Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial

Eva L. Koekenbier; Konstantin Fohse; BCG-PRIME study group; Josephine S. van de Maat; Jan Jelrik Oosterheert; Cees van Nieuwkoop; Jacobien J. Hoogerwerf; Martin P. Grobusch; Maurice A.A.J. van den Bosch; Janneke H.H. van de Wijgert; Mihai G. Netea; Frits R. Rosendaal; Marc J.M. Bonten; C. H.(Henri) van Werkhoven

doi:10.1016/j.cmi.2023.01.019

Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial

Eva L. Koekenbier^*
, Konstantin Fohse
, BCG-PRIME study group
, Josephine S. van de Maat
, Jan Jelrik Oosterheert
, Cees van Nieuwkoop
, Jacobien J. Hoogerwerf
, Martin P. Grobusch
, Maurice A.A.J. van den Bosch
, Janneke H.H. van de Wijgert
, Mihai G. Netea
, Frits R. Rosendaal
, Marc J.M. Bonten
, C. H.(Henri) van Werkhoven

^*Corresponding author for this work

Utrecht University
Radboud University Medical Center
Haga Ziekenhuis
University of Amsterdam
Amsterdam UMC
Onze Lieve Vrouwe Gasthuis
University of Bonn
Leiden University Medical Centre
Noordwest Ziekenhuis
Catharina Hospital
Medisch Spectrum Twente
Canisius Wilhelmina Hospital
Meander Medical Center
VU University Medical Center
Santeon
Martini Ziekenhuis
University Medical Centre Groningen
Maastricht University
St. Antonius Ziekenhuis
Rijnstate Hospital
Ikazia Hospital

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

36 Citations (Scopus)

94 Downloads (Pure)

Abstract

Objectives: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. Methods: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. Results: A total of 6112 participants with a median age of 69 years (interquartile range, 65–74) and median of 2 (interquartile range, 1–3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87–1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46–1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35–1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66–1.28). Discussion: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs.

Original language	English
Pages (from-to)	781-788
Number of pages	8
Journal	Clinical Microbiology and Infection
Volume	29
Issue number	6
DOIs	https://doi.org/10.1016/j.cmi.2023.01.019
Publication status	Published - Jun 2023

Bibliographical note

Funding Information:
E.L.K. is the lead and corresponding author. J.S.v.d.M., C.v.N., J.J.H., M.A.A.J.v.d.B., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. conceptualized the study. J.S.v.d.M., J.J.O., J.J.H., J.H.H.v.d.W., F.R.R., M.J.M.B., and C.H.v.W. developed methodology. J.S.v.d.M. was responsible for the software. C.H.v.W. performed the formal analysis. E.L.K., K.F., J.S.v.d.M., J.J.O., J.J.H., M.P.G., and C.H.v.W. performed the investigation. J.J.O., C.v.N., M.A.A.J.v.d.B., M.J.M.B., and C.H.v.W. were responsible for the resources. E.L.K., K.F., and C.H.v.W. were responsible for data curation. E.L.K., M.J.M.B., and C.H.v.W. wrote the original draft of the manuscript. E.L.K., K.F., J.S.v.d.M., C.v.N., M.P.G., J.H.H.v.d.W., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. reviewed and edited the manuscript. E.L.K. and C.H.v.W. were responsible for visualization. J.S.v.d.M., J.J.O., M.P.G., M.A.A.J.v.d.B., J.H.H.v.d.W., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. were responsible for supervision. E.L.K., K.F., J.S.v.d.M., J.J.H., F.R.R., and C.H.v.W. were responsible for project administration. J.J.H., J.H.H.v.d.W., M.A.A.J.v.d.B., F.R.R., M.G.N., M.J.M.B., and C.H.v.W. were responsible for funding acquisition.

Publisher Copyright:
© 2023 The Author(s)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbiditiesFinal published version, 886 KBLicence: CC BY

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Koekenbier, E. L., Fohse, K., BCG-PRIME study group, van de Maat, J. S., Oosterheert, J. J., van Nieuwkoop, C., Hoogerwerf, J. J., Grobusch, M. P., van den Bosch, M. A. A. J., van de Wijgert, J. H. H., Netea, M. G., Rosendaal, F. R., Bonten, M. J. M., & Werkhoven, C. H. V. (2023). Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial. Clinical Microbiology and Infection, 29(6), 781-788. https://doi.org/10.1016/j.cmi.2023.01.019

