Discussion
RTIs
RESPIRATORY INFECTIONS, EVENTS, SARS-COV-2 INFECTION
The results of the present study show that the time of day of BCG vaccination did not affect the susceptibility to respiratory infections. We observed some differences in the cumulative incidence of SARS-CoV-2 infections, especially in the first six months after vaccination, but the number of events was too low and consequently confidence intervals were too wide to draw any conclusion. Notably, the direction of the effects was even in the opposite direction of our initial hypothesis that BCG vaccination offers better protection in the morning. It is important mentioning that the initial trial was not powered nor designed to analyze the effect of circadian rhythm. The most likely explanation for our findings is that BCG vaccination simply has no effect on the protection against RTIs and SARS-CoV-2 infections in this study. A protective effect has previously been demonstrated in several smaller studies (We have chosen for greater intervals of vaccination in this study to give a better reflection of common practice of vaccination and to guarantee a certain number of events per group. Furthermore, the median age of the individuals in the study from de Bree et al. was 26 years, while in contrast, the median age in our cohort was 67. Ageing has been associated with both changes in circadian-influenced biological processes and innate immune responses (A protective effect has previously been demonstrated in several (smaller) studies (On the cellular level, virtually all cell lines of the innate and the adaptive immune system have been associated with circadian variations (Although we did not detect that BCG vaccination, either in the morning or the afternoon, offers beter protection than placebo against RTIs or COVID-19, we believe that further unravelling the mechanisms of clock-controlled immunomodulation has the potential to enhance both the immunogenicity of vaccines and the efficacy of immunotherapies. Therefore, further research is needed to identify potential clinical implications of the previously found 