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PLoS Negl Trop Dis. 2014 Apr 17;8(4):e2796. doi: 10.1371/journal.pntd.0002796. eCollection 2014 Apr.

Differing patterns of selection and geospatial genetic diversity within two leading Plasmodium vivax candidate vaccine antigens.

Author information

1
School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
2
Program in Bioinformatics and Integrative Biology, University of Massachusetts, Worcester, Massachusetts, United States of America; Division of Transfusion Medicine, School of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
3
Program in Bioinformatics and Integrative Biology, University of Massachusetts, Worcester, Massachusetts, United States of America; School of Medicine, University of Massachusetts, Worcester, Massachusetts, United States of America.
4
National Malaria Center, Phnom Penh, Cambodia.
5
United States Navy, Naval Medical Research Unit #2, Phnom Penh, Cambodia.
6
Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.

Abstract

Although Plasmodium vivax is a leading cause of malaria around the world, only a handful of vivax antigens are being studied for vaccine development. Here, we investigated genetic signatures of selection and geospatial genetic diversity of two leading vivax vaccine antigens--Plasmodium vivax merozoite surface protein 1 (pvmsp-1) and Plasmodium vivax circumsporozoite protein (pvcsp). Using scalable next-generation sequencing, we deep-sequenced amplicons of the 42 kDa region of pvmsp-1 (n = 44) and the complete gene of pvcsp (n = 47) from Cambodian isolates. These sequences were then compared with global parasite populations obtained from GenBank. Using a combination of statistical and phylogenetic methods to assess for selection and population structure, we found strong evidence of balancing selection in the 42 kDa region of pvmsp-1, which varied significantly over the length of the gene, consistent with immune-mediated selection. In pvcsp, the highly variable central repeat region also showed patterns consistent with immune selection, which were lacking outside the repeat. The patterns of selection seen in both genes differed from their P. falciparum orthologs. In addition, we found that, similar to merozoite antigens from P. falciparum malaria, genetic diversity of pvmsp-1 sequences showed no geographic clustering, while the non-merozoite antigen, pvcsp, showed strong geographic clustering. These findings suggest that while immune selection may act on both vivax vaccine candidate antigens, the geographic distribution of genetic variability differs greatly between these two genes. The selective forces driving this diversification could lead to antigen escape and vaccine failure. Better understanding the geographic distribution of genetic variability in vaccine candidate antigens will be key to designing and implementing efficacious vaccines.

PMID:
24743266
PMCID:
PMC3990511
DOI:
10.1371/journal.pntd.0002796
[Indexed for MEDLINE]
Free PMC Article

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