Abstract
BackgroundThe RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5–17-month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program. Work is ongoing to optimise this vaccine, with higher efficacy for a different schedule demonstrated in a phase 2a challenge study. The objective of our study was to investigate the population-level impact of a modified RTS,S/AS01 schedule and dose amount in order to inform the target product profile for a second-generation malaria vaccine.MethodsWe used a mathematical modelling approach as the basis for our study. We simulated the changing anti-circumsporozoite antibody titre following vaccination and related the titre to vaccine efficacy. We then implemented this efficacy profile within an individual-based model of malaria transmission. We compared initial efficacy, duration and dose timing, and evaluated the potential public health impact of a modified vaccine in children aged 5–17 months, measuring clinical cases averted in children younger than 5 years.ResultsIn the first decade of delivery, initial efficacy was associated with a higher reduction in childhood clinical cases compared to vaccine duration. This effect was more pronounced in high transmission settings and was due to the efficacy benefit occurring in younger ages where disease burden is highest. However, the low initial efficacy and long duration schedule averted more cases across all age cohorts if a longer time horizon was considered. We observed an age-shifting effect due to the changing immunological profile in higher transmission settings, in scenarios where initial efficacy was higher, and the fourth dose administered earlier.ConclusionsOur findings indicate that, for an imperfect childhood malaria vaccine with suboptimal efficacy, it may be advantageous to prioritise initial efficacy over duration. We predict that a modified vaccine could outperform the current RTS,S/AS01, although fourth dose timing will affect the age group that derives the greatest benefit. Further, the outcome measure and timeframe over which a vaccine is assessed are important when prioritising vaccine elements. This study provides insight into the most important characteristics of a malaria vaccine for at-risk groups and shows how distinct vaccine properties translate to public health outcomes. These findings may be used to prioritise target product profile elements for second-generation childhood malaria vaccines.
Highlights
The RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5–17month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program
For the three-dose vaccine schedule, initial efficacy was associated with a higher reduction in childhood clinical cases compared to vaccine duration
We found that the low initial efficacy and long duration profile resulted in more clinical cases averted when measuring cases in all age groups, and over a longer time window; this is likely due to the functional form of this efficacy profile allowing the vaccine benefit to extend for far longer than expected in practice
Summary
The RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5–17month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program. The phase 3 trial of RTS,S/AS01 was conducted over the period 2009–2014, in two target age groups and for three- and four-dose schedules. In infants aged 6– 12 weeks at enrolment who received four doses of the trial vaccine, efficacy was 27.8% (21.7–33.4 95% CI) over a 32-month follow-up period. In 5–17-month-old children who received four doses, efficacy against clinical malaria was 43.9% (39.7–47.8 95% CI) over the same time period [4]. RTS,S/AS01 will be evaluated through a large-scale pilot implementation program in 5–17-month-old children in three sub-Saharan Africa settings: Ghana, Kenya and Malawi [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
