Timing of the fourth dose of RTS,S/AS01 malaria vaccine in perennial settings: a modelling study

Abstract Background The recommendation of the RTS,S/AS01 malaria vaccine for use in children in moderate to high transmission areas by the WHO in 2021 provided another crucial tool in reducing malaria morbidity and mortality. As countries introduce the RTS,S/AS01 vaccine, there is an interest in exploring vaccination schedules that align with existing routine health touchpoints and to optimize vaccine coverage. Methods This study used OpenMalaria, an individual-based, stochastic model of malaria transmission and disease progression, to assess the impact of different vaccination timing schedules and coverage on uncomplicated malaria cases, severe malaria cases, and malaria-related deaths across different archetypal transmission settings. We ran simulations comparing fourth dose protection against infection and timings at 6-, 9-, 12-, 15- and 18-month intervals following the primary series, including exploring ranges of plausible protection assumptions for many of the dose timings. Results The primary series substantially reduces the malaria burden across transmission settings, regardless of timing of the fourth vaccine dose. For example, at a baseline Plasmodium falciparum prevalence in 2–10 year olds ( Pf PR 2-10 ) of 20%, our modeling suggests that the primary series is responsible for around 73–93% of the total uncomplicated and 74%-92% of severe cases averted regardless of fourth dose timing in perennial settings. Additionally, a fourth dose of the vaccine in this transmission setting could avert additional 8–38% of uncomplicated and 9–36% of severe malaria cases in addition to the primary series alone. While the number of cases averted varies by baseline prevalence, we find potential flexibility in timing this dose, especially when focused on 6 to 12 months following the primary series. Conclusions A fourth dose delivered between 15- and 21-months of age (corresponding to a 6–12 month interval after the third dose) with high population coverage will likely avert the largest proportion of cases of uncomplicated malaria, severe malaria, and deaths in perennial settings, across transmission intensities. Therefore, the delivery of the fourth dose of the RTS,S/AS01 vaccine can be tailored to country-specific context and linked to existing health touchpoints to ensure adequate coverage of this dose to optimize its impact.