Reply to "Parasite Strain, Host Immunity, and Circulating Blood Cells with Dead Parasites: Why Predicting Malaria Parasite Clearance Is Not a Simple Task".

We welcome the comments of Simpson et al. (1). There is clearly a need to understand the basic properties of parasite clearance rates and their potential role as policy decision tools. Simpson et al. state that our models are “limited with respect to two key parameters, the infecting parasite strain and host immunity.” We address each point in turn, noting that our nomenclature (2) recognized that it is infected red blood cells (iRBC), not parasites directly, which are cleared from the circulation. Simpson et al. (1) note that “immunity is complex” (and that we acknowledged this in our paper) and make the specific point of immunity reducing the parasite multiplication factor at the end of the 48-h cycle. We were aware of this factor and addressed it on page 6432 in the text starting “The dynamics can be understood as the interactions among the three factors that determine iRBC clearance dynamics, i.e., spleen clearance rates, sequestration rates, and new merozoite release rates” (2). We argued that spleen clearance rates completely dominate any decrease in the rate of successful RBC invasions of merozoites (equivalent to merozoite release rates) so took this potential immune effect into account in our modeling. Simpson et al. (1) also noted the effect of “infecting parasite strain.” Importantly, Plasmodium falciparum is sexual, with frequent genetic recombination, so resistant and sensitive “strains” are defined only by short regions of DNA surrounding the resistance locus. The remainder of the strain genetic background (which includes antigen-encoding loci) reflects that of the local population. Interestingly, we did address this issue of immunity acting against the resistance/sensitivity genotype (or strains) in our original submission in a paragraph that read as follows (with citation numbers updated):