The contribution of functional antimalarial immunity to measures of parasite clearance in therapeutic efficacy studies of artemisinin derivatives.
O'Flaherty K., Ataíde R., Zaloumis SG., Ashley EA., Powell R., Feng G., Reiling L., Dondorp AM., Day NP., Dhorda M., Fairhurst RM., Lim P., Amaratunga C., Pukrittayakamee S., Hien TT., Htut Y., Mayxay M., Faiz MA., Beeson JG., Nosten F., Simpson JA., White NJ., Fowkes FJI.
BACKGROUND:Antibodies to the blood-stages of malaria enhance parasite-clearance and antimalarial efficacy. The antibody subclass and functions that contribute to parasite-clearance during anti-malarial treatment and their relationship with malaria transmission intensity have not been characterised. METHODS:IgG subclasses and C1q-fixation in response to P. falciparum merozoite antigens (EBA-175RIII-V, MSP-2 and MSP-142), and opsonic-phagocytosis of merozoites were measured in a multinational trial assessing the efficacy of artesunate across 11 South-East Asian sites. Regression analyses assessed the effects of antibody seropositivity on parasite-clearance half-life (hours)(PC½), PC½≥5 hours, and day-3 parasitemia. RESULTS:IgG3, followed by IgG1, was the predominant IgG subclass detected (seroprevalence range IgG1: 5%-35% and IgG3: 27%-41%), varied across study-sites, and was lowest in study-sites with the lowest transmission intensity, and slowest mean PC½. IgG3, C1q-fixation and opsonic-phagocytosis seropositivity were associated with faster PC½ (mean reduction in PC½ range 0.47-1.16 (hours), p-range: 0.001-0.03) and reduced odds of PC½≥5 hours and day-3 parasitemia. CONCLUSIONS:Prevalence of IgG3, complement-fixing antibodies and merozoite phagocytosis vary according to transmission intensity, are associated with faster parasite-clearance and may be a sensitive surrogate of augmented clearance capacity of infected-erythrocytes. Determining the functional immune mechanisms associated with parasite-clearance will improve characterisation of artemisinin resistance.