Seasonal Variation in BCG-Induced Trained Immunity

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