The contribution of functional antimalarial immunity to measures of parasite clearance in therapeutic efficacy studies of artemisinin derivatives.

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.