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Immunity to Plasmodium falciparum (Pf) malaria is only acquired after years of repeated infections and wanes rapidly without ongoing parasite exposure. Antibodies are central to malaria immunity, yet little is known about the B-cell biology that underlies the inefficient acquisition of Pf-specific humoral immunity. This year-long prospective study in Mali of 185 individuals aged 2 to 25 years shows that Pf-specific memory B-cells and antibodies are acquired gradually in a stepwise fashion over years of repeated Pf exposure. Both Pf-specific memory B cells and antibody titers increased after acute malaria and then, after six months of decreased Pf exposure, contracted to a point slightly higher than pre-infection levels. This inefficient, stepwise expansion of both the Pf-specific memory B-cell and long-lived antibody compartments depends on Pf exposure rather than age, based on the comparator response to tetanus vaccination that was efficient and stable. These observations lend new insights into the cellular basis of the delayed acquisition of malaria immunity. [ABSTRACT FROM AUTHOR]

Background. The World Health Organization (WHO) recently recommended that the time to first malaria episode serve as the primary end point in phase III malaria vaccine trials-the first of which will be held in Africa. Although common red blood cell (RBC) polymorphisms such as sickle hemoglobin (HbS) are known to protect against malaria in Africa, their impact on this end point has not been investigated. Methods. A longitudinal study of 225 individuals aged 2-25 years was conducted in Mali. The association between common RBC polymorphisms and the time to first malaria episode was evaluated. Results. Among children aged 2-10 years, sickle cell trait (HbAS) was associated with a 34-day delay in the median time to first malaria episode (P = .017). Cox regression analysis showed that greater age (hazard ratio [HR], 0.87 [95% CI, 0.80-0.94]; P = .001), HbAS (HR, 0.48 [95% CI, 0.26-0.91]; P = .024), and asymptomatic parasitemia at enrollment (HR, 0.35 [95% CI, 0.14-0.85]; P = .021) were associated with decreased malaria risk. Conclusion. Given the delay in the time to first malaria episode associated with HbAS, it would be advisable for clinical trials and observational studies that use this end point to include Hb typing in the design of studies conducted in areas where HbAS is prevalent. [ABSTRACT FROM AUTHOR]