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

Konstantin Föhse; Esther J M Taks; Simone J C F M Moorlag; Marc J M Bonten; Reinout van Crevel; Jaap Ten Oever; Cornelis H van Werkhoven; Mihai G Netea; Josephine S van de Maat; Jacobien J Hoogerwerf

doi:10.3389/fimmu.2023.980711

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

Front Immunol. 2023 Feb 16:14:980711. doi: 10.3389/fimmu.2023.980711. eCollection 2023.

Authors

Konstantin Föhse^{1

2}, Esther J M Taks^{1

2}, Simone J C F M Moorlag^{1

2}, Marc J M Bonten³, Reinout van Crevel^{1

2}, Jaap Ten Oever^{1

2}, Cornelis H van Werkhoven³, Mihai G Netea^{1

2

4}, Josephine S van de Maat^{1

2}, Jacobien J Hoogerwerf^{1

2}

Affiliations

¹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, Netherlands.
² Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
³ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
⁴ Department of Immunology and Metabolism, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany.

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.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
BCG Vaccine
COVID-19*
Circadian Rhythm
Humans
Middle Aged
Mycobacterium bovis*
Respiratory Tract Infections*
SARS-CoV-2
Vaccination

Substances

BCG Vaccine

Associated data

ClinicalTrials.gov/NCT04417335

Grants and funding

This work was investigator initiated and supported by the Radboud University Medical Center and the University Medical Center (UMC) Utrecht, Emergent Ventures (unconditional fast grant), the Mercator Center, George Mason University, Willem Bakhuys Roozeboomstichting, the European Research Council (advanced grant number 833247), and the Netherlands Organization for Scientific Research (Spinoza grant to MN).