Non- Inferiority Fractional-doses Trial for Yellow Fever Vaccine
Condition: Yellow Fever
MeSH terms: Yellow Fever; Fever; Hyperthermia
Study type: Interventional
Phase: Phase 4

Summary: 
      In the recent past there has been a number of large urban Yellow Fever outbreaks in
      sub-Saharan Africa, tropical South Americas, The demand for Yellow Fever vaccines in response
      to the large urban outbreaks occurring concurrently and the risk of further spread through
      Africa and to Asia was larger than the available global supply. In this situation, the World
      Health Organisation (WHO) developed recommendations for the use of fractional doses of Yellow
      Fever vaccine as a dose-sparing strategy. These recommendations were based on data from a
      limited number of clinical trials, none of which had been conducted in Africa. This was due
      to the uncertainties on the minimum dose requirement.

      Our study complements a study which is comparing full standard dose to 1/5th of standard dose
      of all four WHO-prequalified YF vaccines in adults (ClinicalTrials.gov number: NCT02991495),
      and is currently ongoing at KEMRI CGMRC and Epicentre, Mbarara which is designed to answer
      questions on the use of current stock of YF vaccines with a potency as close as possible to
      each manufacturers' minimum release. Data from this trial will inform a WHO recommendation on
      using 1/5th of the current standard dose of vaccine for outbreak control. However, since many
      vials will contain excess YF vaccine such that 1/5th of a vial is likely to be substantially
      above the current minimum potency requirements, these data may not be scientifically
      explanatory regarding the minimum dose required for preventive use.

      The new complementary study, aims to determine the lowest YF vaccine dose that is
      non-inferior to the current standard full dose among populations in sub-Saharan Africa. The
      study will be conducted in Kenya (KEMRI Center for Geographical Medicine Research-Coast
      (CGMR-C), Kilifi) and Uganda (Epicentre, Mbarara) with trial participants recruited at both
      sites, using vaccine from one WHO-prequalified manufacturer (Institut Pasteur de Dakar,
      Senegal (IPD)).
    

Detailed description: 
      Yellow fever (YF) is a disease caused by a mosquito-borne flavivirus that is endemic in
      sub-Saharan Africa and tropical South America. Ninety percent of YF cases are in Africa where
      YF virus is transmitted by different mosquito genera in three recognized transmission cycles.
      A sylvatic cycle involves transmission between forest-dwelling mosquitoes (Haemagogus spp)
      and non-human primate reservoirs, with sporadic incidental transmission to humans (e.g.
      forest workers). An intermediate cycle, occurring only in Africa, involves mosquito
      transmission between non-human primates and humans, or human-to-human transmission among
      humans living or working close to forested areas. An urban cycle involves transmission
      between humans and urban mosquito vectors, primarily Aedes aegypti, and occurs when a
      viraemic person, infected in the sylvatic or intermediate cycle, introduces YF virus to areas
      with a large non-immune population and A. aegypti vectors resulting in disease outbreaks.

      Infection with YF virus is characterised by a wide range of manifestations, ranging from
      subclinical infection with mild and non-specific symptoms, to severe, life-threatening
      illness with jaundice, renal failure and haemorrhage.

      A highly effective vaccine is available for use against YF in adults and children aged ≥9
      months. The vaccine is a freeze-dried preparation of live attenuated YF virus strain 17D,
      which was developed in 1937 and is produced by four WHO-prequalified manufacturers. A single
      dose of YF vaccine is considered sufficient to confer life-long protective immunity against
      all seven known genotypes of wild-type YF virus. Protective levels of YF virus neutralizing
      antibodies are developed in 80-100% vaccine recipients within 10 days after vaccination, and
      in 99% within a month.

      Although fractional dosing has recently been used in vaccination campaigns in Kinshasa and
      Brazil in 2016, 2017 and 2018, WHO recommendations were based on a limited number of clinical
      studies and important data gaps remain.

      fractional vaccine dosing is compounded by the uncertainty surrounding minimum dose
      requirements.

      This study therefore aims to determine the lowest dose in International Units (IU/dose) that
      is non-inferior to the standard full dose among populations in sub-Saharan Africa. The data
      generated in this study will provide information regarding the re-definition of the minimal
      dose and potency requirements of the vaccine. The study will also provide further confidence
      in the use of fractional doses of YF vaccine during epidemics. In addition, the investigators
      will assess the range of views and perceptions of key stakeholders in vaccine policy and
      implementation on reduced vaccine dose usage during YF epidemics and for routine use.

      . The study will be conducted at the KEMRI CGMRC in Kilifi, Kenya and at Epicentre in
      Mbarara, Uganda. Both these sites are already working together in an ongoing study
      (ClinicalTrials.gov number: NCT02991495).

      Adult participants (n=480) will be randomized for vaccination with full standard dose or with
      1000, 500 or 250 IU (i.e. 4 arms) with a 1:1:1:1 allocation ratio. Results for the safety and
      primary outcome of the adult study will then be reviewed by the DSMB, and the lowest
      non-inferior dose in the adult study selected for assessment in children aged 9 months to 5
      years (n=420) in comparison to full standard dose (i.e. 2 arms) with a 1:1 allocation ratio.
      The determination of the non-inferior dose to use in children will be made by the sponsor in
      discussion with the study Data Safety and Monitoring Board (DSMB), vaccine manufacturer and
      relevant stakeholders, and the final decision communicated to the various regulatory
      authorities as a notification (i.e. Scientific and Ethics Review Board (SERU) at KEMRI,
      Oxford Tropical Research Ethics Committee (OxTREC) and Pharmacy and Poisons board (PPB) for
      the Kilifi site, Mbarara University of Science and Technology's Research Ethics Committee
      (MUST-REC), Uganda National Council of Science and Technology (UNCST) and National Drug
      Authority (NDA) for the Mbarara site).

      Adult vaccinees will be followed up for 2 years, and children for 1 year. There will be no
      gradual age de-escalation on the basis that there are few safety concerns with the full dose
      of YF vaccines, having been used in millions of children worldwide.
    

Intervention name(s): Yellow fever vaccine, Institut Pasteur
Intervention type(s): Biological
Intervention description(s): Full dose and 500IU/dose
Other intervention name(s): Children sub-study
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Adult participants (n=480) will be randomized for vaccination with full standard dose or with 1000, 500 or 250 IU (i.e. 4 arms) with a 1:1:1:1 allocation ratio. Results for the safety and primary outcome of the adult study will then be reviewed by the DSMB, and the lowest non-inferior dose in the adult study selected for assessment in children aged 9 months to 5 years (n=420) in comparison to full standard dose (i.e. 2 arms) with a 1:1 allocation ratio.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Yellow Fever vaccine; Fractional doses; Yellow Fever; Vaccine dose