In this week's PLoS Medicine
, Christopher King and colleagues 
report results from a study designed to directly address the hypothesis that prenatal exposure to parasite antigens directly affects the risk of malaria in infancy. The authors recruited 586 pregnant women and their newborn children from an area of stable transmission of P. falciparum
parasites in coastal Kenya. Venous and placental blood from the mothers as well as cord blood from the babies was examined by microscopy and PCR for presence of parasites to evaluate prenatal exposure to parasite antigens. The authors then tested the parasite antigen-specific immune reactivity in the offspring at delivery and every six months thereafter for the first three years of life. The antigens examined were parasite proteins involved in merozoite invasion of erythrocytes, targets of protective immunity, and vaccine candidates. Antigen-induced responses included lymphocyte proliferation and cytokine production. Furthermore, the authors measured plasma levels of IgG with specificity for some of the antigens used in the in vitro assays of cellular immunity.
Once all data were collected, the authors compared the results in three sub-groups of the children. The first of these was composed of the 246 “sensitized” children, where cytokine responses (other than IL-10) could be detected in antigen-stimulated cord blood cultures. The second sub-group included the 120 “not sensitized” children, whose cord blood cells did not produce cytokine responses despite parasitological evidence of in utero exposure. Finally, the third sub-group consisted of the 220 “not exposed” children, where no antigen-induced cord lymphocyte cytokines were detected, but where parasitological evidence of prenatal exposure could not be obtained.
The “not sensitized” children who appeared to have been tolerized to P. falciparum
antigens before birth were approximately 40% more likely to become infected during the follow-up period than either sensitized or unexposed children. In contrast to earlier studies 6
, maternal parity did not influence the risk of infection in the children. Parasitemias tended to be low, and not much different between groups. Nevertheless, the putatively tolerized children were more anemic than the other children. In addition, lymphocytes from the “not sensitized” children were less likely to produce cytokines such as IFN-γ and IL-2 and more likely to produce IL-10 in response to antigenic stimulation, particularly in the second half of the follow-up period. Similar and high plasma levels of malaria antigen-specific IgG were detected in all newborns (due to passive transfer of maternal IgG across the placenta). As expected, these levels fell to very low levels in the second half of the first year, and then slowly increased during the second year as the children started to acquire immunity to the parasites. There were no obvious differences between the groups of children with respect to acquisition of parasite-specific antibodies.