What is the problem/background? Yellow fever (YF) is a mosquito-borne viral disease that is endemic in 34 countries in Africa and 14 in South America. YF virus infection can cause mild or severe illness, leading to jaundice, kidney failure, bleeding and death. The YF vaccine is shown to be very effective for outbreak control as well as for the prevention of outbreaks. However insufficient vaccine is produced for routine use, and the stockpile of 2 million doses reserved for outbreak control is frequently depleted. What questions are we trying to answer? The WHO has recommended consideration of using one fifth of a standard dose to be able to vaccinate more individuals with a given quantity of vaccine. We will compare the immune response after vaccination for a standard dose of the vaccine versus the response after one fifth of a vaccine dose for four different yellow fever vaccine manufacturers. We will also compare adverse events after vaccination for a standard vaccine dose versus one fifth of a vaccine dose. Where is the study taking place, how many people does it involve and how are they selected? The study will take place in Kilifi, Kenya and Mbarara, Uganda. The study will include 480 adults in Kilifi. The inclusion criteria will include: • Individuals aged ≥18 - <60 years of age. • Providing informed consent to participate in the study • HIV status o HIV negative on serological screening OR o HIV positive on serological testing, and no symptoms suggestive of current clinical immunosuppression and CD 4 count>200 within the last 6 months. The exclusion criteria include: • Known contraindications to YF vaccination such as allergies to egg protein, immunodeficiency due to symptomatic (i.e. clinical stage 3 or 4) HIV infection, known thymus disorder, such as thymoma and myasthenia gravis • Acute febrile disease on the day of vaccination • Previous YF vaccination as determined from history • Previous YF infection as determined from history • Pregnancy (as determined by a urine test on the proposed day of vaccination) and lactating women • Planning to migrate out of the study areas before the end of the study follow-up • Planning to travel to a country requiring YF vaccination certificate within the first year after vaccination. What does the study involve for those who are in it? Participants who have previously not had the yellow fever vaccine and/or infection will be screened for HIV infection and for any significant health problems, then receive a single dose of yellow fever vaccine. Participants will then need to attend follow up on a further 3 occasions to have blood tests for antibody levels, to show immune responses to the vaccine, and to be asked about any side effects. What are the benefits and risks/costs of the study for those involved? The risks relate to the possibility of developing an allergic or other reaction upon administration of the yellow fever vaccine. There are no immediate health benefits to individuals participating in this study other than information about their health. If there was a yellow fever outbreak in the future, then participants getting full dose would be expected to be protected and there is a chance that participants who receive the lower dose would be protected against infection. We are not able to issue yellow fever vaccination certificates to participants or provide reassurance regarding protection. Once we have unblinded the study we will be able to reassure those receiving full dose that they are protected, and if we see non-inferiority of immunogenicity then we will be able to reassure those receiving one-fifth doses regarding protection. The laboratory testing is not intended to provide reassurance on an individual by individual basis and we would not provide individual-level immunological data to participants. The participants will be compensated for the fares that they will incur during the visits to the study clinic. They will also be compensated a preset KSH 500 for the time spent at the clinic. How will the study benefit society? If one fifth of a vaccine dose raises the same immune response as a full dose, then in effect this finding will substantially increase the number of doses that can be given based on the world’s currently available vaccine stock and will enhance our ability to prevent and control yellow fever outbreaks.

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 global 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 data from a limited number of clinical trials and additional studies should be conducted 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 (Mbarara, MSF Epicentre) and in Kenya (in KEMRI CGMR-C). The main objective is to assess the non-inferiority of 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 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 (i.e. 480 per site) for the main study. Results for the safety and primary outcome for the main study will be reviewed by the study Data and Safety Monitoring Board and one vaccine will then be selected for the studies in children (n=418) and HIV positive adults (n=250). Both sites will participate in the main study (i.e. 480 adults per site), whereas the sub-study in children will be done in Mbarara and the sub-study in HIV positive adults will be conducted in Kilifi.