Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children

Abstract

Background: Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure.

Methods: We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease.

Results: Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine.

Conclusions: Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity.

Keywords: epidemiology; heterogeneity in transmission; immunity; malaria.

Figure 1.

A, Figure showing the infection history of a subset of participants throughout the 5-year follow-up. Each row represents the experience of a specific participant. Children are sorted on the basis of their estimated individual frailty, from low exposure to high exposure. B, Times between subsequent infections for children in the data set. Each box plot represents the distribution of gap times (times to reinfection) for a particular child. Abbreviations: AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine.

Figure 2.

Figure showing survival curves and daily hazards for children in the dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) groups. The left panel shows the survival curves of the times to reinfections (in days) for both treatment arms. The right panel shows the average estimated daily hazards (average daily rates of infection) obtained by fitting models that allowed the hazard to vary as a function of time since the last treatment.

Figure 3.

A, Histogram showing distribution of estimated individual frailties (relative hazards of infection as compared to the population average) after adjustment for body surface area and location of residence. B, Relative hazards of individuals living in urban versus rural households. The average relative hazard of individuals living in rural households versus urban households (reference group) is shown in black. Abbreviations: AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine.

Figure 4.

Data and fit of model to the mean monthly probability of infection (A), probability of malaria, given infection (B), and resulting monthly probability of malaria (C) as a function of age. Data are shown as dots. Thick lines represent mean fitted values, and thin lines represent draws from the posterior distribution (uncertainty around mean values). Whereas panel A shows the fit of the model to mean probabilities, panel B illustrates fitted individual probabilities across 3 tertiles of exposure (tertiles of estimated frailties). Thin lines represent specific trajectories predicted for a subset of children within each tertile and thus illustrate the large heterogeneity that exists in the sample. Thick lines represent the mean expected trajectory for each tertile of frailty values.

Figure 5.

Predicted mean probabilities of infection and clinical malaria for different ages and exposures. A, Monthly probability of infection. B, Probability of malaria, given infection. C, Monthly probability of malaria.