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

Abstract

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.

Immunological profiles associated with distinct parasitemic states in volunteers undergoing malaria challenge in Gabon

“…Exploration of the Plasmodium gene expression database shows that these genes were preferentially expressed in the asexual blood-stage parasites, which suggests the importance of these correlates in protection against blood-stage malaria. Indeed, the protective role of naturally acquired anti-MSP4 antibodies has been shown previously 32 , 33 . With that said, we also observed an early decrease in the frequencies of IFNγ-producing CD4 + T cells in TBS − subjects, which could indicate migration into lymph nodes and tissues, to facilitate parasite control 34 .…”

Systems biology of malaria explored with nonhuman primates

“…While ongoing studies continue to establish a basis for new directions for malaria vaccine development, they are just the beginning. For example, a recent study assessed the global diversity and population structure of high priority P. falciparum vaccine candidate antigens [ 7 ]. This analysis included data from over 2600 parasite genomes from 15 malaria endemic countries and evaluated and compared the target haplotypes and 3-dimensional structures.…”

“…Once molecular biological methods took hold in the 1970s, attempts to make a malaria vaccine became the envisioned panacea (reviewed in [ 4 ]). These efforts continue today, with the full recognition that making and introducing an effective malaria vaccine(s) is no small task, especially since the ultimate protection worldwide will require vaccines that have long-lasting immunity and are effective against multiple species of Plasmodium with their ever-changing genetic variation (reviewed in [ 5 – 7 ]). Many factors must be considered to ensure the effectiveness of vaccines in malaria endemic communities [ 8 ].…”

A Molecular Analysis of Memory B Cell and Antibody Responses Against Plasmodium falciparum Merozoite Surface Protein 1 in Children and Adults From Uganda

“…PfMSP1 has long been considered a vaccine target since antibody responses against this protein have been associated with protection ( 6 , 21 , 23 ), although results from PfMSP1-based vaccine trials have been disappointing ( 24 , 25 ). However, since PfMSP1 has high antigenic heterogeneity across Pf strains ( 26 , 27 ), it is a model antigen well-suited to assess antibody cross-strain reactivity elicited by natural infection. In addition, PfMSP1 is commonly used to study Plasmodium -specific MBCs in both humans ( 15 , 16 , 28 , 29 ) and mice ( 30 – 32 ), and this study therefore adds to a growing body of literature on PfMSP1-specific B cell responses.…”