Understanding Naturally Acquired Immunity to Plasmodium falciparum Malaria

Two papers have recently been published in Infection and Immunity on the role of anti-Plasmodium falciparum erythrocyte membrane protein 1 in immunity to clinical malaria (5, 14). The structure and biology of these antigens have been reviewed recently (4, 6, 10). Ofori and colleagues showed seroconversion to P. falciparum-infected erythrocyte surface antigens (PIESAs) expressed during acute infection. They also showed that PIESAs from isolates from young children were more commonly recognized by (heterologous) sera from other children than were PIESAs from isolates from older children (14). This paper and others by the group (8, 7, 13) are consistent with the results of Peter Bull and colleagues, who showed that commonly recognized parasite isolates are associated not just with infection in younger children but also with severe disease (1, 2, 3). It is reassuring that the two groups report similar result while using different methods to measure antibodies directed at PIESAs. Whether these commonly recognized PIESAs have specific functional or adhesive properties that are causally related to the development of severe disease remains an intriguing question. A second paper by Chattopadhyay and colleagues shows seroconversion to PIESAs during acute infection and also considerable seroconversion to heterologous isolates compared to that seen in some (2, 9, 11, 15), but not other, areas (8). Moreover, Chattopadhyay demonstrated a “wide” degree of cross-reactivity of agglutinating antibodies by using the mixed-agglutination assay, which measures the formation of agglutinates of two strains labeled with different fluorescent dyes (12). They saw that 20 to 30% of the agglutinates 10 to 20 cells in size were of mixed color and concluded that there are more common epitopes on PIESAs on different Indian isolates than that reported in African isolates (12). It may be that, in India, the spectrum of P. falciparum erythrocyte membrane protein 1 epitopes is more limited than in tropical Africa, where transmission is higher. The high degree of seroconversion to PIESAs expressed by heterologous isolates seen in India is consistent with this explanation. Does a high proportion of mixed-color agglutinates imply that the PIESAs expressed by test isolates are very similar? Not necessarily, as the proportion of mixed-color agglutinates can be quite high even when the degree of cross-reactivity is low. For example, if 20% of all 10-cell agglutinates are mixed in color, it implies that the chance of any two infected cells from the test strains agglutinating with each other is only 3.8% (see Materials and Methods in reference 16). So, sharing only a few percent of the epitopes on PIESAs gives a high proportion of mixed-color agglutinates in this assay. Quantitative use of this assay in future studies may be useful if results are to inform decisions about effectiveness of vaccine constructs. These recent papers are especially valuable in an area where fieldwork is difficult and time-consuming and where the data are unique to each location. One hopes that, at a later date, there will be a role for more extensive cooperation and coordination on studies and methods to yield the fastest way forward in a field where the resources are dwarfed by the scale of the problems.