A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses

New strategies are required to identify the most important targets of prote ctive immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium falc iparum(1-3). Analysis of allele frequency distributions could identify the loci under most intense selection(4-7). The merozoite surface protein 1 (Ms p1) is the most-abundant surface component on the erythrocyte-invading stag e of P. falciparum(8-10). Immunization with whole Msp1 has protected monkey s completely against homologous(11) and partially against non-homologous(12 ) parasite strains. The single-copy msp1 gene, of about 5 kilobases, has hi ghly divergent alleles(13) with stable frequencies in endemic populations(1 4,15). To identify the region of msp1 under strongest selection to maintain alleles within populations, we studied multiple intragenic sequence loci i n populations in different regions of Africa and Southeast Asia. On both co ntinents, the locus with the lowest inter-population variance in allele fre quencies was block 2 indicating selection in this part of the gene. To test the hypothesis of immune selection, we undertook a large prospective longi tudinal cohort study. This demonstrated that serum IgG antibodies against e ach of the two most frequent allelic types of block 2 of the protein were s trongly associated with protection from P. falciparum malaria.