke and van Dam, Koos and Besten, Yaëlle and Kummer, Laura and Steenhuis, Maurice and van Kempen, Zoé and Killestein, Joep and Volkers, Adriaan G. and Tas, Sander and van der Kooi, Anneke J. and Raaphorst, Joost and Löwenberg, Mark 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 Vegting, Yosta and Bemelman, Frederike J. and Voskuyl, Alexandre and Broens, Bo and Sanchez, Agner Parra and van Els, Cecile and de Wit, Jelle and Rutgers, Abraham and de Leeuw, Karina and Horváth, Barbara and Verschuuren, Jan J.G.M. and Ruiter, Annabel M. and van Ouwerkerk, Lotte and van der Woude, Diane and Allaart, Cornelia F. and Teng, Onno YK and van Paassen, Pieter and Busch, Matthias and Jallah, Papay B.P. and Brusse, Esther and van Doorn, Pieter and Baars, Adája E. and Hijnen, Dirk Jan and Schreurs, Corine R.G. and van der Pol, Ludo and Goedee, H. Stephan and Vogelzang, Erik and Leeuw, Maureen and Atiqi, Sadaf and van Vollenhoven, Ronald and Gerritsen, Martijn and van der Horst-Bruinsma, Irene E. and Lems, Willem F. and Nurmohamed, Michael and Boers, Maarten and Keijzer, Sofie and Keijser, Jim and Boogaard, Arend and Cristianawati, Olvi and ten Brinke, Anja and Verstegen, Niels and Zwinderman, Aeilko H. and van Ham, Marieke and Rispens, Theo and Kuijpers, Taco and Wolbink, Gertjan and Eftimov, Filip, SARS-CoV-2 Delta Breakthrough Infections in Vaccinated Patients with Immune-Mediated Inflammatory Diseases Using Immunosuppressants – Data from Two Controlled Prospective Cohort Studies. Available at SSRN: https://ssrn.com/abstract=4035408 or http://dx.doi.org/10.2139/ssrn.4035408

Laura Boekel (Contact Author)

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre, Location Reade ( email )

Amsterdam
Netherlands

Eileen Stalman

Amsterdam UMC - Department of Neurology and Neurophysiology ( email )

Netherlands

Luuk Wieske

Amsterdam UMC - Department of Neurology and Neurophysiology ( email )

Spui 21
Amsterdam, 1018 WB
Netherlands

Femke Hooijberg

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Koos Van Dam

Amsterdam UMC - Department of Neurology and Neurophysiology ( email )

Meibergdreef 9
Amsterdam, Noord Holland 1105
Netherlands

Yaëlle Besten

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre, Location Reade ( email )

Amsterdam
Netherlands

Laura Kummer

Amsterdam UMC - Department of Neurology and Neurophysiology ( email )

Netherlands

Maurice Steenhuis

Sanquin Research - Department of Immunopathology

Amsterdam
Netherlands

Zoé Van Kempen

Amsterdam UMC, Vrije Universiteit - Department of Neurology ( email )

Spui 21
Amsterdam, 1018 WB
Netherlands

Joep Killestein

Amsterdam UMC, Vrije Universiteit - Department of Neurology ( email )

Meibergdreef 9
Amsterdam, Noord Holland 1105
Netherlands

Adriaan G. Volkers

University of Amsterdam - Department of Gastroenterology and Hepatology ( email )

Sander Tas

University of Amsterdam - Department of Rheumatology and Clinical Immunology ( email )

Amsterdam
Netherlands

Anneke J. Van der Kooi

University of Amsterdam - Department of Neurology ( email )

Joost Raaphorst

University of Amsterdam - Department of Neurology ( email )

Mark Löwenberg

affiliation not provided to SSRN ( email )

No Address Available

R. Bart Takkenberg

University of Amsterdam - Department of Gastroenterology and Hepatology ( email )

Geert R.A.M. D'Haens

University of Amsterdam - University Medical Center ( email )

VU University Amsterdam - Department of Epidemiology & Data Science ( email )

Phyllis I. Spuls

University of Amsterdam - Department of Dermatology ( email )

Marcel W. Bekkenk

University of Amsterdam - Department of Dermatology ( email )

Annelie H. Musters

University of Amsterdam - Department of Dermatology ( email )

Nicoline F. Post

University of Amsterdam - Department of Dermatology ( email )

Angela L. Bosma

University of Amsterdam - Department of Dermatology ( email )

