Potential public health impact of RTS,S malaria candidate vaccine in sub-Saharan Africa: a modelling study

Abstract

Background: Adding malaria vaccination to existing interventions could help to reduce the health burden due to malaria. This study modelled the potential public health impact of the RTS,S candidate malaria vaccine in 42 malaria-endemic countries in sub-Saharan Africa.

Methods: An individual-based Markov cohort model was constructed with three categories of malaria transmission intensity and six successive malaria immunity levels. The cycle time was 5 days. Vaccination was assumed to reduce the risk of infection, with no other effects. Vaccine efficacy was assumed to wane exponentially over time. Malaria incidence and vaccine efficacy data were taken from a Phase III trial of the RTS,S vaccine with 18 months of follow-up (NCT00866619). The model was calibrated to reproduce the malaria incidence in the control arm of the trial in each transmission category and published age distribution data. Individual-level heterogeneity in malaria exposure and vaccine protection was accounted for. Parameter uncertainty and variability were captured by using stochastic model transitions. The model followed a cohort from birth to 10 years of age without malaria vaccination, or with RTS,S malaria vaccination administered at age 6, 10 and 14 weeks or at age 6, 7-and-a-half and 9 months. Median and 95% confidence intervals were calculated for the number of clinical malaria cases, severe cases, malaria hospitalizations and malaria deaths expected to be averted by each vaccination strategy. Univariate sensitivity analysis was conducted by varying the values of key input parameters.

Results: Vaccination assuming the coverage of diphtheria-tetanus-pertussis (DTP3) at age 6, 10 and 14 weeks is estimated to avert over five million clinical malaria cases, 119,000 severe malaria cases, 98,600 malaria hospitalizations and 31,000 malaria deaths in the 42 countries over the 10-year period. Vaccination at age 6, 7-and-a-half and 9 months with 75% of DTP3 coverage is estimated to avert almost 12.5 million clinical malaria cases, 250,000 severe malaria cases, 208,000 malaria hospitalizations and 65,400 malaria deaths in the 42 countries. Univariate sensitivity analysis indicated that for both vaccination strategies, the parameters with the largest impact on the malaria mortality estimates were waning of vaccine efficacy and malaria case-fatality rate.

Conclusions: Addition of RTS,S malaria vaccination to existing malaria interventions is estimated to reduce substantially the incidence of clinical malaria, severe malaria, malaria hospitalizations and malaria deaths across 42 countries in sub-Saharan Africa.

Figures

Fig. 1

Model structure. M maternal protection, S susceptible, I infected (parasites emerging from the liver), C clinical disease episode, F severe disease episode and there are 6 levels of immunity with compartments S, I, C and F divided into 6 levels, R resistant, wm waning of maternal immunity, q probability of infection, s susceptibility to infection as a function of age, a probability of asymptomatic infection, r recovery rate from clinical disease, w waning rate of acquired immunity, rimm probability of developing full immunity. The model assumes two processes for acquisition of immunity, one process that protects against clinical malaria of any severity and a faster process that protects against severe malaria

Fig. 2

Model validation, incidence of clinical malaria. Incidence of clinical malaria (defined as in Table 1) per child per year over the 18-month follow-up period observed in the control arm of the Phase III trial and predicted by the model in each transmission category in a the 6–12 weeks age group and b the 5–17 months age group

Fig. 3

Age distribution of clinical and severe malaria cases predicted by the model compared with published data. Comparison of the age distribution of a clinical malaria cases and b severe malaria cases predicted by the model with age distribution data published by Carneiro et al. [14]. To allow for differences in transmission intensity definitions, the high transmission data from the model were compared with the moderate transmission data from Carneiro et al., and for clinical cases the moderate transmission data from the model were compared against an average calculated from the moderate and low transmission data from Carneiro et al. Severe cases were compared against the hospitalized cases from Carneiro et al. for which data are not available for low transmission settings without seasonality. The Y axis shows the percentage of events occurring in a particular month of age out of the total number of events during the observation period

Fig. 4

Predicted percentage of clinical malaria cases averted with RTS,S vaccination at age 6, 10 and 14 weeks and at age 6, 7-and-a-half and 9 months in children under 5 years of age (a) and in children under 10 years of age (b) for low (PP < 5 %), moderate (5 < PP < 40 %) and high transmission levels (PP > 40 %)

Fig. 5

a Univariate sensitivity analysis on vaccination at 6, 10 and 14 weeks. Effect of varying each indicated input parameter to the upper and lower values shown on the total number of malaria deaths expected to be averted over 10 years by vaccination at age 6, 10 and 14 weeks CT, artemisinin-based combination therapy; CFR case-fatality rate, DTP diphtheria-tetanus-pertussis, VE vaccine efficacy, MAP Malaria Atlas Project. b Univariate sensitivity analysis on vaccination at 6, 7-and-a-half and 9 months. Effect of varying each indicated input parameter to the upper and lower values shown on the total number of malaria deaths expected to be averted over 10 years by vaccination at age 6, 7-and-a-half and 9 months. ACT artemisinin-based combination therapy, CFR case-fatality rate, DTP diphtheria-tetanus-pertussis, VE vaccine efficacy, MAP Malaria Atlas Project