Low-dose yellow fever vaccination in infants: a randomised, double-blind, non-inferiority trial

BACKGROUND: WHO recommends fractional dose vaccination to address yellow fever vaccine shortages during outbreaks. In adults, a 500 IU dose has recently been shown to be non-inferior to the full standard dose, but the minimum effective dose for children is unknown. METHODS: We conducted a randomised, double-blind, non-inferiority trial at two centres in Kenya and Uganda, including infants aged 9-12 months with no previous yellow fever vaccination or infection. Participants were randomly assigned 1:1 in blocks of variable sizes of four, six, or eight to receive either the standard dose (>13 000 IU) or 500 IU of the Institut Pasteur de Dakar (Dakar, Senegal) 17D-204 yellow fever vaccine, co-administered with the measles-rubella vaccine. The primary outcome was seroconversion 28 days post-vaccination, defined as a four-fold or greater increase in antibody titre at day 28 from baseline (day 0), as measured by the 50% plaque reduction neutralisation test. Non-inferiority was shown if the lower bound of the 95% CI for the difference in seroconversion rates between doses exceeded -10 percentage points. Safety was assessed in the safety population, which included all participants who received a study vaccine dose. This study is registered with ClinicalTrials.gov (NCT04059471) and is complete. FINDINGS: Between Oct 7, 2021, and June 14, 2023, 420 infants were enrolled and randomly assigned (210 participants in each group). The seroconversion rate at day 28 was 99% (95% CI 96-100; 177 of 179 infants) for the standard dose and 93% (88-96; 166 of 179 infants) for the 500 IU dose in the per-protocol population. The difference in seroconversion rate was -6·15 percentage points (95% CI -10·27 to -2·02); therefore, non-inferiority was not met for the 500 IU dose. 12 serious adverse events were reported in the study (eight in the 500 IU dose group and four in the standard dose group), but all were considered unrelated to vaccination. INTERPRETATION: Compared with the standard yellow fever vaccine dose, a dose of 500 IU did not meet the non-inferiority criterion, suggesting that minimum dose requirements in adults are not generalisable to infants. Therefore, standard yellow fever doses should be used for infants in the routine WHO Expanded Programme on Immunization. FUNDING: European and Developing Countries Clinical Trials Partnership and the Wellcome Trust.