Immunogenicity and Safety of Fractional Doses of Yellow Fever Vaccines (YEFE)
Condition: Yellow Fever
MeSH terms: Yellow Fever; Fever
Study type: Interventional
Phase: Phase 4

Summary: 
      In July 2016, the demand for yellow fever vaccines in response to the large urban outbreaks
      occurring concurrently and the risk of further spread through the African continent and even
      to Asia, was larger than the available supply. In this situation, the World Health
      Organization (WHO) developed recommendations for the use of fractional-dose of yellow fever
      vaccine as a dose-sparing strategy. These recommendations were based on limited number of
      clinical trials and additional studies should assess the applicability of the fractional dose
      to all WHO-prequalified vaccines, the persistence of neutralizing antibodies and the
      performance of the fractional dose in young children and populations in Africa including
      those with HIV.

      This study aims to respond to some of the research questions that would allow broadening the
      recommendations on the use of fractional doses of yellow fever vaccine in emergency
      situations. The study will be conducted in Uganda and Kenya and the main objective is to
      assess the non-inferiority is seroconversion 28 days after vaccination of a fractional dose
      compared to full dose for each WHO-prequalified manufacturer. As secondary objectives the
      study will assess seroprotection 10 days and 1 year after vaccination, to assess rapidity and
      persistence of protective antibody levels; describe the geometric mean titre and the change
      in neutralizing antibody on Day 28 days after vaccination with fractional and full doses; and
      assess the occurrence of adverse events and serious adverse events (SAE) during 28 days after
      administration of fractional and full doses.

      The study consists of a randomized non-inferiority trial. The study aims to start in April
      2017 in the two sites and aims to recruit 960 adults. Results for the main outcome will be
      reviewed by the study Data and Safety Monitoring Board and one vaccine will be selected for
      the studies in children and HIV positive adults.
    

Detailed description: 
      Yellow fever (YF) is a mosquito-borne viral disease that is endemic in 34 countries in the
      African region and 14 in South America. YF virus infection can be asymptomatic or cause a
      wide spectrum of disease, from mild symptoms to severe, potentially lethal illness with
      jaundice, renal failure and haemorrhage. The vast majority of reported cases and deaths occur
      in sub-Saharan Africa where yellow fever is a major health problem occurring in epidemic
      patterns. There is no specific treatment for yellow fever infection. However, YF vaccine is
      shown to be very effective for outbreak control as well as for the prevention of outbreaks.
      YF vaccination confers protection in most vaccinated individuals and this is considered to be
      life-long.

      In 2016, YF outbreaks occurred in Africa (Angola, Democratic Republic of Congo (DRC) and
      Uganda) as well as in South America (Brazil, Colombia and Peru). Factors such increased
      urbanization in poor areas without proper water and sanitation systems and population
      movements, have the potential to contribute to increasing incidence of yellow fever and large
      epidemics. In July 2016, the demand for yellow fever vaccines in response to the large urban
      outbreaks occurring concurrently and the risk of further spread through the African continent
      and even to Asia, was larger than the available supply. In this situation, the World Health
      Organization (WHO) developed recommendations for the use of fractional-dose of yellow fever
      vaccine as a dose-sparing strategy. This strategy consisted on delivering 1/5th of the
      conventional dose and was used to vaccinate over 7 million people in Kinshasa, the capital
      city of DRC.

      The evidence to recommend the use of fractional dosing was based on a limited number of
      clinical studies. However this was considered sufficient to provide emergency
      recommendations. In order to broaden and also possibly simplify WHO recommendations of
      fractional dose use in case of need for emergency campaigns, additional data is needed to
      respond to the important data gaps. These include the applicability of the fractional dose to
      all WHO-prequalified vaccines, the persistence of neutralizing antibodies and the performance
      of the fractional dose in young children and populations in Africa including those with HIV.
      Following these data gaps, WHO called for research to be conducted.

      This study aims to respond to some of the research questions that would allow to broaden the
      recommendations on the use of fractional doses of yellow fever vaccine in emergency
      situations. The study will be conducted in Uganda and Kenya and the main objective is to
      assess the non-inferiority is seroconversion 28 days after vaccination of a fractional dose
      compared to full dose for each manufacturer. As secondary objectives the study will assess
      seroprotection 10 days and 1 year after vaccination, to assess rapidity and persistence of
      protective antibody levels; describe the geometric mean titre and the change in neutralizing
      antibody on Day 28 after vaccination with fractional and full doses; and assess the
      occurrence of adverse events and serious adverse events (SAE) during 28 days after
      administration of fractional and full doses. The study aims to recruit 960 adults (480 in
      Mbarara, Uganda, and 480 in Kilifi, Kenya). Results for the main outcome will be reviewed by
      the study Data and Safety Monitoring Board (DSMB) and if results are considered satisfactory,
      the study will continue with the recruitment of 420 children in Uganda and 250 HIV infected
      adults in Kenya, to assess non-inferiority of one of the WHO prequalified vaccines.
    

Intervention name(s): Stamaril, Sanofi Pasteur; Yellow fever vaccine, Bio-Manguinhos; Yellow fever vaccine, Institut Pasteur; Yellow fever vaccine, Chumakov Institute; Yellow fever vaccine, Chumakov Institute; Yellow fever vaccine, Chumakov Institute
Intervention type(s): Biological; Biological; Biological; Biological; Biological; Biological
Intervention description(s): Full dose
Fractional dose: one fifth (1/5); Full dose
Fractional dose: one fifth (1/5); Full dose
Fractional dose: one fifth (1/5); Full dose
Fractional dose: one fifth (1/5); Full dose
Fractional dose: one fifth (1/5); Full dose
Fractional dose: one fifth (1/5)
Other intervention name(s): Children sub-study; HIV + adults
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Epidemic response