Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients
Guy Hazan, … , David Greenberg, Jeffrey A. Haspel
Guy Hazan, … , David Greenberg, Jeffrey A. Haspel
Published April 25, 2023
Citation Information: J Clin Invest. 2023;133(11):e167339. https://doi.org/10.1172/JCI167339.
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Clinical Medicine COVID-19 Vaccines

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.

Authors

Guy Hazan, Or A. Duek, Hillel Alapi, Huram Mok, Alex Ganninger, Elaine Ostendorf, Carrie Gierasch, Gabriel Chodick, David Greenberg, Jeffrey A. Haspel

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Figure 3

Variation in adjusted COVID-19 breakthrough infection and hospitalization risk as a function vaccine timing.

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Variation in adjusted COVID-19 breakthrough infection and hospitalizatio...
Data points represent adjusted HRs ± 95% CI, relative to dosing between 800 and 959 hours, which serves as a nonoverlapping index bin for this analysis. Best-fit sinusoidal trend lines (black lines), amplitudes (Amp), goodness of fit (r2), and METACYCLE-generated P values for periodicity are depicted within each graph. (A–C) HRs for breakthrough infections (black symbols) based on the timing of vaccine (A) dose 2, (B) dose 3, and (C) dose 4. (D) HRs for COVID-19–associated hospitalizations based on the timing of dose 4. We define COVID-19–associated ED visits or hospitalization as occurring between –7 to +7 days of a COVID-19–positive test (see Methods). For patient demographic breakdown, sample sizes, and a tabular presentation of these data, see Supplemental Tables 10, 11, and 13. For the complete METACYCLE output, see Supplemental Table 14.