Figure 1.

The risk of severe malaria decreases exponentially with exposure. (A and B) Data were extracted from Gonçalves et al. (2014) to examine the frequency of severe (A) or complicated (B) malaria during the first 14 infections of life in infants living in a hyperendemic setting. We performed maximum likelihood estimation to select the best model fit for these data; the black line shows the best fit and grey shading represents the 95% confidence intervals. In both cases, an exponential decay provided a better fit than either a linear decay or constant risk. In A, n = 102 severe episodes and in B, n = 199 complicated episodes of malaria (see Fig. S1, A and B for case imputation and model performance). (C–G) Healthy malaria-naive adults were infected up to three times with P. falciparum (clone 3D7) by direct blood challenge. Repeated sampling before, during, and after each infection allowed us to track the development of disease tolerance in real-time. (C) Parasite growth curves for first, second, and third infection; each line represents a volunteer, and lines are color-coded by infection number. Parasite density was measured in peripheral blood by qPCR every 12 h. The grey box represents the lower limit of quantification (20 parasites ml⁻¹) and the treatment threshold of 10,000 parasites ml⁻¹ is denoted by the black line. (D and E) Maximum core body temperature (D) and minimum hemoglobin (E) were recorded during each infection (up to 48 h after treatment). Each symbol represents one volunteer with a line shown at the median. Grey shading indicates a normal range (115–165 g liter⁻¹ hemoglobin for females and 130–180 g liter⁻¹ hemoglobin for male volunteers). (F and G) Lymphocytes (F) and platelets (G) were quantified in circulation the day before infection (baseline), 6 days after challenge (c6), at the peak of infection (diagnosis), and ∼1 mo after drug treatment (convalescence). Boxplots show the median and interquartile range (IQR), and whiskers represent the 95% confidence intervals. Sample size (n) is 10 for the first and second infections and n = 6 for the third infection. There was no statistically significant difference between groups using a significance threshold of 5% (Kruskal–Wallis test). These data are also presented in Salkeld et al. (2022).