Seasonal Variation in BCG-Induced Trained Immunity

35 Pages Posted: 14 Mar 2024

See all articles by Gizem Kilic

Gizem Kilic

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Priya A. Debisarun

Radboud University Nijmegen - Radboud University Medical Center

Ahmed Alaswad

Helmholtz Centre for Infection Research

Marijke P. Baltissen

Radboud University Nijmegen

Lieke A. Lamers

Radboud University Nijmegen

Charlotte J. de Bree

Radboud University Nijmegen - Radboud University Medical Center

Christine Stabell Benn

University of Southern Denmark - Odense Patient Data Explorative Network (OPEN); Bandim Health Project, INDEPTH Network

Peter Aaby

Bandim Health Project, INDEPTH Network; Bandim Health Institute - OPEN, Institute of Clinical Research

Helga Dijkstra

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Heidi Lemmers

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Joost H.A. Martens

Radboud University Nijmegen

Jorge Domínguez-Andrés

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Reinout Van Crevel

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Yang Li

Helmholtz Centre for Infection Research

Cheng-Jian Xu

Helmholtz Centre for Infection Research

Mihai G. Netea

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI); Radboud University Nijmegen - Department of Internal Medicine

Abstract

The Bacille Calmette-Guerin (BCG) vaccine is a well-established inducer of innate immune memory (also termed trained immunity), causing increased cytokine production upon heterologous secondary stimulation. Innate immune responses are known to be influenced by season, but whether seasons impact induction of trained immunity is not known. To explore the influence of season on innate immune memory induced by the BCG vaccine, we vaccinated healthy volunteers with BCG either during winter or spring. Three months later, we measured the ex vivo cytokine responses against heterologous stimuli, analyzed gene expressions and epigenetic signatures of the immune cells, and compared these with the baseline before vaccination. BCG vaccination during winter induced a stronger increase in the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) upon stimulation with different bacterial and fungal stimuli, compared to BCG vaccination in spring. In contrast, winter BCG vaccination resulted in lower IFNγ release. Furthermore, NK cells of the winter-vaccinated people had a greater pro-inflammatory cytokine and IFNγ production capacity upon heterologous stimulation. BCG vaccination had only minor effects on the transcriptome of PBMCs 3 months later. In contrast, we identified season-dependent epigenetic changes in monocytes and NK cells induced by BCG vaccination, partly explaining the higher immune cell reactivity in the winter BCG vaccination group. These results suggest that BCG vaccination during winter is more prone to induce a robust trained immunity response by activating and reprogramming the immune cells, especially NK cells. (Dutch clinical trial registry no. NL58219.091.16)

Note:
Funding declaration: This study was supported by an ERC Advanced Grant (833247) to MGN. JDA is supported by the Dutch Research Council (VENI grant no. 09150161910024).

Conflict of Interests: MGN is a scientific founder of TTxD, Lemba, and Biotrip. All other authors declare that they have no competing interests.

Ethical Approval: The local ethics committee, METC Oost117 Nederland, gave ethical approval for the study. Inclusion and experimentation procedures were conducted according to the principles of the Declaration of Helsinki. Written informed consent was obtained from all volunteers.

Trial Registration: NL58219.091.16

Keywords: BCG, vaccines, trained immunity, seasonality, NK cells

Suggested Citation

Kilic, Gizem and Debisarun, Priya A. and Alaswad, Ahmed and Baltissen, Marijke P. and Lamers, Lieke A. and de Bree, Charlotte J. and Benn, Christine Stabell and Aaby, Peter and Dijkstra, Helga and Lemmers, Heidi and Martens, Joost H.A. and Domínguez-Andrés, Jorge and Van Crevel, Reinout and Li, Yang and Xu, Cheng-Jian and Netea, Mihai G., Seasonal Variation in BCG-Induced Trained Immunity. Available at SSRN: https://ssrn.com/abstract=4751987 or http://dx.doi.org/10.2139/ssrn.4751987

Gizem Kilic (Contact Author)

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI) ( email )

Nijmegen
Netherlands

Priya A. Debisarun

Radboud University Nijmegen - Radboud University Medical Center ( email )

Ahmed Alaswad

Helmholtz Centre for Infection Research ( email )

Germany

Marijke P. Baltissen

Radboud University Nijmegen ( email )

Lieke A. Lamers

Radboud University Nijmegen ( email )

Charlotte J. De Bree

Radboud University Nijmegen - Radboud University Medical Center ( email )

Christine Stabell Benn

University of Southern Denmark - Odense Patient Data Explorative Network (OPEN) ( email )

J. B. Winsløws Vej 4
Odense
Denmark

Bandim Health Project, INDEPTH Network ( email )

Bissau
Guinea-Bissau

Peter Aaby

Bandim Health Project, INDEPTH Network ( email )

Bissau
Guinea-Bissau

Bandim Health Institute - OPEN, Institute of Clinical Research ( email )

Odense
Denmark

Helga Dijkstra

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI) ( email )

Nijmegen
Netherlands

Heidi Lemmers

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI) ( email )

Nijmegen
Netherlands

Joost H.A. Martens

Radboud University Nijmegen ( email )

Jorge Domínguez-Andrés

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI) ( email )

Nijmegen
Netherlands

Reinout Van Crevel

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI) ( email )

Nijmegen
Netherlands

Yang Li

Helmholtz Centre for Infection Research ( email )

Germany

Cheng-Jian Xu

Helmholtz Centre for Infection Research ( email )

Germany

Mihai G. Netea

Radboud University Nijmegen - Radboud Center for Infectious Diseases (RCI)

Nijmegen
Netherlands

Radboud University Nijmegen - Department of Internal Medicine ( email )

Nijmegen
Netherlands

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