Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau

Mike Leonardus Theodorus Berendsen; Pauli Bles; Louise Charlotte Johanna de Bree; Kristoffer Jarlov Jensen; Clara Clipet Jensen; Christian Wejse; Delfim Vicente Mendes; Mihai Gheorghe Netea; Christine Stabell Benn

doi:10.1016/j.vaccine.2024.126439

Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau

Mike Leonardus Theodorus Berendsen^*, Pauli Bles, Louise Charlotte Johanna de Bree, Kristoffer Jarlov Jensen, Clara Clipet Jensen, Christian Wejse, Delfim Vicente Mendes, Mihai Gheorghe Netea, Christine Stabell Benn

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Background: The beneficial effects of Bacillus Calmette-Guérin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries. Methods: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327). Findings: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53–9·96]) and increased release of the pro-inflammatory innate cytokines IL-1β, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98–2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline. Interpretation: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.

Original language	English
Article number	126439
Journal	Vaccine
Volume	42
Issue	26
Number of pages	8
ISSN	0264-410X
DOIs	https://doi.org/10.1016/j.vaccine.2024.126439
Publication status	Published - 2 Dec 2024

Keywords

Bacillus Calmette-Guérin
Boosting
Immunosenescence
Non-specific effects
Older adults
Trained immunity

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10.1016/j.vaccine.2024.126439

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Berendsen, M. L. T., Bles, P., de Bree, L. C. J., Jensen, K. J., Jensen, C. C., Wejse, C., Mendes, D. V., Netea, M. G., & Benn, C. S. (2024). Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau. Vaccine, 42(26), Article 126439. https://doi.org/10.1016/j.vaccine.2024.126439

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title = "Bacillus Calmette-Gu{\'e}rin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau",

abstract = "Background: The beneficial effects of Bacillus Calmette-Gu{\'e}rin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries. Methods: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327). Findings: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53–9·96]) and increased release of the pro-inflammatory innate cytokines IL-1β, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98–2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline. Interpretation: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.",

keywords = "Bacillus Calmette-Gu{\'e}rin, Boosting, Immunosenescence, Non-specific effects, Older adults, Trained immunity",

author = "Berendsen, {Mike Leonardus Theodorus} and Pauli Bles and {de Bree}, {Louise Charlotte Johanna} and Jensen, {Kristoffer Jarlov} and Jensen, {Clara Clipet} and Christian Wejse and Mendes, {Delfim Vicente} and Netea, {Mihai Gheorghe} and Benn, {Christine Stabell}",

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doi = "10.1016/j.vaccine.2024.126439",

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Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau. / Berendsen, Mike Leonardus Theodorus; Bles, Pauli; de Bree, Louise Charlotte Johanna et al.
In: Vaccine, Vol. 42, No. 26, 126439, 02.12.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age

T2 - A randomized trial in Guinea-Bissau

AU - Berendsen, Mike Leonardus Theodorus

AU - Bles, Pauli

AU - de Bree, Louise Charlotte Johanna

AU - Jensen, Kristoffer Jarlov

AU - Jensen, Clara Clipet

AU - Wejse, Christian

AU - Mendes, Delfim Vicente

AU - Netea, Mihai Gheorghe

AU - Benn, Christine Stabell

PY - 2024/12/2

Y1 - 2024/12/2

N2 - Background: The beneficial effects of Bacillus Calmette-Guérin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries. Methods: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327). Findings: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53–9·96]) and increased release of the pro-inflammatory innate cytokines IL-1β, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98–2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline. Interpretation: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.

AB - Background: The beneficial effects of Bacillus Calmette-Guérin (BCG) as an intervention against non-mycobacterial infections have been extensively studied in randomized trials. These non-specific effects have been linked to a heterologous increase of pro-inflammatory cytokine production by innate immune cells. It is unknown if BCG induces such responses in older individuals from TB-endemic countries. Methods: In a single-blinded trial in Guinea-Bissau, 40 adults over 50 years of age were randomized 1:1 in a block of 40 to intradermal injection of BCG-Japan (intervention) or solvent (placebo). Production of interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was measured by ELISA in supernatant of peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis and heterologous pathogens. The trial was registered at clinicaltrials.gov (NCT02953327). Findings: Between January 25 and March 7, 2017, 40 individuals were randomized. Two months after vaccination, BCG-Japan recipients (n = 11) had higher production of IFN-γ to M. tuberculosis stimulation (Geometric mean ratio (GMR): 3·91 [95 % Confidence Interval (CI), 1·53–9·96]) and increased release of the pro-inflammatory innate cytokines IL-1β, IL-6 and TNF-α to non-specific stimuli (GMR TNF-α: 1·47 [95 % CI, 0·98–2·19]) than their controls (n = 13). Both the specific and non-specific responses were more pronounced among those with a positive QuantiFERON at baseline. Interpretation: BCG-Japan can induce a trained immunity phenotype in older adults. These effects were particularly strong in previously M. tuberculosis exposed individuals. Future randomized trials are needed to determine BCG's potential to protect the older populations from infections-driven morbidity and mortality.

KW - Bacillus Calmette-Guérin

KW - Boosting

KW - Immunosenescence

KW - Non-specific effects

KW - Older adults

KW - Trained immunity

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DO - 10.1016/j.vaccine.2024.126439

M3 - Journal article

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AN - SCOPUS:85206338306

SN - 0264-410X

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JO - Vaccine

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ER -

Bacillus Calmette-Guérin vaccination induces a trained innate immunity phenotype in adults over 50 years of age: A randomized trial in Guinea-Bissau

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Keywords

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