Immunity to Plasmodium falciparum in adults living in endemic areas involves a fine-balance between cellular and humoral immune mechanisms to different stages of the parasite. If this balance is altered, immune individuals become susceptible to both infection and disease. In response to this RFA, the investigators seek to identify humoral and cellular factors involved in resistance and/or susceptibility. Pregnancy represents one natural intervention whereby individuals who are normally immune become susceptible, but immunity is re-established during the third trimester or soon after delivery. Recent data show that during pregnancy there is a down-regulation of inflammatory-type Th1 responses and an accompanying shift to a predominant Th2-response. This shift in cytokines may well alter the fine balance in pregnant women that is required for immunity. Thus, the investigators propose to follow changes in antimalarial immune responses throughout pregnancy and compare them with changes in immune status. This group hypothesizes that women with the greatest shift in Th1/Th2 balance will have the most severe consequences from malaria.

Newborns are a second age group in which immunity is lost over a relatively short period of time. All neonates born in hyperendemic areas have passively acquired antimalarial antibodies essentially equivalent to that of their mothers. In addition, infants whose mothers have placental malaria may also be exposed to malarial antigens in utero and develop T cells primed in a Th2 environment. Thus, longitudinal studies in neonates in endemic areas allow one to examine the effector functions of antibodies (Ab) to malaria in the

absence of other acquired immune responses, as well as the influence of CD4-primed T cells in the absence of primed-CD8 cells.

This group has selected to evaluate 5 immunological parameters with a high probability of correlating with protection, including: (1) CD8+ T cells to liver-stage antigens; (2) ratio of antigen-specific Th1 and Th2 CD4+ T cells to asexual-stage antigens; (3) antimalarial Ab with definable fine specificities (e.g., avidities) to epitopes involved in sporozoite or merozoite invasion; (4) predominance of Ab isolates with high affinity for Fc-receptors (FcR); and (5) anemia as a potential marker for pathology. Parallel immunologic studies will be conducted within the city of Yaounde where transmission is low and in Ngali, a rural village with high year-round transmission of malaria. The hope is that one or a combination of these identifiable immune responses will correlate with susceptibility/resistance and can be used to predict the immune status of people in endemic populations.

U01AI043888

1998-09-30

2006-08-31