In July 2016, the demand for yellow fever (YF) vaccines was larger than the available global supply. In this situation, the WHO developed recommendations for the use of fractional doses of YF vaccine as a dose-sparing strategy. Although YF vaccine is highly effective, the current supply shortages constrain vaccination activities, and particularly outbreak response. The yellow fever studies aim to provide additional information on the use of fractional doses.
The aim of this study was to generate the data needed to recommend fractional doses of any WHO prequalified YF vaccine to be used in emergency situations when there are insufficient standard doses to protect the population at risk. The priority was to determine if a fraction of a vaccine dose (i.e. 1/5th) administered subcutaneously would be safe and immunogenic. We designed a double-blinded randomized controlled trial to assess the immunological non-inferiority and safety of a fractional dose compared to full dose for each of the four WHO pre-qualified YF vaccines in an adult population. Each vaccine was delivered in either its full dose or fractional dose. The study included an adult population, children and HIV infected adults.
Sponsor, Scientific Oversight, Study site
Fractional dose yellow fever vaccines for outbreak response
This is a double blinded, randomized, non-inferiority trial. Fractional dose was defined as 1/5th of a standard dose. Unvaccinated adults were randomly assigned to vaccine manufacturer and dosage (standard or 1/5th) and seen 10 days, 28 days and 1 year post-vaccination for immunogenicity and safety assessment. The primary objective is non-inferiority in seroconversion, with a 10% margin, of a fractional dose compared to standard dose for each pre-qualified vaccine at 28 days post-vaccination, measured by PRNT50. Sub-studies on children and HIV+ adults are ongoing with one vaccine.
A total of 1029 adult participants were screened and 960 vaccinated (240 per manufacturer and 120 per dose). Overall, 55.1% of participants were female and mean age at enrollment was 35.7 years.
At baseline, 5.1% participants were positive for yellow fever by PRNT50. Baseline characteristics were not significantly different between standard and fractional dose groups for each manufacturer. At 28 days postvaccination 99.4% participants seroconverted. The maximum difference between fractional and standard dose group was –6.1%.
Fractional dose of YF vaccine meets non-inferiority criteria for all pre-qualified manufacturers 28 days after vaccination. There were no safety concerns of the reduced dose. Results are pending to evaluate the rapidity of protection (10 days follow-up) and the persistence of antibodies at 1 year post-vaccination.
Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial.
Immunogenicity of fractional dose of Yellow Fever vaccine in children and HIV+ adults
The children sub-study was conducted at Epicentre Mbarara, Uganda and the HIV sub-study was conducted at KEMRI, Kilifi, Kenya. Children aged 9 months - 5 years or HIV positive adults without contraindications for vaccination were randomly assigned to standard or fractional dose (1/5th) at each site. Investigators, participants, and laboratory personnel were blinded to group allocation. Participants were followed up at day 10, day 28 and 1 year post-vaccination. The primary outcome was non-inferiority in seroconversion (-10% margin) 28 days post-vaccination measured by PRNT50.
A total of 433 children and 303 HIV+ adults were assessed and 420 and 250 recruited respectively and randomized to standard dose or to fractional dose. At 28 days post-vaccination, >95% of participants in each study group seroconverted and fractional doses met the non-inferiority criterion. The absolute difference in seroconversion in the per-protocol population between fractional and standard dose groups was -2.42 (95%CI: -4.82, 0.7) in children and -2.56 (95%CI: -6.92 to 1.79) in HIV+ adults. There was no observed difference in occurrence of adverse events and serious adverse events in both arms.
The fractional dose met the non-inferiority criterion in children 9 months – 5 years and non-immunocompromised HIV+ adults. These results will support extending the current WHO recommendation for fractional dosing in the event of a shortage for children and HIV+ adults.