Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients

Abstract

BACKGROUND Circadian rhythms are evident in basic immune processes, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between COVID-19 vaccination timing and effectiveness. METHODS We retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations ( 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 visits and hospitalizations. Our main comparison was among patients vaccinated during morning (800–1159 hours), afternoon (1200–1559 hours), or evening hours (1600–1959 hours). We employed Cox regression to adjust for differences in age, sex, and comorbidities. RESULTS Breakthrough infections differed based on vaccination time, with lowest the rates associated with late morning to early afternoon and highest rates associated with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and comorbidities. Results were consistent in patients who received the basic 2-dose series and who received booster doses. The relationship between COVID-19 immunization time and breakthrough infections was sinusoidal, consistent with a biological rhythm that modifies vaccine effectiveness by 8.6%–25%. The benefits of daytime vaccination were concentrated in younger (<20 years old) and older patients (>50 years old). COVID-19–related hospitalizations varied significantly with the timing of the second booster dose, an intervention reserved for older and immunosuppressed patients (HR = 0.64, morning vs. evening; 95% CI, 0.43–0.97; P = 0.038). CONCLUSION We report a significant association between the time of COVID-19 vaccination and its effectiveness. This has implications for mass vaccination programs. FUNDING NIH.

Using routinely collected clinical data for circadian medicine: A review of opportunities and challenges

“…Further, by analyzing breakthrough Coronavirus disease 2019 (COVID-19) infection in 1.5 million patients as a function of time of vaccination, late morning to early afternoon was found to offer better protection than evening vaccination [ 64 ]. The authors of this study were able to construct a continuous efficacy curve over a 12-hour period using EHR data.…”

“…Besides pitfalls that pertain to research with EHR in general, the use of these databases for circadian medicine purposes introduces multiple challenges ( Table 1 ). The COVID-19 vaccine timing study [ 64 ] offers a good example. In that study, an individual’s occupation may have independently influenced both the time of vaccination and the risk of COVID-19 infection ( Fig 2A ).…”

Time of day for COVID vaccine administration linked to clinical effectiveness

“…When time of dosing was examined in smaller intervals, the lowest rates of breakthrough infections were found in those vaccinated in the late morning to early afternoon. Interestingly, prior studies looking at time of day of COVID vaccination and subsequent antibody titers have been equivocal ( 2 , 3 ), and this is the first study to our knowledge that included clinical protection as an outcome ( 1 ).…”

“…In this issue of the JCI , Hazan et al ( 1 ) report on whether time of day of COVID vaccination associates with subsequent breakthrough COVID-19 infection in 1,515,754 patients, using data from a large Israeli health maintenance organization. The authors found evidence to support that the timing of vaccine dosing associated with clinical outcomes.…”

“…Hazan et al add to a list of critically important COVID-19 papers using data from the Israeli health care system ( 1 , 4 , 5 ). The rapid adoption and administration of the COVID vaccine (almost entirely BNT162b2) in Israel, coupled with Israel’s integrated payer–provider health care organizations offering mandatory health care coverage and comprehensive electronic health record systems, has provided well-powered, critical data for rapid COVID-19 investigation and reporting.…”