BIOLOGICAL RHYTHMS IN COVID-19 VACCINE EFFECTIVENESS
Authors: Hazan Guy , Duek Or A. , Alapi Hillel , Mok Huram , Ganninger Alex , Ostendorf Elaine , Gierasch Carrie , Chodick Gabriel , Greenberg David , Haspel Jeffrey A. 
Published: November 2022

ABSTRACTImportanceCircadian rhythms affect fundamental immune processes, but how this translates to clinical outcomes like real-world vaccine effectiveness is unclear.ObjectiveTo examine associations between Coronavirus Infectious Disease 2019 (COVID-19) vaccination timing and effectiveness.Design, Setting, and ParticipantsRetrospective cohort study of database records from Maccabi Healthcare Services (MHS), a major Israeli Health Maintenance Organization (HMO). We included all individuals over 12 with at least one timestamped vaccine dose and no documented COVID-19 infection prior to completing the initial 2-dose immunization series (n=1,515,754, 99.2% receiving BNT162b2). Database records spanned December 19, 2020, to April 25, 2022, encompassing two spikes in COVID infection dominated by the delta (B.1.617.2) and omicron (B.1.1.529) SARS-CoV-2 variants.Main Outcomes and MeasuresOutcomes 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.ResultsBreakthrough infections differed based on vaccination time, with lowest rates associated with late morning to early afternoon, and highest rates with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and co-morbidities (HR=0.88 afternoon vs. evening, [95% CI 0.87-0.90]). Results were consistent in patients who received the basic two-dose vaccine series and who received booster doses. The relationship between COVID-19 immunization time and breakthrough infection risk was sinusoidal, consistent with a biological rhythm in vaccine effectiveness. Vaccination timing altered breakthrough infection risk by 8.6-25% in our cohort, depending on patient age and dose number. The benefits of daytime vaccination were concentrated in younger and elderly patients. In contrast to breakthrough infections, COVID-19 related ED visits correlated with age and medical comorbidities but not with time of vaccination.Conclusions and RelevanceWe report a significant association between the time of COVID-19 vaccination and its clinical effectiveness in terms of breakthrough infection. These data have implications for mass vaccination programs.KEY POINTSQuestionDoes the time of day patients receive their COVID-19 vaccinations influence their clinical benefit?FindingsIn this population-level cohort study that included 1,515,754 individuals aged 12 and over, COVID-19 vaccination during the late morning to early afternoon was associated with fewer breakthrough infections compared to other times. Vaccination timing altered breakthrough infection risk by 8.6-25%, depending on patient age and dose number.MeaningPrioritizing children and the elderly for late morning to early afternoon immunization could improve the effectiveness of mass vaccinations against COVID-19, and potentially other infectious diseases.