Host immunity exerts strong selective pressure on pathogens. Population-level genetic
analysis can identify signatures of this selection, but these signatures reflect the net
selective effect of all hosts and vectors in a population. In contrast, analysis of pathogen
diversity within hosts provides information on individual, host-specific selection
pressures. Here, we combine these complementary approaches in an analysis of the
malaria parasite Plasmodium falciparum using haplotype sequences from thousands of
natural infections in sub-Saharan Africa. We find that parasite genotypes show
preferential clustering within multi-strain infections in young children, and identify
individual amino acid positions that may contribute to strain-specific immunity. Our
results demonstrate that natural host defenses to P. falciparum act in an allele-specific
manner to block specific parasite haplotypes from establishing blood-stage infections.
This selection partially explains the extreme amino acid diversity of many parasite
antigens and suggests that vaccines targeting such proteins should account for allelespecific immunity.