Reverse immunodynamics: a new method for identifying targets of protective immunity

Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. Epidemiological models predict that strong immune selection can cause antigenic variants to structure into genetically discordant sets of antigenic types (e.g. serotypes). A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations of amino acids among co-circulating antigenic variants. We propose a novel population genetics methodology that combines such predictions with phylogenetic analyses to identify genetic loci (epitopes) under strong immune selection. We apply this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and find evidence of epitopes among certain regions of low variability which could render them ideal vaccine candidates. The proposed method can be applied to a myriad of multi-strain pathogens for which vast amounts of genetic data has been collected in recent years.