Background. Circadian rhythms regulate fundamental immune processes, but how this relates to clinical endpoints like vaccine efficacy is unknown.  Here, we examined associations between COVID-19 vaccination timing and efficacy.

Methods.  We analyzed COVID-19 vaccine efficacy as a function of time-of-administration in a large cohort of Israeli patients (n=1,515,754 patients over 12 years-old, 99.2% receiving BNT162b2).  Endpoints included COVID-19 breakthrough infection and COVID-19 associated emergency department (ED) visits.  Our main comparison was between patients vaccinated exclusively during morning hours (8:00-11:59), afternoon (12:00-15:59), or evening hours (16:00-19:59).  We employed Cox multivariate regression to adjust for differences in age, sex, and co-morbidities.

Results.  Breakthrough infections differed based on vaccination time, with lowest rates associated with late morning to early afternoon, and highest rates with evening vaccination (Figure 1).  Vaccination timing remained significant after adjustment for patient age, sex, and co-morbidities.  Results were consistent in patients who received the basic two-dose vaccine series and who received booster doses.  The association between COVID immunization time and infection risk followed a sinusoidal pattern, consistent with a diurnal rhythm in vaccine efficacy (Figure 2).  In contrast to breakthrough infections, COVID-19 related ED visits correlated with age and medical comorbidities but not with time of vaccination.    

Conclusions.  We report a significant association between the time of COVID-19 vaccination and its clinical efficacy in terms of breakthrough infection. These data have implications for mass vaccination programs.