The effects of a partitioned var gene repertoire of Plasmodium falciparum on antigenic diversity and the acquisition of clinical immunity

This study presents a mathematical analysis of how recombination hierarchies affect diversity, and, by using simple stochastic simulations, investigates how intra- and inter-genic diversity influence the rate at which individuals acquire clinical immunity.The analysis demonstrates that the partitioning of the var gene repertoire has a limiting effect on the total diversity attainable through recombination and that the limiting effect is strongly influenced by the respective sizes of each of the partitions. Furthermore, by associating expression of one of the groups with severe malaria it is demonstrated how a small number of infections can be sufficient to protect against disease despite a seemingly limitless number of possible non-identical repertoires.Recombination hierarchies within the var gene repertoire of P. falciparum have a severe effect on strain diversity and the process of acquiring immunity against clinical malaria. Future studies will show how the existence of these recombining groups can offer an evolutionary advantage in spite of their restriction on diversity.Although the acquisition of immunity to malaria is poorly understood, it appears to rely on repeated exposure to different antigenic variants of the malaria parasite Plasmodium falciparum (for a review see [1,2]). Adults living in an endemic region will, therefore, have been exposed to, and generated antibodies to, most of the variants circulating in the parasite population [3-6] (although this is also dependent on transmission intensity, see for example [7,8]). In spite of this gradual accumulation of immunity with age and exposure, young children seem to be protected against the most severe forms of the disease after only a few episodes [9].One of the main targets of protective immune responses against P. falciparum are the highly polymorphic variant surface antigens (VSA) [3,10-13], such as the Plasmodium falciparum Erythrocyte Surface Proteins, PfEMP1. These proteins are important virulence