Pre-erythrocytic vaccines
At a reference transmission setting with annual entomological inoculation rate (EIR) of 21, the simulations predict that a PEV with 52% initial efficacy could be very cost-effective when delivered via EPI alone. At a vaccine price of US$2 per dose, the cost per uncomplicated malaria episode averted would be around US$ 5, the cost per severe malaria episode averted US$ 269, the cost per DALY averted around US$ 35 and the cost per death averted US$1057 (see table S1 and S2, Additional file 1). The cost-effectiveness ratios are lower for higher effectiveness levels (Figure 1). They increase almost proportionally with vaccine price reaching US$ 160 per DALY averted and US$ 4869 per death averted for a vaccine price of US$ 10 per dose (see table S3 and S4, Additional file 1).
The proportion of events averted by PEV delivered via EPI with booster doses is slightly higher, but the cost per uncomplicated episode averted is 20% higher (see table S1, Additional file 1), and cost per DALY and death averted is around 31% higher (see table S2, Additional file 1).
With EPI and mass vaccination the proportion of events averted is 5% higher for mass vaccination coverage of 50% and 8% higher for coverage of 70%[14], and the cost per uncomplicated episode averted is slightly lower. However, the costs per DALY and death averted are around 60%–66% higher (see table S1 and S2, Additional file 1). For higher efficacy levels the pattern is similar, showing that the incremental benefits of these deployment modalities, in this transmission setting, are modest (Figure 1).
In low transmission settings, while the cost per uncomplicated episode averted under EPI alone is similar to that in the reference transmission setting (see table S1 and S2, Additional file 1), the cost per DALY and death averted are lower at US$ 31 per DALY averted and US$ 925 per death averted at a vaccine price of US$ 2 per dose (see table S2 and S4, Additional file 1). Adding booster doses leads to higher cost-effectiveness ratios for efficacy levels up to around 60%, but at near 100% efficacy the cost-effectiveness ratios become similar (Figure 1). In contrast, when mass vaccination is added to EPI, the cost-effectiveness ratios decrease substantially, by around 70% for the cost per uncomplicated case averted (see table S1 and S3, Additional file 1), and by 24% to 28% for the cost per DALY and death averted (see table S2 and S4, Additional file 1).
In high transmission settings, the effectiveness of PEV is low[14] and the cost-effectiveness ratios are therefore higher than in the other transmission settings irrespective of delivery modality. For some outcomes, vaccination even leads to an increase in the number of clinical events[14], and, therefore, to negative cost-effectiveness ratios and negative case management cost savings (see table S5, Additional file 1).
Across all transmission settings, the incremental benefits of booster doses are small and the cost-effectiveness ratios are higher. Adding mass campaigns has little impact on overall effect when the primary efficacy is low. However, for high vaccine efficacy and high coverage, this strategy is predicted to lead to local elimination of the parasite in low transmission settings and substantially reduce transmission in medium transmission settings[14] at low additional costs. Under these conditions, because of the effects of the vaccine on transmission, delivery via mass campaigns plus EPI becomes a cost-effective alternative to EPI alone.
Blood-stage vaccines
At the reference transmission intensity, BSV of moderate efficacy with a price of US$ 2 per dose applied through EPI achieves a cost per uncomplicated episode averted of about US$ 9 (see table S1, Additional file 1), which is higher than for the corresponding PEV, but the costs per DALY averted (US$ 21) and per death averted (US$ 630) are lower than for PEV (see table S2, Additional file 1). At higher efficacy levels, the cost-effectiveness ratios decrease, following the same patterns as for PEV (Figure 2). Adding booster doses increases the cost-effectiveness ratios somewhat. Mass campaigns also increase the cost-effectiveness ratios except for uncomplicated episodes, where they decrease.
At low transmission intensity BSV averts a lower proportion of uncomplicated and severe cases and deaths than PEV[14] and the cost effectiveness ratios are higher for all outcomes. Adding booster doses leads to slightly higher costs per uncomplicated episode averted (see table S1 and S3, Additional file 1), and much higher costs per DALY and death averted (see table S2 and S3, Additional file 1, and Figure 2). Adding mass campaigns to EPI leads to a dramatic reduction in the cost per uncomplicated episode averted, but the costs per DALY and death averted are only slightly lower (see table S1, S2, S3, Additional file 1, and Figure 3, 4).
In high transmission settings BSV is more effective than PEV especially in averting severe and mortality events[14] and it is also more efficient. Under EPI alone the cost per uncomplicated episode averted, in the highest transmission setting, is US$ 3.8, the cost per DALY averted is US$13.5 and the cost per death averted is US$401, at vaccine price US$ 2 per dose (see table S1 and S2, Additional file 1, and Figure 3). Adding boosters or mass campaigns, leads to higher incremental costs than incremental benefits (see table S1, S2, S3, Additional file 1, and Figure 2).
