Fractional Dosing of Yellow Fever Live Attenuated 17D Vaccine: A Perspective

Yellow fever virus (YFV) is a mosquito-borne flavivirus that causes over 109,000 severe infections and over 51,000 deaths annually in endemic areas of sub-Saharan Africa and tropical South America. The virus has a transmission cycle involving mosquitoes and humans or non-human primates (NHPs) as the vertebrate hosts. Although yellow fever (YF) is prevented by a live attenuated vaccine (strain 17D), recent epidemics in Angola, the Democratic Republic of the Congo (DRC), and Brazil put great pressure on vaccine stockpiles. This resulted in the World Health Organization (WHO) and Pan American Health Organization (PAHO) implementing, on an emergency basis only, off-label dose-sparing techniques and policies during 2016-2018 to protect as many people in DRC and Brazil as possible from disease during unexpected large outbreaks of YF. Subsequently non-inferiority studies involving full doses compared to fractional doses indicated promising results, leading some policy-makers and scientists to consider utilizing YF vaccine fractional doses in non-emergency scenarios. Although the additional data on the immunogenicity and safety of fractional doses are promising, there are several questions and considerations that remain regarding the use of fractional doses, including differences in the initial antibody kinetics, differences in the immune response in certain populations, and durability of the immune response to fractional doses compared to full doses. Until the remaining knowledge gaps are addressed, full doses instead of fractional doses should continue to be used unless there are insufficient doses of the vaccine available to control outbreaks of YF.Plain Language Summary: Yellow fever (YF) disease is prevented by a live attenuated vaccine, strain 17D. Its production is confined by the need to be grown and harvested in embryonated chicken eggs. This can result in limited supplies of 17D vaccine, particularly during periods of increased demand. In 2016-2018, the vaccine stockpile was exhausted on multiple occasions. This led to the vaccine being used at one-fifth of a dose, so-called "dose-sparing" or "fractional dosing". Clinical trials support the safety and immunogenicity of fractional dosing, with all 17D vaccines used as a fractional dose having a non-inferior antibody response (ie, seroconversion) to a full dose at 28 days. The use of fractional dosing during 2016-2018 was very successful in controlling outbreaks. However, there are limited data on the use of fractional doses in populations who might have an altered immune response and the durability of the immune response. As such, the World Health Organization only approves use of fractional dosing in emergency scenarios. The successes of fractional dosing campaigns and clinical trials are encouraging and could lead to further consideration of the use of fractional doses of YF vaccine once the remaining knowledge gaps have been addressed.