Calibration of an intrahost malaria model and parameter ensemble evaluation of a pre-erythrocytic vaccine

Abstract

Background: A pre-erythrocytic vaccine could provide a useful tool for burden reduction and eventual eradication of malaria. Mathematical malaria models provide a mechanism for evaluating the effective burden reduction across a range of transmission conditions where such a vaccine might be deployed.

Methods: The EMOD model is an individual-based model of malaria transmission dynamics, including vector lifecycles and species-specific behaviour, coupled to a mechanistic intrahost model of malaria parasite and host immune system dynamics. The present work describes the extension of the EMOD model to include diagnoses of severe malaria and iterative calibration of the immune system parameters and parasite antigenic variation to age-stratified prevalence, incidence and severe disease incidence data obtained from multiple regions with broadly varying transmission conditions in Africa. An ensemble of calibrated model parameter sets is then employed to evaluate the potential impact of routine immunization with a pre-erythrocytic vaccine.

Results: The reduction in severe malaria burden exhibits a broad peak at moderate transmission conditions. Under sufficiently intense transmission, a vaccine that reduces but does not eliminate the probability of acquisition from a single challenge bite may delay infections but produces minimal or no net reduction. Conversely, under sufficiently weak transmission conditions, a vaccine can provide a high fractional reduction but avert a relatively low absolute number of cases due to low baseline burden.

Conclusions: Roll-out of routine immunization with pre-erythrocytic malaria vaccines can provide substantial burden reduction across a range of transmission conditions typical to many regions in Africa.

Figure 1

(Two left columns) Age-stratified prevalence data and simulation results from four regions in Nigeria and Tanzania. (Right column) Age-stratified incidence data and simulation results from two regions in Senegal. In both panels, the blue-shaded regions represent the 68/95/100% quantiles of simulations passing the likelihood threshold.

Figure 2

(Left) Age-stratified severe disease incidence data and results from simulations from five regions in Africa; note the changing y-axis when comparing. (Right) Proportions of severe disease incidence in various categories. In both panels, the blue-shaded regions represent the 68/95/100% quantiles of simulations passing the likelihood threshold. PfPR_2–10 is the proportion of 2–10 years olds testing positive for falciparum parasites.

Figure 3

The two pre-erythrocytic vaccine models evaluated: 80% efficacy with nine-month halflife and 60% efficacy with three-year halflife.

Figure 4

Severe disease incidence per 1,000 children per year at annual EIR = 15. The median baseline incidence is in dark red, and incidence with the fast-waning vaccine is shown in dark blue. The region of incidence reduction at young ages is highlighted in light blue. The disease incidence rebounds at ~2.5 years of age, and the rebound is highlighted in light red.

Figure 5

Period of severe (left) and clinical (right) case reduction prior to rebound for the fast-waning and slow-waning vaccine models. The lines follow the median output value from the ensemble of model parameters, and shaded areas outline the 68% quantiles.

Figure 6

EIR-dependent reduction in relative (top) and total (bottom) incidence of severe (left) and clinical (right) malaria; incidence, per 1,000 children over the first ten years of life, for both vaccine models. The lines follow the median output value from the ensemble of model parameters, and shaded areas outline the 68% quantiles.

Figure 7

(left) Malaria Atlas Project estimates of transmission intensity (EIR values interpolated from PfPR _2–10 ). Expected cases averted per 1,000 children vaccinated over a ten-year horizon, 100% infant immunization coverage with (center) fast-waning vaccine and (right) slow-waning vaccine.