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

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.

A phase 3, randomized, observer-blind non-inferiority trial will be undertaken to assess the safety and immunogenicity of fractional doses of the yellow fever vaccine when administered to 9-12 month olds in The Gambia. In 2016, the worst epidemic of yellow fever in 30 years occurred in Central Africa on a background of year on year increases in disease despite the availability of a safe and highly effective vaccine. A revised global strategy for epidemic elimination published by the WHO highlighted the critical role played by vaccine supply shortages in the current disease resurgence. These shortages became acute during the recent epidemic when, faced with the impending exhaustion of vaccine stockpiles, fractional (one fifth, 0.1mL) doses of the vaccine were recommended for ongoing emergency campaigns. This trial aims to generate a comprehensive data set on which to base future policy decisions regarding the use of fractional dose of the yellow fever vaccine in infants and children in sub-Saharan Africa. The following research questions will be addressed:
1. Does the administration of a fractional subcutaneous or intradermal dose of a yellow fever vaccine result in seroconversion rates which are non-inferior to those induced by a full subcutaneous dose of the same vaccine?
2. Is there a difference in the geometric mean antibody titres induced by fractional yellow fever vaccine doses according to whether administered by the subcutaneous or intradermal route?
3. Is there a difference in the safety profile of fractional yellow fever vaccine doses according to whether administered by the subcutaneous or intradermal route?
Immunogenicity will be compared based on neutralizing antibodies. Local and systemic reactogenicity will be collected according to standard criteria. Other adverse events following immunization will also be recorded. The data are expected to influence future global vaccine policy decisions regarding fractional dose yellow fever vaccine use.

In 2016, the worst epidemic of yellow fever in over 30 years occurred in Central Africa on a background of progressive increases in disease over the past two decades. Most recent estimates suggest that annually there are now more than 1.3 million infections including 180,000 severe cases and 78,000 deaths in Africa alone. This, despite the availability of a safe and effective vaccine which confers lifelong protection following only a single dose. The revised 'Global Strategy to Eliminate Yellow Fever Epidemics' subsequently published by the WHO underlined the critical role played by vaccine supply shortages in disease resurgence. These became acute during the epidemic when, faced with uncontrolled spread and the impending exhaustion of vaccine stockpiles, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization took the decision to recommend the use of fractional (0.1mL rather than 0.5mL) doses of the yellow fever vaccine for on-going emergency campaigns, thus substantially increasing the coverage achievable. This trial addresses the subsequent research priorities related to the potential future use of fractional yellow fever vaccine doses in sub-Saharan Africa.
The findings will be of direct importance to the WHO and it is through providing high quality evidence on which the SAGE committee are able to base their recommendations that the maximum impact of the trial will be felt. Given the current level of population immunity in sub-Saharan Africa further large epidemics are considered near inevitable. Safety and immunogenicity data to support the use of fractional doses of the vaccine during subsequent emergency campaigns would substantially reduce the size of the vaccine stockpile which must be reserved for this purpose as well as facilitating rapid epidemic control. It would also reduce the risk of needing vaccine intended for programmatic use and preventative campaigns to be re-directed to outbreak control. This happened during the recent epidemic and ultimately compromises the long term control strategy.
Data supporting a recommendation by SAGE endorsing the use of fractional yellow fever vaccine doses for preventative campaigns and/or for programmatic administration to infants would have substantial additional impact and would largely overcome the chronic vaccine shortages which are allowing current disease resurgence. As indicated in the revised elimination strategy, it is only through the consistent use of both approaches that population immunity will reach a threshold above which person to person spread and hence epidemic disease is prevented. Supportive data on fractional dosing could be key to this given vaccine supply is not expected to demand within the next decade.
Even without a general recommendation, data to support fractional dosing would be of direct value to the National Immunization Technical Advisory Groups (NITAGs) that are responsible for providing national policy recommendations. Many countries that have introduced yellow fever vaccination into their immunization schedule have faced vaccine stock-outs due to the re-direction of vaccines for epidemic control. Supportive safety and immunogenicity data could readily be used by NITAGs to back national fractional dose use, preventing cohorts of infants going unimmunized, even if a booster was later judged to be necessary.
Finally, the trial is expected to have important value at an individual level for health professionals administering yellow fever vaccines and parents taking their children to be immunized. The trial will generate a strong set of safety and immunogenicity data regarding fractional dose use in this age group. Irrespective of setting, parental confidence in vaccination is critically dependent on the availability of such data and on the ability of health care providers to provide such information honestly. Thus, generating a data set of relevance to infants and children in sub-Saharan Africa is essential.