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Project Topic
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Yellow Fever virus is endemic in 34 countries in Africa, causing at least 130,000 symptomatic cases and 80,000 deaths in Africa every year. Life-long immunity can be conferred by a single dose of a highly effective vaccine, but this has not translated to sustainable control as a result of difficulties with vaccine supply. Vaccine production relies on laborious processes and capacity to produce increased stock in response to outbreaks is limited. In 2015, Unicef estimated the total country forecasts to be 64 million doses per year, exceeding current availability of vaccines by 42%. The limits of preventive activities have led to periodic major outbreaks and the stockpile of doses to respond to these is inadequate. Efficient use of available stock is therefore essential. Previous data suggest that fractional doses (i.e. using one fifth of a standard full dose) are likely to be sufficiently immunogenic to produce responses above the internationally recognized threshold for protection. The WHO SAGE committee recently recommended that fractional doses be considered in emergency responses to outbreaks where stock is limited, but did not consider the currently available data (which do not include any trials in Africa) to allow a broader recommendation. We therefore propose a trial with formal non-inferiority criteria and sufficient power to provide greater certainty regarding non-inferiority in sub-Saharan Africa. We will then conduct a trial in children using the dose defined from the adult study in order to confirm generalizability in children. We will vaccinate 1,935 adults to test the immunogenicity of full standard dose, 1,000, 500, and 250 IU (i.e. 4 arms), and then vaccinate 700 children with full standard dose and the lower non-inferior dose from the adult study (i.e. 2 arms). Our primary outcome will be the proportion of serological responses above the protective threshold 28 days after vaccination in an adult population in Africa. Secondary outcomes will include immunogenicity at 2 years, post-vaccination viraemia and serious adverse events. The participating institutions include two sites with experience of clinical vaccine trials (i.e. Mbarara, supported by Epicentre MSF, and Kilifi, supported by KEMRI-Wellcome Trust and University of Oxford), the Uganda National Health Research Organisation for work on viraemia and neutralizing assays, and a manufacturer of WHO prequalified vaccine, Institut Pasteur de Dakar, who will supply vaccine stock. In addition we will be supported by Robert Koch Institute, who will be contracted to supply serology standards, and by an independent consultant in regulatory applications for vaccines.
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