A non-inferiority trial to assess the safety and immunogenicity of yellow fever vaccine dose sparing strategies for campaign and programmatic use

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Yellow fever is a viral infection which is transmitted from person to person by mosquitos. The virus is found in a total of 44 countries across sub-Saharan Africa and South America and most recent estimates suggest that it now causes more than one-million infections each year including 180 000 severe cases and 78 000 deaths in Africa alone. These infections continue to occur despite the availability of a safe and highly effective vaccine which confers lifelong protection against disease after only a single injection. In 2016, the worst epidemic (disease outbreak) of yellow fever in 30 years occurred in Central Africa. Cases due to international travel, also occurred in China sparking fears of uncontrolled disease spread in Asia. The epidemic occurred on the background of progressive increases in yellow fever disease over the past two decades and drove the publication of a new 'Global Strategy to Eliminate Yellow Fever Epidemics' by the World Health Organisation (WHO) in late 2016. This document highlighted the emerging global threat posed by the yellow fever and the major role played by shortages of the yellow fever vaccine in the current disease resurgence. Nearly half of the 34 countries which have introduced the vaccine into their routine immunization schedule for infants ran out of vaccine between 2013 and 2015 with many countries receiving only 50% of the number of doses of the vaccine they needed. These shortages got worse during the recent epidemic when, faced with the possibility of running out of vaccine completely, the WHO took the decision to recommend that 'fractional' doses of the vaccine should be used in the emergency vaccination campaigns being used to control the outbreak. In this way, one fifth (0.1mL) of the normal dose (0.5mL) is given to each person meaning that five times as many people can be vaccinated. There are no studies to see how good fractional doses of the yellow fever vaccine are in babies and children and no studies of have tested fractional doses of the vaccine in sub-Saharan Africa. This is why this study is important. The mains questions we want to ask in 9 to 12 month old Gambian infants are:1. Does giving a fractional dose of a yellow fever vaccine to an infant given them as much protection from yellow fever infection as giving them a full dose of the vaccine? 2. Is there a difference in the amount of protection from yellow fever generated when a fractional dose is given subcutaneously (under the skin - the normal way yellow fever vaccines are given) or intradermally (into the skin)3. Is there any difference in the safety of a fractional dose of the vaccine depending on whether it is given subcutaneously or intradermally? The results of the study will give the WHO expert committee on vaccination policy important information. It will help them to decide if fractional rather than full doses of the yellow fever vaccine can be recommended for future emergency vaccination campaigns including infants and children. It will also help them to decide if fractional rather than full doses can be given to infants as part of their routine scheduled vaccinations or in preventative campaigns. It is hoped that the results of the study will help to stop yellow fever epidemics across sub-Saharan Africa in the future.