Modeled estimates of the effect of the RTS,S vaccine allow for comparisons of uncomplicated cases and deaths averted, and the efficiency of different delivery strategies to avert those cases and deaths, in a variety of malaria transmission settings.
In most transmission settings studied, an approximately proportional relationship between the number of deaths averted and the number of doses administered through EPI, EPI plus catch-up and EPI plus school-based campaigns, was observed over the ten year period simulated. That is, among the delivery strategies that target a portion of the population, the greater the number of doses administered, the greater the total number of lives that can be saved.
The EPI strategy immunized the fewest people over ten years, and consequently averted the fewest deaths, but with a relatively high efficiency per 1000 doses administered across transmission settings. This strategy also provided the most consistent impact across transmission settings studied. EPI has demonstrated its feasibility and is compatible with current clinical trial and regulatory plans. The opportunity to make use of the thus far successful EPI infrastructure is a strong argument to use this strategy in (all) transmission settings where it is likely to be cost-effective to deliver RTS,S this way.
Supplementing EPI delivery with a one-time catch-up vaccination reaching children below 18 months may be particularly appealing in an environment with decreasing transmission (setting c). The catch-up delivery round would require additional investment and planning beyond that seen for EPI, although most likely less than required for repeated school-based or mass campaigns.
School-based delivery strategies did not increase efficiency in any of the transmission settings studied, so its main benefits are in reaching a greater number of people. A recent pilot of school-based strategies for delivering human papilloma-virus (HPV) vaccine could be part of the momentum to strengthen and expand school-based strategies over time 
The findings for mass campaigns were more complex. Mass campaigns reached many times more people than EPI alone, and simulations suggested this delivery strategy could be expected to avert more cases and deaths in some situations. Highest efficiency was seen in very low transmission settings (e.g. EIR of 2 ibpa), whether naturally occurring or achieved by other interventions (settings b and f). Efficiency decreased as transmission increased, making mass campaigns much less efficient than EPI at EIRs above 2 ibpa.
The impact of mass campaigns varied the most between different transmission settings, and there were wide ranges in the model predictions. In contrast to EPI, the expected benefits of mass vaccination were highly sensitive to model assumptions about transmission heterogeneity and immunity. The amount of field data on older children in semi-immune populations and adults is small, and there is a clear need to improve the evidence base for parameterizing these aspects of the models. Impact estimates from mass vaccination in low transmission settings were magnified by herd immunity. Vaccinating a large proportion of the population could decrease the likelihood that mosquitoes bite a person with circulating parasites, thereby decreasing the number of infectious mosquitoes in a region. Herd immunity is unlikely to arise with EPI strategies given that the vaccinated infants represent a relatively small portion of the population so would not significantly impact the number of circulating mosquitoes with parasites.
Part of the uncertainty about impact of mass-vaccination (also reaching adults) arose because relatively sparse data about disease incidence in older people were available when the models were fitted 
. In our models, the main effect of reducing transmission on disease is to shift morbidity to older ages. It is not clear how important this shift is in settings where transmission is currently reducing. If this shift is less important, independently of the effects of the vaccine, we might have expected to see larger effects of reducing transmission on morbidity and mortality rates. In contrast to most field datasets, the presented rates are calculated over the entire population and simulated events in adults dilute the effects on children. Thus, caution is advised when interpreting model results of mass campaigns until further data is available.
Mass vaccination also appears the most distant potential RTS,S delivery strategy. New clinical trials, in older age groups potentially with different safety questions and needing different doses, may be necessary. Regulatory, cost-effectiveness and feasibility considerations related to mass campaigns of a multi-dose vaccine given at one-month intervals, may also need to be addressed. The findings suggest that further work is needed to more clearly understand the impact and feasibility of mass campaigns, potentially when partnered with other interventions to rapidly decrease transmission. The potential for significant impact in some settings may make it worth beginning to anticipate such work.
Estimates of efficiency in this paper are expressed using the ratio of deaths averted per 1000 doses of vaccine. This can be converted to deaths averted per 1000 vaccinees, a ratio used by the GAVI Alliance (GAVI) when considering the impact of various vaccines it supports financially 
. The ratio of deaths averted by pneumococcal conjugate vaccine in African infants is estimated from trial data to be 7 per 1000 vaccinees (59 deaths averted in 8000 vaccinees) 
. Immunizing 1000 infants with RTS,S via EPI, given the coverage assumptions stated earlier, equates to delivering approximately 2770 doses of vaccine. Given the ratios under transmission settings above, simulations suggest RTS,S in EPI would avert 2–4 deaths per 1000 doses, equivalent to 6–11 deaths per 1000 vaccinees. While one should be cautious comparing data from field studies with those from modeling studies, these ratios suggest a favorable comparison with the pneumococcal vaccine, for which implementation planning is progressing rapidly in Africa and some $3 billion in financing have been committed 
The findings across the different settings suggest that for understanding the potential impact of pre erythrocytic vaccines, it is probably sufficient to use fixed transmission settings in modeling efforts, even for situations where the underlying baseline transmission is believed to be decreasing or increasing. The simulations used in this paper used IRS to create trends in transmission. Effects would have been slower if the transmission changes were induced by LLIN use, but there is no reason to assume that the relative impact of the delivery strategies would be different.
The effect for RTS,S was expected to be at maximum in the transmission range studied in these simulations (2–20 ibpa). It is reasonable to expect that EPI, EPI plus catch-up and EPI plus school-based strategies will have comparable effects to those seen in this paper at somewhat higher transmission settings than studied. Although cost-effectiveness estimates for EPI are available 
, the other impact estimates could be further informed by cost and cost-effectiveness analyses which were beyond the scope of this paper.
The development of the RTS,S malaria vaccine is progressing. If the vaccine is shown to be safe and efficacious in the current phase III trial, as has been shown in earlier trials, and it is made available to countries in Africa, there will be a complex decision-making process to determine how and where it should be used. In order to help this process, the authors studied the potential impact and efficiency of RTS,S delivered through various strategies and under changing levels of malaria transmission patterns, although findings suggest that it is probably sufficient for future simulations to consider constant EIR levels. The type of impact sought, whether on mortality and morbidity, or on transmission as well, together with assumptions about feasibility of different delivery strategies, may lead to different conclusions about the role of RTS,S.
Findings support further investigation of RTS,S to determine its potential contribution to malaria transmission reduction through high coverage of an all age population in low transmission settings. At 2 ibpa, mass campaigns could avert the most deaths and decrease transmission; however, a lot of uncertainty was associated with these findings. Also, the feasibility of mass campaigns delivering a multi-dose immunization requires assessment. Further consideration of the regulatory implications, clinical studies required to address questions of the extent of the benefit, and other product development activities will be important to anticipate, prior to RTS,S being used in mass campaigns. Such considerations would benefit from early planning due to their lengthy nature.
The findings also support going forward with EPI delivery as an initial strategy for RTS,S. If delivered via established EPI systems, RTS,S could avert approximately 6–11 deaths per 1000 vaccinees in all examined settings, an efficiency consistent with or superior to other new vaccines being implemented across Africa. However, it would have little effect on transmission when delivered via EPI. The number of events averted increases somewhat with the EPI plus catch-up and the EPI plus school-based strategies. The increase is essentially proportional to the larger population covered, and because that larger population coverage is modest, it is not an enormous added benefit. These results, combined with those of other modeling studies, should provide information to help policy-makers at international and country-levels to take evidence-based decisions on optimal strategies to avert malaria cases and deaths in Africa.