Estimated impact of RTS,S/AS01 malaria vaccine allocation strategies in sub-Saharan Africa: A modelling study

Background The RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5-17 months. Pilot vaccine implementation has recently begun in 3 African countries. If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards. Vaccine demand may, however, outstrip initial supply. We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling. Methods and findings Using a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0-5 years in sub-Saharan Africa under 2 scenarios for vaccine coverage (100% and realistic) and 2 scenarios for other interventions (current coverage and World Health Organization [WHO] Global Technical Strategy targets). We used a prioritisation algorithm to identify potential allocative efficiency gains from prioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted. If malaria burden at introduction is similar to current levels-assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%-we estimate that 4.3 million malaria cases (95% credible interval [CrI] 2.8-6.8 million) and 22,000 deaths (95% CrI 11,000-35,000) in children younger than 5 years could be averted annually at a dose constraint of 30 million. This decreases to 3.0 million cases (95% CrI 2.0-4.7 million) and 14,000 deaths (95% CrI 7,000-23,000) at a dose constraint of 20 million, and increases to 6.6 million cases (95% CrI 4.2-10.8 million) and 38,000 deaths (95% CrI 18,000-61,000) at a dose constraint of 60 million. At 100% vaccine coverage, these impact estimates increase to 5.2 million cases (95% CrI 3.5-8.2 million) and 27,000 deaths (95% CrI 14,000-43,000), 3.9 million cases (95% CrI 2.7-6.0 million) and 19,000 deaths (95% CrI 10,000-30,000), and 10.0 million cases (95% CrI 6.7-15.7 million) and 51,000 deaths (95% CrI 25,000-82,000), respectively. Under realistic vaccine coverage, if the vaccine is prioritised sub-nationally, 5.3 million cases (95% CrI 3.5-8.2 million) and 24,000 deaths (95% CrI 12,000-38,000) could be averted at a dose constraint of 30 million. Furthermore, sub-national prioritisation would allow introduction in almost double the number of countries compared to national prioritisation (21 versus 11). If vaccine introduction is prioritised in the 3 pilot countries (Ghana, Kenya, and Malawi), health impact would be reduced, but this effect becomes less substantial (change of <5%) if 50 million or more doses are available. We did not account for within-country variation in vaccine coverage, and the optimisation was based on a single outcome measure, therefore this study should be used to understand overall trends rather than guide country-specific allocation. Conclusions These results suggest that the impact of constraints in vaccine supply on the public health impact of the RTS,S malaria vaccine could be reduced by introducing the vaccine at the sub-national level and prioritising countries with the highest malaria incidence. Author summary Why was this study done? The RTS,S/AS01 malaria vaccine has previously been shown to be moderately efficacious in children, preventing approximately 36% of malaria cases in children who received 4 doses in a clinical trial. A pilot vaccine introduction is now ongoing in 3 African countries. Previous modelling has shown that implementing the vaccine could have a substantial public health impact and be cost-effective in preventing malaria cases and deaths in children. If the vaccine is recommended for wider introduction, it is likely that there will be an initial constraint on the number of doses available. What did the researchers do and find? We used an established model of malaria transmission to estimate the impact of the RTS,S malaria vaccine in sub-Saharan African countries, for different levels of RTS,S coverage. We applied a ranking algorithm to explore optimal vaccine allocation at the country and sub-national level, for different supply constraints. If initial malaria vaccine demand is higher than supply, prioritising the countries with the highest incidence would have the greatest impact in reducing malaria burden. Allocating the vaccine at the sub-national level was more efficient and allowed the vaccine to be introduced in almost double the number of countries compared to country-level introduction. What do these findings mean? If the RTS,S vaccine is implemented beyond the pilot introduction, prioritising areas with the highest malaria burden may avert a substantial number of childhood deaths. Allocating the vaccine sub-nationally would maximise the overall public health benefit in terms of clinical malaria cases and deaths averted. Sub-national allocation would also allow more countries to introduce the vaccine earlier, ensuring more equitable access for populations at highest risk. Any sub-national introduction would involve challenges, and additional research would be needed to define locally appropriate metrics for vaccine prioritisation, including in the context of other malaria interventions.