Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2023 Feb 16:14:980711.
doi: 10.3389/fimmu.2023.980711. eCollection 2023.

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections

Konstantin Föhse  1   2 , Esther J M Taks  1   2 , Simone J C F M Moorlag  1   2 , Marc J M Bonten  3 , Reinout van Crevel  1   2 , Jaap Ten Oever  1   2 , Cornelis H van Werkhoven  3 , Mihai G Netea  1   2   4 , Josephine S van de Maat  1   2 , Jacobien J Hoogerwerf  1   2
Affiliations
Randomized Controlled Trial

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections

Konstantin Föhse et al. Front Immunol. .

Erratum in

Abstract

Background and objective: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs).

Methods: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h).

Results: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods.

Conclusion: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.

Keywords: BCG; COVID-19; SARS-CoV-2; circadian clock; circadian rhythm; heterologous protection; respiratory tract infection; trained immunity.

PubMed Disclaimer

Conflict of interest statement

MN is scientific founder of TTxD and Lemba has received scientific support from GSK, Ono Pharma, and TTxD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

    1. Netea MG, Quintin J, van der Meer JW. Trained immunity: A memory for innate host defense. Cell Host Microbe (2011) 9(5):355–61. doi: 10.1016/j.chom.2011.04.006 - DOI - PubMed
    1. Koeken VA, de Bree LCJ, Mourits VP, Moorlag SJ, Walk J, Cirovic B, et al. . BCG Vaccination in humans inhibits systemic inflammation in a sex-dependent manner. J Clin Invest (2020) 130(10):5591–602. doi: 10.1172/JCI133935 - DOI - PMC - PubMed
    1. Flanagan KL, van Crevel R, Curtis N, Shann F, Levy O, Optimmunize N. Heterologous ("nonspecific") and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. Clin Infect Dis (2013) 57(2):283–9. doi: 10.1093/cid/cit209 - DOI - PMC - PubMed
    1. Angelidou A, Diray-Arce J, Conti MG, Smolen KK, van Haren SD, Dowling DJ, et al. . BCG As a case study for precision vaccine development: Lessons from vaccine heterogeneity, trained immunity, and immune ontogeny. Front Microbiol (2020) 11:332. doi: 10.3389/fmicb.2020.00332 - DOI - PMC - PubMed
    1. Butkeviciute E, Jones CE, Smith SG. Heterologous effects of infant BCG vaccination: Potential mechanisms of immunity. Future Microbiol (2018) 13:1193–208. doi: 10.2217/fmb-2018-0026 - DOI - PMC - PubMed

Publication types

Associated data