Marc L. Hilhorst

University of Amsterdam - Department of Internal Medicine ( email )

Yosta Vegting

University of Amsterdam - Department of Internal Medicine ( email )

Frederike J. Bemelman

University of Amsterdam - Department of Internal Medicine ( email )

Alexandre Voskuyl

VU University Medical Center - Amsterdam Rheumatology and Immunology Center ( email )

Bo Broens

University of Amsterdam - Department of Clinical Immunology and Rheumatology ( email )

Agner Parra Sanchez

University of Amsterdam - Department of Clinical Immunology and Rheumatology ( email )

Cecile Van Els

National Institute for Public Health and the Environment (RIVM) - Centre for Infectious Disease Control

Jelle De Wit

National Institute for Public Health and the Environment (RIVM) - Centre for Infectious Disease Control ( email )

Abraham Rutgers

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Karina De Leeuw

University of Groningen - Department of Rheumatology and Clinical Immunology ( email )

Groningen
Netherlands

Barbara Horváth

University of Groningen - Department of Dermatology ( email )

Jan J.G.M. Verschuuren

Leiden University - Department of Neurology ( email )

Annabel M. Ruiter

Leiden University - Department of Neurology ( email )

Lotte Van Ouwerkerk

Leiden University - Department of Rheumatology ( email )

Leiden, 2333 ZA
Netherlands

Diane Van der Woude

Leiden University - Department of Rheumatology ( email )

Cornelia F. Allaart

Leiden University - Department of Rheumatology ( email )

Leiden, 2333 ZA
Netherlands

Onno YK Teng

Leiden University - Department of Nephrology ( email )

Pieter Van Paassen

Maastricht University - Division of Nephrology and Clinical Immunology ( email )

Netherlands

Matthias Busch

Department of Immunology, Maastricht UMC+ ( email )

Papay B.P. Jallah

affiliation not provided to SSRN ( email )

No Address Available

Esther Brusse

Erasmus University Rotterdam (EUR) - Department of Neurology ( email )

Pieter Van Doorn

Erasmus University Rotterdam (EUR) - Department of Neurology

Adája E. Baars

Erasmus University Rotterdam (EUR) - Department of Neurology ( email )

Dirk Jan Hijnen

Erasmus University Rotterdam (EUR) - Department of Dermatology ( email )

Corine R.G. Schreurs

Erasmus University Rotterdam (EUR) - Department of Dermatology ( email )

Ludo Van der Pol

Utrecht University - Brain Center Rudolf Magnus ( email )

Utrecht
Netherlands

H. Stephan Goedee

Utrecht University - University Medical Center (Utrecht) ( email )

Erik Vogelzang

University of Amsterdam - Department of Medical Microbiology and Infection Control ( email )

Amsterdam
Netherlands

Maureen Leeuw

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Sadaf Atiqi

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Ronald Van Vollenhoven

University of Amsterdam - Department of Rheumatology and Clinical Immunology ( email )

Amsterdam
Netherlands

Martijn Gerritsen

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Irene E. Van der Horst-Bruinsma

affiliation not provided to SSRN ( email )

No Address Available

Willem F. Lems

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Michael Nurmohamed

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Maarten Boers

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre

Amsterdam
Netherlands

Sofie Keijzer

Sanquin Research - Department of Immunopathology

Amsterdam
Netherlands

Jim Keijser

Sanquin Research - Department of Immunopathology ( email )

Netherlands

Arend Boogaard

Sanquin Research ( email )

Amsterdam
Netherlands

Olvi Cristianawati

Sanquin Research - Department of Immunopathology ( email )

Netherlands

Anja Ten Brinke

Sanquin Research ( email )

Amsterdam
Netherlands

Niels Verstegen

Sanquin Research ( email )

Aeilko H. Zwinderman

University of Amsterdam - University Medical Center ( email )

Marieke Van Ham

Sanquin Research - Department of Immunopathology

Amsterdam
Netherlands

Theo Rispens

Sanquin Research - Department of Immunopathology

Amsterdam
Netherlands

Taco Kuijpers

University of Amsterdam - Department of Pediatric Immunology, Rheumatology and Infectious Disease ( email )

Gertjan Wolbink

University of Amsterdam - Amsterdam Rheumatology and Immunology Centre ( email )

Amsterdam
Netherlands

Filip Eftimov

Amsterdam UMC - Department of Neurology and Neurophysiology ( email )

Spui 21
Amsterdam, 1018 WB
Netherlands