Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens

Naung, M. T. and Martin, E. and Munro, J. and Mehra, S. and Guy, A. J. and Laman, M. and Harrison, G. L. A. and Tavul, L. and Hetzel, M. and Kwiatkowski, D. and Mueller, I. and Bahlo, M. and Barry, A. E.. (2022) Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens. PLoS Comput Biol, 18 (2). e1009801.

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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 of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global 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. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used 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. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. 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 adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Health Interventions > Intervention Effectiveness and Impact (Hetzel)
UniBasel Contributors:Hetzel, Manuel W.
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1553-7358 (Electronic)1553-734X (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Dec 2022 19:31
Deposited On:27 Dec 2022 19:31

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