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Unlocking the global antigenic diversity and balancing selection of Plasmodium falciparum

Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies on Plasmodium falciparum antigen diversity have focused on well-known vaccine candidates while the diversity of several others has never been studied. Here we provide an overview of the diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. We developed a stringent variant calling pipeline to extract high quality antigen gene sequences from the global dataset and a new R-package named VaxPack to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. We found that current malaria vaccine formulations are based on rare variants and thus may have limited efficacy. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptations to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens for inclusion in the design of the next generation of malaria vaccines.