Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomized, double-blind, non-inferiority trial

Background Yellow fever vaccine stocks have been insufficient to cover exceptional demands for outbreak response. Fractional dosing evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared to standard dose of each of the four WHO-prequalified yellow fever vaccines produced from three substrains. Methods We conducted a randomized, double-blind, non-inferiority trial in Mbarara, Uganda and Kilifi, Kenya. 960 participants aged 18-59 years without previous yellow fever vaccination or infection were recruited from communities and randomized to receive one of four vaccines and to standard or fractional dosage. Vaccine was administered subcutaneously by unblinded nurse. Other study personnel and participants were blinded to vaccine allocation. Primary immunogenicity outcome, seroconversion, was measured in the per-protocol population; safety outcomes included all vaccinated participants. We defined non-inferiority as no more than 10% decrease in seroconversion in fractional compared to standard dose arms 28 days post-vaccination. Seroconversion was defined as ≥4-fold rise in neutralizing antibody titers measured by 50% plaque reduction neutralization test (PRNT50). ClinicalTrials.gov Identifier: NCT02991495, following participants. Findings Between 6th November 2017 and 21st February 2018, 960 participants, total sample goal, were randomized. The primary per-protocol analysis includes 899 participants, with 110 to 117 participants per arm. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1.71% (95%CI: -2.60, 5.28), -0.90% (95%CI: -4.24, 3.13), 1.82% (95%CI: -2.75, 5.39), 0.0% (95%CI: -3.32, 3.29). Fractional doses from all four vaccines met the non-inferiority criterion. There were no safety concerns. Interpretation These results support fractional dosing of all WHO-prequalified yellow fever vaccines for the general adult population for outbreak response in situations of vaccine shortage. Funding The study was funded by Medecins Sans Frontieres Foundation, Wellcome Trust (grant no. 092654) and the UK Department for International Development. Vaccines were donated in kind.