Chrono-optimization of influenza vaccine administration: A systematic review and meta-analysis

Background There is growing evidence that the strength of vaccine responses depends on the time of day of vaccine administration. This systematic review provides an overview of the literature regarding the effect of the timing of influenza vaccination on the vaccine response. To estimate the extent of this effect, we conducted a meta-analysis of randomized controlled trials (RCTs) in which antigen-specific antibody titers were monitored following either morning or afternoon administration of the influenza vaccine.

and results A systematic literature search identified five relevant studies that reported antigen-specific titers against multiple influenza vaccine strains after both morning and afternoon vaccination. Four of the five studies reported higher antibody titers for at least one vaccine strain following morning vaccination. Two RCTs were included in the meta-analysis, each of which reported the response to three vaccine strains, resulting in a total of six responses. The meta-analysis revealed that morning vaccination elicited a stronger antibody response than afternoon vaccination, with a pooled standardized mean difference (SMD) of 0.24 (95% CI=0.01–0.47). The between-study heterogeneity (I2=66%) was mainly due to the significantly 01greater effect of morning vaccination among adults aged 65 years or older than among adults aged 60 years or younger (SMD=0.32, 95% CI=0.21–0.43 versus SMD=0.00, 95% CI=−0.16–0.16, respectively).

Influenza vaccinations administered in the morning induced a stronger antibody response in adults aged 65 years or older, who represent a major target group for influenza vaccination programs. Therefore, chrono-optimization of influenza vaccination could offer a safe and simple strategy for enhancing vaccine effectiveness. The paucity of relevant studies suggests that accounting for the time of vaccine administration in future vaccination trials could provide valuable insights into the potential benefits of chrono-optimization strategies. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work is part of the BioClock Consortium (with project number 1292.19.077) of the research programme NWA-ORC which is (partly) financed by the Dutch Research Council (NWO). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All (aggregated) data used in this study were from the following articles: Long, J.E., et al., Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial. Vaccine, 2016. 34(24): p. 2679-85. Liu, Y., et al., The impact of circadian rhythms on the immune response to influenza vaccination in middle-aged and older adults (IMPROVE): a randomised controlled trial. Immunity & Ageing, 2022. 19(1): p. 46. Some data from Long et al. was collected via contacting the authors. Abbreviations - RCT - Randomized controlled trial - PRISMA - Preferred reporting items for systematic reviews and meta-analyses - RoB2 - Risk of bias tool 2 - ROBINS-I - Risk of bias in nonrandomized studies of interventions - SD - Standard deviation - SMD - Standardized mean difference - BCG - Bacillus Calmette-Guérin