Editors' ChoiceCIRCADIAN IMMUNIZATION

Chrono-immunization with BCG: It is about “time”!

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Science Translational Medicine  05 Aug 2020:
Vol. 12, Issue 555, eabd4766
DOI: 10.1126/scitranslmed.abd4766

Abstract

Morning vaccination with BCG enhances immunity.

Circadian rhythms have been known to affect almost all facets of human physiology. These effects are very prominent in the regulation of the immune system, where cell numbers, response, and trafficking have been described to be under tight control of the circadian clock. One imminently translational facet of this clock-gating of immunity is its application to vaccination.

de Bree et al. examined the effect of time of vaccination on host immune response. They used the tuberculosis or Bacillus Calmette-Guérin (BCG) vaccine for this purpose. BCG vaccination results in a reduction in all-cause mortality in children. This is thought to be secondary to trained immunity, which is defined as nonspecific immunomodulatory effects that help the host fight a wide range of infections. This study investigated the differences in both vaccine-specific immunity as well as “trained immunity” based on time of day of immunization. The BCG vaccine was administered at either 8 a.m. or between 6 and 6:30 p.m. to a group of healthy volunteers nested within the 300BCG study. Clock gene expression, epigenetic landscape, and in vitro response to Staphylococcus aureus were determined after vaccination. Not only Mycobacterium tuberculosis-specific immunity but also several markers of trained immunity were induced in the morning group but absent in the evening group. Although serum cortisol levels did oscillate, these rhythms were not found to be responsible for the better response to morning vaccination. However, they found that clock genes Arntl and Clock were up-regulated and their accessibility enhanced by epigenetic modifications in circulating monocytes among volunteers in the morning group. Overall their data supported the role of the cell-intrinsic clock for these differences in induced immunity.

This study underscores the time of day at administration as another variable that can be used to optimize the efficacy of vaccines. Further, it posits that these circadian mechanisms may be an important driver for the inherent biological heterogeneity in vaccine response. The importance of using chronoimmunization strategies is further underscored by the current pandemic as we race to find a vaccine against SARS-CoV-2.

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