@article{b79a06489cad4b8e96eb0ae8421fec80,

title = "Bacillus Calmette-Gu{\'e}rin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial",

abstract = "Objectives: To test whether Bacillus Calmette-Gu{\'e}rin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. Methods: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. Results: A total of 6112 participants with a median age of 69 years (interquartile range, 65{\textendash}74) and median of 2 (interquartile range, 1{\textendash}3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95\% CI, 0.87{\textendash}1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95\% CI, 0.46{\textendash}1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95\% CI, 0.35{\textendash}1.43), of which 11 deaths (35\%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95\% CI, 0.66{\textendash}1.28). Discussion: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs.",

author = "Koekenbier, \{Eva L.\} and Konstantin Fohse and \{BCG-PRIME study group\} and \{van de Maat\}, \{Josephine S.\} and Oosterheert, \{Jan Jelrik\} and \{van Nieuwkoop\}, Cees and Hoogerwerf, \{Jacobien J.\} and Grobusch, \{Martin P.\} and \{van den Bosch\}, \{Maurice A.A.J.\} and \{van de Wijgert\}, \{Janneke H.H.\} and Netea, \{Mihai G.\} and Rosendaal, \{Frits R.\} and Bonten, \{Marc J.M.\} and Werkhoven, \{C. H.(Henri) van\} and \{Aardenburg-van Huisstede\}, Astrid and Ammerlaan, \{Heidi S.M.\} and Boersma, \{Willem G.\} and Kees Brinkman and Bruijning-Verhagen, \{Patricia C.J.\} and \{van Crevel\}, Reinout and Corine Delsing and \{ten Doesschaten\}, Thijs and Dofferhoff, \{Anton S.M.\} and Ruud Duijkers and Groenwold, \{Rolf H.H.\} and \{de Haas\}, Corine and Hassing, \{Robert Jan\} and \{de Hoog\}, \{Marieke L.A.\} and Huijts, \{Susanne M.\} and \{van Hylckama-Vlieg\}, Astrid and Eefje Jong and \{de Jong\}, \{Hanna K.\} and Martijn Knap and Michael Koenders and Kouijzer, \{Ilse J.E.\} and Henk Kramer and \{van de Laar\}, Roel and Arief Lalmohamed and Lensen, \{Karel Jan D.F.\} and Lijfering, \{Willem M.\} and Fabienne Magdelijns and Bob Meek and Middelburg, \{Rutger A.\} and Moeniralam, \{Hazra S.\} and Mooijaart, \{Simon P.\} and \{van Munster\}, \{Barbara C.\} and \{ten Oever\}, Jaap and Goossens, \{Marc Padros\} and Vincent Peters and Postma, \{Douwe F.\} and Annelies Verbon",

note = "Funding Information: E.L.K. is the lead and corresponding author. J.S.v.d.M., C.v.N., J.J.H., M.A.A.J.v.d.B., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. conceptualized the study. J.S.v.d.M., J.J.O., J.J.H., J.H.H.v.d.W., F.R.R., M.J.M.B., and C.H.v.W. developed methodology. J.S.v.d.M. was responsible for the software. C.H.v.W. performed the formal analysis. E.L.K., K.F., J.S.v.d.M., J.J.O., J.J.H., M.P.G., and C.H.v.W. performed the investigation. J.J.O., C.v.N., M.A.A.J.v.d.B., M.J.M.B., and C.H.v.W. were responsible for the resources. E.L.K., K.F., and C.H.v.W. were responsible for data curation. E.L.K., M.J.M.B., and C.H.v.W. wrote the original draft of the manuscript. E.L.K., K.F., J.S.v.d.M., C.v.N., M.P.G., J.H.H.v.d.W., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. reviewed and edited the manuscript. E.L.K. and C.H.v.W. were responsible for visualization. J.S.v.d.M., J.J.O., M.P.G., M.A.A.J.v.d.B., J.H.H.v.d.W., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. were responsible for supervision. E.L.K., K.F., J.S.v.d.M., J.J.H., F.R.R., and C.H.v.W. were responsible for project administration. J.J.H., J.H.H.v.d.W., M.A.A.J.v.d.B., F.R.R., M.G.N., M.J.M.B., and C.H.v.W. were responsible for funding acquisition. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jun,

doi = "10.1016/j.cmi.2023.01.019",

language = "English",

volume = "29",

pages = "781--788",

journal = "Clinical Microbiology and Infection",

issn = "1198-743X",

publisher = "Elsevier",

number = "6",

}

Koekenbier, EL, Fohse, K, BCG-PRIME study group, van de Maat, JS, Oosterheert, JJ, van Nieuwkoop, C, Hoogerwerf, JJ, Grobusch, MP, van den Bosch, MAAJ, van de Wijgert, JHH, Netea, MG, Rosendaal, FR, Bonten, MJM & Werkhoven, CHV 2023, 'Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial', Clinical Microbiology and Infection, vol. 29, no. 6, pp. 781-788. https://doi.org/10.1016/j.cmi.2023.01.019

Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial. / Koekenbier, Eva L.; Fohse, Konstantin; BCG-PRIME study group et al.
In: Clinical Microbiology and Infection, Vol. 29, No. 6, 06.2023, p. 781-788.

