W192 - Maturation of the Cytokine Response to Sequential Plasmodium Falciparum Challenges

Abstract Text: The development of natural immunity against malaria requires multiple exposures and even after protection develops against clinical disease individuals continue to be susceptible to infections. To study the dynamics of the immune response to repetitive P. falciparum-infected mosquito exposures, we used controlled human malaria challenges (CHMI) with the same strain of P. falciparum. Consistent with the gradual immune response observed in the field, after 4 sequential parasite exposures over 2 years, symptoms decreased and the time to parasite detection on a blood smear increased significantly, but all the volunteers continued to be susceptible to infections. Anti-parasite antibody levels varied between individuals, but overall gradually increased through the repeat exposures. Cytokine responses peaked with peak parasitemia, except for IL-18 which continued to increase for another 7 days. Despite decreasing symptoms after repeat exposures, cytokine levels remained similar except IFNγ, which could be due to the decrease in γδ2 or increase in γδ1 T cells observed after repeat exposures. The cytokine profile was compared to that observed in a cohort of pediatric malaria patients aged 1-13 years. As in the CHMI data, the cytokine profile was similar for 1-2 year-olds and those >2 years which is consistent with exposure not decreasing the response. IL-18 was the one exception and it was higher in younger children. Levels of most of the 23 cytokines tested were comparable between the children and CHMI participants. However, IL-10 and IL-8 were markedly higher in children, while IL-1RA, IL-21, IL-4 CCL4, CCL3 were higher in the CHMI participants.