Across all transmission settings, the incremental costs of adding booster doses to EPI are higher than the incremental benefits and this is particularly true for severe episodes, DALYs, and mortality (see table S1, S2, S3, Additional file 1, and Figure 2). In low transmission settings, campaigns improve cost-effectiveness for uncomplicated episodes averted, but do not change cost-effectiveness estimates for DALYs and deaths averted. However, in moderate to high transmission settings, the incremental costs of campaigns are higher than the incremental benefits (see table S1, S2, S3, Additional file 1, and Figure 2).
Combination vaccines and MSTBV
Combining BSV with PEV (with matched efficacies) in general, improves or matches the cases averted over PEV alone for all transmission settings and vaccine delivery modalities[14]. The cost-effectiveness ratios for this combination are lower than those of PEV in all transmission settings particularly for the cost per DALY and per death averted and in moderate to high transmission settings (see table S1, S2, S3 in Additional file 1, and Figure 3, 4). Compared to BSV alone, the cost-effectiveness ratios of combining BSV with PEV are lower, though the difference is smaller than for PEV and in this case it is higher in moderate to lower transmission settings than in high transmission settings. Adding booster doses to EPI leads to higher cost-effectiveness ratios across all transmission settings for this combination – the costs per uncomplicated episode averted increases by around 19%–23% while those per DALY and death averted show even larger increases (around 30%–40%).
Adding mass campaigns in low to moderate settings lead to incremental uncomplicated episodes averted that are higher than the incremental costs. However, in terms of DALYs and deaths averted the benefits exceed the costs only in the lowest transmission setting, while they are significantly lower in the reference and in high transmission settings. In high transmission settings even the additional uncomplicated episodes averted are lower than the additional costs.
Combinations of MS TBV with PEV or BSV and the triple combination do not improve the effectiveness of the vaccines alone when delivered via EPI or EPI with boosters[14]. However, adding mass campaigns leads to greater effectiveness in all transmission settings (Figure 4). The additional benefits of these combination vaccines are then much higher than the additional costs compared to delivering the vaccines under EPI alone and to all delivery modalities of PEV and BSV alone. In the reference transmission setting, for instance, the cost per uncomplicated episode averted of combining BSV with MSTBV, delivered via EPI and mass campaigns, is (at a vaccine price of US$2) US$1.8 and US$2.3 for 70% and 50% coverage (see table S1, Additional file 1), while the cost per DALY averted is US$20 and US$ 22 for 70% and 50% coverage (see table S2, Additional file 1). The costs per DALY averted vary between US$ 12 and US$40 across transmission settings with the lowest value in the lowest transmission setting where the greatest improvement to effectiveness is observed. The very favourable cost-effectiveness ratios in low transmission settings are related to the case-management cost savings, which may compensate up to more than 50% of the costs of the vaccine intervention (see table S4, Additional file 1).
Effect of delivery modalities
Adding boosters to EPI does not improve effectiveness or cases averted over EPI alone by very much even at the very high coverage level modeled, but it does incur additional costs. This delivery modality does therefore not represent a cost-effective alternative to EPI alone in any scenario (see table S1, S2, S3, Additional file 1).
Delivering all vaccines and combinations via population based campaigns improves the effectiveness at mass vaccination coverage of 50%, especially in low transmission settings[14]. Depending on the transmission setting and the vaccine type considered, the incremental costs of delivering vaccines via population based campaigns can be lower than the incremental benefits, leading to a significant reduction in the cost-effectiveness ratios (see table S1, S2, S3, Additional file 1, and Figure 4). Disseminating vaccines via population-based campaign in these cases is predicted to be a more cost-effective way of delivering malaria vaccines than EPI alone. Increasing the coverage of the mass vaccination campaigns increases the effectiveness and cases averted for all vaccine and vaccine combinations under most transmission settings[14]. However, the incremental benefits of increasing coverage are often lower than the incremental costs of achieving it (Figure 5). In some cases, the predictions suggest an optimal cost-effectiveness ratio at intermediate values for the campaign coverage. This is not a consequence of non-proportionality of vaccine delivery costs as a function of coverage (which could be realistic, but not modeled in this study), but of the indirect effects of the vaccines.
Effect of vaccine price
Although the simulations focus on comparative cost-effectiveness of different candidate malaria vaccines and delivery modalities, and not on the sensitivity of cost-effectiveness ratios to vaccine prices, which are hypothetical, it is evident that the cost-effectiveness results are almost directly proportional to the vaccine prices. In fact, at an assumed vaccine price of US$ 10 per dose, most cost-effectiveness ratios are between 4 and 7 times higher than those obtained at US$ 2 per dose (see table S1, S2, S3, Additional file 1). At a vaccine price of US$ 2 per dose, most vaccines and delivery modalities simulated present cost-effectiveness ratios comparable to those of other malaria interventions[9, 10, 41–43], while at a vaccine price of US$ 10 per dose in many of the simulated scenarios the cost-effectiveness ratios are higher.