Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in children (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial.

backgroundCurrent supply shortages constrain yellow fever vaccination activities, particularly outbreak response. Although fractional doses of all WHO-prequalified yellow fever vaccines have been shown to be safe and immunogenic in a randomised controlled trial in adults, they have not been evaluated in a randomised controlled trial in young children (9-59 months old). We aimed to assess the immunogenicity and safety of fractional doses compared with standard doses of the WHO-prequalified 17D-213 vaccine in young children.

methodsThis substudy of the YEFE phase 4 study was conducted at the Epicentre Mbarara Research Centre (Mbarara, Uganda). Eligible children were aged 9-59 months without contraindications for vaccination, without history of previous yellow fever vaccination or infection and not requiring yellow fever vaccination for travelling. Participants were randomly assigned, using block randomisation, 1:1 to standard or fractional (one-fifth) dose of yellow fever vaccine. Investigators, participants, and laboratory personnel were blinded to group allocation. Participants were followed for immunogenicity and safety at 10 days, 28 days, and 1 year after vaccination. The primary outcome was non-inferiority in seroconversion (-10 percentage point margin) 28 days after vaccination measured by 50% plaque reduction neutralisation test (PRNT

findingsBetween Feb 20, 2019, and Sept 9, 2019, 433 children were assessed, and 420 were randomly assigned to fractional dose (n=210) and to standard dose (n=210) 17D-213 vaccination. 28 days after vaccination, 202 (97%, 95% CI 95-99) of 207 participants in the fractional dose group and 191 (100%, 98-100) of 191 in the standard dose group seroconverted. The absolute difference in seroconversion between the study groups in the per-protocol population was -2 percentage points (95% CI -5 to 1). 154 (73%) of 210 participants in the fractional dose group and 168 (80%) of 210 in the standard dose group reported at least one adverse event 28 days after vaccination. At 10 days follow-up, seroconversion was lower in the fractional dose group than in the standard dose group. The most common adverse events were upper respiratory tract infections (n=221 [53%]), diarrhoea (n=68 [16%]), rhinorrhoea (n=49 [12%]), and conjunctivitis (n=28 [7%]). No difference was observed in incidence of adverse events and serious adverse events between study groups.

conclusionsFractional doses of the 17D-213 vaccine were non-inferior to standard doses in inducing seroconversion 28 days after vaccination in children aged 9-59 months when assessed with PRNT

fundingMédecins Sans Frontières Foundation.