The use of reduced doses of the yellow fever vaccine in a sub-Saharan African population: safety, immunogenicity and policy

Thesis

Yellow Fever (YF) is a potentially lethal haemorrhagic fever of significant public and global health importance. The 17-D YF vaccines have been used successfully for several decades with excellent immunogenicity and safety profile. A recent rise in outbreaks in endemic regions has been characterised by a repeated vaccine stock shortage that has led the World Health Organisation (WHO) to recommend the use of fractional doses as a dose sparing strategy. The recommendation was made with limited data from the African region.

A review of literature of the virus, epidemiology, vaccines and the current policies of use the vaccines explored the challenges with an upsurge in disease outbreak in endemic regions and the causes of the recurrent vaccine stock shortage. The literature identified the gaps in evidence on the use of fractional doses as a dose sparing strategy as recommended by the WHO.

Randomised, controlled, non-inferiority clinical trials comparing standard dose and fractional doses were conducted in Kenya and Uganda. In one study, a pragmatic fifth of the standard dose of the 17D-213 vaccine manufactured by the Institute of Poliomyelitis and Viral Encephalitidis, Russian Federation was tested against the standard in HIV-infected individuals. The second study was a dose-response study testing de-escalated doses of the 17D 204 vaccine manufactured by the Institut Pasteur de Dakar against a standard dose in a general population in Kenya and Uganda. The studies assessed safety and immunogenicity, as measured by neutralising antibody assays (PRNT). The studies found the fractional doses to be safe and sufficiently immunogenic with doses as low as 500 IU/dose immunogenically non-inferior to standard doses.

A systematised review of vaccine policy identified actors, mapped out policy processes and elements that influence the direction of vaccines when introducing new vaccine policies and changing existing vaccine policies. A stakeholder analysis with actors involved with YF vaccines explored their perceptions, positions, vaccine policy processes and factors that are vital to consider for wider use of fractional doses beyond the current recommendations by WHO.

In these policy analysis studies, I found that there are systematised processes for introducing and changing vaccine policies at the global and regional levels and that each vaccine policy is unique. There was general support for use of fractional doses of the YF vaccines. However, more evidence is needed for firmer recommendations. Additionally, vaccine policy processes are heavily political with advocacy, lobbying, actor coordination and communication playing important roles.

Authors: Mbaabu, DK

• DOI: 10.5287/ora-wxbqngej6
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: safety; immunogenicity; non-inferiority; fractional doses; yellow fever; clinical trial; vaccine policy
• Subjects: Policy makers; Human participants