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

TY - JOUR

T1 - Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities

T2 - a randomized controlled trial

AU - Koekenbier, Eva L.

AU - Fohse, Konstantin

AU - BCG-PRIME study group

AU - van de Maat, Josephine S.

AU - Oosterheert, Jan Jelrik

AU - van Nieuwkoop, Cees

AU - Hoogerwerf, Jacobien J.

AU - Grobusch, Martin P.

AU - van den Bosch, Maurice A.A.J.

AU - van de Wijgert, Janneke H.H.

AU - Netea, Mihai G.

AU - Rosendaal, Frits R.

AU - Bonten, Marc J.M.

AU - Werkhoven, C. H.(Henri) van

AU - Aardenburg-van Huisstede, Astrid

AU - Ammerlaan, Heidi S.M.

AU - Boersma, Willem G.

AU - Brinkman, Kees

AU - Bruijning-Verhagen, Patricia C.J.

AU - van Crevel, Reinout

AU - Delsing, Corine

AU - ten Doesschaten, Thijs

AU - Dofferhoff, Anton S.M.

AU - Duijkers, Ruud

AU - Groenwold, Rolf H.H.

AU - de Haas, Corine

AU - Hassing, Robert Jan

AU - de Hoog, Marieke L.A.

AU - Huijts, Susanne M.

AU - van Hylckama-Vlieg, Astrid

AU - Jong, Eefje

AU - de Jong, Hanna K.

AU - Knap, Martijn

AU - Koenders, Michael

AU - Kouijzer, Ilse J.E.

AU - Kramer, Henk

AU - van de Laar, Roel

AU - Lalmohamed, Arief

AU - Lensen, Karel Jan D.F.

AU - Lijfering, Willem M.

AU - Magdelijns, Fabienne

AU - Meek, Bob

AU - Middelburg, Rutger A.

AU - Moeniralam, Hazra S.

AU - Mooijaart, Simon P.

AU - van Munster, Barbara C.

AU - ten Oever, Jaap

AU - Goossens, Marc Padros

AU - Peters, Vincent

AU - Postma, Douwe F.

AU - Verbon, Annelies

N1 - Funding Information: E.L.K. is the lead and corresponding author. J.S.v.d.M., C.v.N., J.J.H., M.A.A.J.v.d.B., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. conceptualized the study. J.S.v.d.M., J.J.O., J.J.H., J.H.H.v.d.W., F.R.R., M.J.M.B., and C.H.v.W. developed methodology. J.S.v.d.M. was responsible for the software. C.H.v.W. performed the formal analysis. E.L.K., K.F., J.S.v.d.M., J.J.O., J.J.H., M.P.G., and C.H.v.W. performed the investigation. J.J.O., C.v.N., M.A.A.J.v.d.B., M.J.M.B., and C.H.v.W. were responsible for the resources. E.L.K., K.F., and C.H.v.W. were responsible for data curation. E.L.K., M.J.M.B., and C.H.v.W. wrote the original draft of the manuscript. E.L.K., K.F., J.S.v.d.M., C.v.N., M.P.G., J.H.H.v.d.W., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. reviewed and edited the manuscript. E.L.K. and C.H.v.W. were responsible for visualization. J.S.v.d.M., J.J.O., M.P.G., M.A.A.J.v.d.B., J.H.H.v.d.W., M.G.N., F.R.R., M.J.M.B., and C.H.v.W. were responsible for supervision. E.L.K., K.F., J.S.v.d.M., J.J.H., F.R.R., and C.H.v.W. were responsible for project administration. J.J.H., J.H.H.v.d.W., M.A.A.J.v.d.B., F.R.R., M.G.N., M.J.M.B., and C.H.v.W. were responsible for funding acquisition. Publisher Copyright: © 2023 The Author(s)

PY - 2023/6

Y1 - 2023/6

N2 - Objectives: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. Methods: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. Results: A total of 6112 participants with a median age of 69 years (interquartile range, 65–74) and median of 2 (interquartile range, 1–3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87–1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46–1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35–1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66–1.28). Discussion: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs.

AB - Objectives: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. Methods: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. Results: A total of 6112 participants with a median age of 69 years (interquartile range, 65–74) and median of 2 (interquartile range, 1–3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87–1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46–1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35–1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66–1.28). Discussion: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs.

UR - https://www.scopus.com/pages/publications/85150018682

U2 - 10.1016/j.cmi.2023.01.019

DO - 10.1016/j.cmi.2023.01.019

M3 - Article

C2 - 36736662

AN - SCOPUS:85150018682

SN - 1198-743X

VL - 29

SP - 781

EP - 788

JO - Clinical Microbiology and Infection

JF - Clinical Microbiology and Infection

IS - 6

ER -

Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial

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Bibliographical note

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