In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations

Abstract

Genetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima’s D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima’s D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

An In Silico Analysis of Malaria Pre-Erythrocytic-Stage Antigens Interpreting Worldwide Genetic Data to Suggest Vaccine Candidate Variants and Epitopes

“…Importantly, the allele in the 3D7 reference strain, on which in-development vaccines incorporating these antigens are based [27,75,79], was the predominate variant in all countries. Consistent with published reports [20,80,81], our analyses of worldwide samples have shown high nucleotide diversity in African samples compared to Asian, South American, and Oceanic samples. In addition, haplotype diversity and the distribution of the frequencies of major alleles were higher in Africa compared to the rest of the world.…”

“…Additional analyses based on F ST , haplotype geographic distribution, supported a low-to-moderate subdivision of these three antigens by country and continent. Parallel to our findings, previous studies [80,81] that focused on the erythrocyte stage of parasite development also found subpopulations and substructuring at the country and continent levels. These population subdivisions could be explained by the same immune mechanism happening during the liver and erythrocyte stages.…”

Poly-basic peptides and polymers as new drug candidate againstPlasmodium falciparum

“…While both cytoplasmic and membrane proteins were enriched as identified via LC-MS analysis, due to the observed membrane binding of FITC-PLLs, we focused on secreted, adherent, and membrane-inserted proteins of Plasmodium in the obtained data ( Supplementary Table 2 ). Amongst these proteins, the most significant and potential targets of PLLs were Clag9 (PF3D7_0935800), expressed on the merozoite surface and involved in merozoite invasion of human erythrocytes, PIHSTb, c (PF3D7_0401800, PF3D7_0801000 respectively) which are; possible vaccine candidate, GARP (PF3D7_0113000; involved in programmed cell death), EMP1-trafficking protein (PTP4; PF3D7_0730900; required in virulence and rigidity), and PIESP2 (PF3D7_0501200) a; considered as a possible vaccine candidate ( 52–56 ). Furthermore, additional identification of MDR1 and Kelch13 ( 57, 58 ) in LC-MS experiments as potential targets of PLLs indicates further possibility to address the resistance to the ACT therapies, as mutations in these proteins give rise to artemisinin resistance.…”

Potential Opportunities and Challenges of Deploying Next Generation Sequencing and CRISPR-Cas Systems to Support Diagnostics and Surveillance Towards Malaria Control and Elimination in Africa

“…Genetic relatedness between parasite samples is positively correlated with reduced transmission, and therefore can be used as a proxy measure of transmission level ( Daniels et al., 2015 ; Cerqueira et al, 2017 ). Using advanced NGS tools, it is also possible to infer malaria transmission networks over a given timescale in a population ( Ajibola et al., 2021 ). Importation of malaria parasites from higher to lower transmission areas, particularly those in the elimination phase, remains a major challenge to malaria elimination, and is difficult to detect using traditional methods.…”