Abstract
BackgroundPlasmodium vivax 48/45 protein is expressed on the surface of gametocytes/gametes and plays a key role in gamete fusion during fertilization. This protein was recently expressed in Escherichia coli host as a recombinant product that was highly immunogenic in mice and monkeys and induced antibodies with high transmission-blocking activity, suggesting its potential as a P. vivax transmission-blocking vaccine candidate. To determine sequence polymorphism of natural parasite isolates and its potential influence on the protein structure, all pvs48/45 sequences reported in databases from around the world as well as those from low-transmission settings of Latin America were compared.MethodsPlasmodium vivax parasite isolates from malaria-endemic regions of Colombia, Brazil and Honduras (n = 60) were used to sequence the Pvs48/45 gene, and compared to those previously reported to GenBank and PlasmoDB (n = 222). Pvs48/45 gene haplotypes were analysed to determine the functional significance of genetic variation in protein structure and vaccine potential.ResultsNine non-synonymous substitutions (E35K, Y196H, H211N, K250N, D335Y, E353Q, A376T, K390T, K418R) and three synonymous substitutions (I73, T149, C156) that define seven different haplotypes were found among the 282 isolates from nine countries when compared with the Sal I reference sequence. Nucleotide diversity (π) was 0.00173 for worldwide samples (range 0.00033–0.00216), resulting in relatively high diversity in Myanmar and Colombia, and low diversity in Mexico, Peru and South Korea. The two most frequent substitutions (E353Q: 41.9 %, K250N: 39.5 %) were predicted to be located in antigenic regions without affecting putative B cell epitopes or the tertiary protein structure.ConclusionsThere is limited sequence polymorphism in pvs48/45 with noted geographical clustering among Asian and American isolates. The low genetic diversity of the protein does not influence the predicted antigenicity or protein structure and, therefore, supports its further development as transmission-blocking vaccine candidate.
Highlights
Plasmodium vivax 48/45 protein is expressed on the surface of gametocytes/gametes and plays a key role in gamete fusion during fertilization
Brazilian P. vivax isolates (n = 13) were obtained from patients attending a tertiary healthcare centre in Manaus (Amazonas State) [19]; Colombian parasite samples (n = 35) were collected in four different malaria-endemic regions described elsewhere [20]; Honduran samples (n = 12) were collected at the University Hospital located in Tegucigalpa, and its origin was determined to seven different localities throughout the country
Genetic polymorphism and amino acid changes Results of the quantitative PCR (qPCR) assay indicated that all samples were specific for P. vivax infections
Summary
Plasmodium vivax 48/45 protein is expressed on the surface of gametocytes/gametes and plays a key role in gamete fusion during fertilization This protein was recently expressed in Escherichia coli host as a recombinant product that was highly immunogenic in mice and monkeys and induced antibodies with high transmission-block‐ ing activity, suggesting its potential as a P. vivax transmission-blocking vaccine candidate. Pfs48/45 is necessary for production of high antibody titers in individuals living in endemic areas [10, 11] that can reduce ookinete production and induce transmission-blocking activity [12,13,14] It is currently considered a potential target for development as a transmission-blocking vaccine. These studies indicated high immunogenicity in both animal models and the elicited antibodies displayed significant and reproducible transmission-blocking activity in ex vivo P. vivax membranefeeding assays (MFA) [9]
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