Time of day for vaccination, outcomes, and relative effectiveness of high-dose vs. standard-dose quadrivalent influenza vaccine: A post hoc analysis of the DANFLU-1 randomized clinical trial.

Objectives: Morning influenza vaccination enhances antibody response. In this post hoc analysis of the DANFLU-1 trial, we sought to evaluate the association between time of day for vaccination (ToV) and outcomes and whether ToV modified the relative effectiveness of high-dose (QIV-HD) vs. standard-dose (QIV-SD) quadrivalent influenza vaccine.
Methods: DANFLU-1 was a pragmatic feasibility trial of QIV-HD vs. QIV-SD. Outcomes included hospitalizations and mortality. For subgroup analysis, the population was dichotomized at median ToV into two groups (early and late).
Results: The study population included 12,477 participants. Mean age was 71.7 ± 3.9 years with 5877 (47.1%) female participants. Median ToV was 11.29 AM. Earlier ToV was associated with fewer respiratory hospitalizations independent of vaccine type, which persisted in adjusted analysis (IRR 0.88 per 1-hour decrement (95% CI 0.78- 0.98, p = 0.025). No effect modification by continuous or dichotomous ToV was found. In subgroup analysis, effects consistently favored QIV-HD against hospitalizations for pneumonia or influenza (early: IRR 0.30; late: 0.29), all-cause hospitalizations (early: IRR 0.87; late: 0.86), and mortality (early: HR 0.53; late: 0.50).
Conclusion: In this exploratory post hoc analysis, earlier ToV was associated with fewer respiratory hospitalizations. The relative effectiveness of QIV-HD vs. QIV-SD was not modified by ToV. Further research is needed to confirm findings.
Trial Registration: Clinicaltrials.gov: NCT05048589.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: JN was previously employed by Sanofi and may own shares and/or stock options in the company. SS, ML, and RCH are full-time employees of Sanofi and may own shares and/or stock options in the company. CSL is chief physician at Danske Lægers Vaccinations Service, part of European LifeCare Group, and has received speaker fees and served on advisory boards for GSK, MSD, Pfizer, Takeda, and Valneva. BLC has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, US2. AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. LK has received speaker fees from Novo Nordisk, Novartis, AstraZeneca, Boehringer Ingelheim, and Bayer. TB-S is chief investigator of the Boston Scientific financed “DANLOGIC-HF” trial, the Sanofi financed “NUDGE-FLU” trial, the Sanofi financed “DANFLU-1” trial, the Sanofi financed “DANFLU-2″ trial and steering committee member of the Boston Scientific sponsored “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System” trial, the Amgen sponsored GALACTIC-HF trial, the Boehringer Ingelheim financed EASi-KIDNEY trial and served on advisory boards for Sanofi, Amgen, CSL Seqirus and GSK and received speaker honorariums from Bayer, Novartis, Sanofi, GE Healthcare and GSK and received research grants from Boston Scientific, GE Healthcare, AstraZeneca, Novo Nordisk, and Sanofi and consulted for Novo Nordisk, IQVIA and Parexel. The remaining authors have nothing to disclose.
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