Abstract
.Reticulocyte-binding homologues (RH) are a ligand family that mediates merozoite invasion of erythrocytes in Plasmodium falciparum. Among the five members of this family identified so far, only P. falciparum reticulocyte–binding homologue-5 (PfRH5) has been found to be essential for parasite survival across strains that differ in virulence and route of host-cell invasion. Based on its essential role in invasion and early evidence of sequence conservation, PfRH5 has been prioritized for development as a vaccine candidate. However, little is known about the extent of genetic variability of RH5 in the field and the potential impact of such diversity on clinical outcomes or on vaccine evasion. Samples collected during a prospective cohort study of malaria incidence conducted in Kalifabougou, in southwestern Mali, were used to estimate genetic diversity, measure haplotype prevalence, and assess the within-host dynamics of PfRH5 variants over time and in relation to clinical malaria. A total of 10 nonsynonymous polymorphic sites were identified in the Pfrh5 gene, resulting in 13 haplotypes encoding unique protein variants. Four of these variants have not been previously observed. Plasmodium falciparum reticulocyte–binding homologue-5 had low amino acid haplotype (h = 0.58) and nucleotide (π = 0.00061) diversity. By contrast to other leading blood-stage malaria vaccine candidate antigens, amino acid differences were not associated with changes in the risk of febrile malaria in consecutive infections. Conserved B- and T-cell epitopes were identified. These results support the prioritization of PfRH5 for possible inclusion in a broadly cross-protective vaccine.
Highlights
Plasmodium falciparum reticulocyte–binding homologue-5 interacts with basigin (CD147), an erythrocyte surface protein, to allow the invasion of the malaria parasite into the erythrocyte
The goal of this study was to assess the genetic diversity, haplotype prevalence, and dynamics of the P. falciparum reticulocyte–binding homologue-5 (PfRH5)-encoding gene to guide the selection of variants and/or B- and T-cell epitopes that are representative of the parasite population of this study site for possible inclusion in a broadly effective malaria vaccine
Clinical trials have shown that some malaria vaccines based on a single strain induce protection that is specific to the vaccine strain.[5,34,35,36]
Summary
Plasmodium falciparum reticulocyte–binding protein homologue-5 (PfRH5) is a promising new blood-stage vaccine antigen that is moving quickly toward clinical development.[7,8,9] The invasion of merozoites into the erythrocyte is a multistep process that starts with merozoite binding and reorientation onto the red blood cell (RBC), followed by the formation of a tight junction and culminates with parasite entry into the erythrocyte. Essential to this process is PfRH5, a 63-kDa protein encoded by a gene located in the subtelomeric region of chromosome 4.
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