title: Differing patterns of selection and geospatial genetic diversity within two leading Plasmodium vivax candidate vaccine antigens.
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.
authors.affiliation: 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.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Parobek
authors.affiliation: 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.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bailey
authors.affiliation: 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.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hathaway
authors.affiliation: National Malaria Center, Phnom Penh, Cambodia.
authors.forename: Duong
authors.initials: D
authors.lastname: Socheat
authors.affiliation: United States Navy, Naval Medical Research Unit #2, Phnom Penh, Cambodia.
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.affiliation: Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Juliano
mesh_terms: D056808:Biostatistics; D002160:Cambodia; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D017780:Malaria Vaccines / Q000235:genetics* / Q000276:immunology; D020066:Merozoite Surface Protein 1 / Q000235:genetics* / Q000276:immunology; D008969:Molecular Sequence Data; D010802:Phylogeny; D058974:Phylogeography; D010966:Plasmodium vivax / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology; D012641:Selection, Genetic
chemical_list: D016054:DNA, Protozoan; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan
references.citation: Malar J. 2013 Jan 08;12:11
references.pmid: 23297680
references.citation: PLoS One. 2007 Sep 12;2(9):e857
references.pmid: 17848988
references.citation: PLoS Med. 2008 Jun 17;5(6):e128
references.pmid: 18563962
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11030-5
references.pmid: 15258291
references.citation: Malar J. 2009 Jan 12;8:10
references.pmid: 19138388
references.citation: Acta Trop. 2008 Oct;108(1):58-63
references.pmid: 18823930
references.citation: Sci Rep. 2013;3:1990
references.pmid: 23771124
references.citation: Malar J. 2009 Jun 05;8:120
references.pmid: 19500348
references.citation: J Immunol. 1995 Jun 1;154(11):6022-30
references.pmid: 7538540
references.citation: Int Microbiol. 1999 Sep;2(3):155-60
references.pmid: 10943408
references.citation: Infect Immun. 2002 Sep;70(9):5328-31
references.pmid: 12183594
references.citation: Genet Res. 1987 Dec;50(3):245-50
references.pmid: 3443297
references.citation: Am J Trop Med Hyg. 2010 Dec;83(6):1230-7
references.pmid: 21118926
references.citation: J Exp Med. 1994 Jul 1;180(1):297-306
references.pmid: 8006589
references.citation: Mol Biol Evol. 1999 Jan;16(1):37-48
references.pmid: 10331250
references.citation: Parasitol Res. 1995;81(1):58-65
references.pmid: 7536921
references.citation: Mol Biol Evol. 2008 Jun;25(6):1007-15
references.pmid: 18195052
references.citation: BMC Genomics. 2012 Aug 05;13:375
references.pmid: 22863213
references.citation: Nature. 1991 Jun 20;351(6328):652-4
references.pmid: 1904993
references.citation: Infect Genet Evol. 2007 Mar;7(2):180-7
references.pmid: 17010678
references.citation: J Infect Dis. 2012 Aug 15;206(4):580-7
references.pmid: 22551816
references.citation: J Parasitol. 2005 Feb;91(1):79-82
references.pmid: 15856876
references.citation: Hum Vaccin. 2010 Jan;6(1):124-32
references.pmid: 20009526
references.citation: Bioinformatics. 2009 Jun 1;25(11):1451-2
references.pmid: 19346325
references.citation: Ann Trop Med Parasitol. 1998 Jul;92(5):539-51
references.pmid: 9797827
references.citation: J Clin Microbiol. 2014 Jan;52(1):298-301
references.pmid: 24131693
references.citation: N Engl J Med. 2011 Sep 15;365(11):1004-13
references.pmid: 21916638
references.citation: Parasitol Res. 2011 Dec;109(6):1571-6
references.pmid: 21556687
references.citation: Genetics. 1998 May;149(1):189-202
references.pmid: 9584096
references.citation: Trans R Soc Trop Med Hyg. 1999 Jul-Aug;93(4):381-4
references.pmid: 10674081
references.citation: Korean J Parasitol. 2011 Sep;49(3):313-6
references.pmid: 22072836
references.citation: Emerg Infect Dis. 2011 Oct;17(10):1799-806
references.pmid: 22000348
references.citation: Trends Parasitol. 2010 Jul;26(7):363-9
references.pmid: 20466591
references.citation: Mol Biochem Parasitol. 1991 Nov;49(1):35-44
references.pmid: 1723148
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16348-53
references.pmid: 12466500
references.citation: Am J Trop Med Hyg. 2011 Feb;84(2 Suppl):51-7
references.pmid: 21292878
references.citation: ISME J. 2010 Jan;4(1):17-27
references.pmid: 19710709
references.citation: Malar J. 2012 Nov 26;11:391
references.pmid: 23181845
references.citation: Mol Biol Evol. 1987 Jul;4(4):406-25
references.pmid: 3447015
references.citation: PLoS Negl Trop Dis. 2013 Oct 31;7(10):e2506
references.pmid: 24205419
references.citation: Sci Transl Med. 2009 Oct 14;1(2):2ra5
references.pmid: 20165550
references.citation: Genetics. 1991 Feb;127(2):345-53
references.pmid: 1706291
references.citation: Infect Genet Evol. 2011 Mar;11(2):391-8
references.pmid: 21147267
references.citation: J Infect Dis. 2008 Aug 1;198(3):409-17
references.pmid: 18582193
references.citation: Microbes Infect. 2010 Mar;12(3):199-206
references.pmid: 20034587
references.citation: Mol Biochem Parasitol. 1992 Aug;54(1):1-12
references.pmid: 1518521
references.citation: Evol Bioinform Online. 2007 Feb 23;1:47-50
references.pmid: 19325852
references.citation: N Engl J Med. 2011 Nov 17;365(20):1863-75
references.pmid: 22007715
references.citation: Mol Biol Evol. 2011 Oct;28(10):2731-9
references.pmid: 21546353
references.citation: Genetics. 2000 Aug;155(4):2011-4
references.pmid: 10924493
references.citation: Vaccine. 2010 Apr 19;28(18):3112-7
references.pmid: 20199765
references.citation: Malar J. 2012 Mar 14;11:68
references.pmid: 22417572
references.citation: Parasite Immunol. 2009 Sep;31(9):560-73
references.pmid: 19691559
references.citation: Evol Bioinform Online. 2007 Feb 22;2:303-20
references.pmid: 19455224
references.citation: Eur J Cell Biol. 1988 Apr;46(1):18-24
references.pmid: 3294006
references.citation: Curr Opin Infect Dis. 2009 Oct;22(5):430-5
references.pmid: 19571748
references.citation: Mol Biol Evol. 1986 Sep;3(5):418-26
references.pmid: 3444411
references.citation: PLoS One. 2009 Dec 30;4(12):e8497
references.pmid: 20041125
references.citation: Science. 1985 Nov 15;230(4727):815-8
references.pmid: 2414847
references.citation: Am J Trop Med Hyg. 2003 Jan;68(1):97-101
references.pmid: 12556156
references.citation: J Comput Biol. 2003;10(3-4):357-72
references.pmid: 12935333
references.citation: J Immunol. 1991 Mar 1;146(5):1674-8
references.pmid: 1704402
references.citation: Am J Trop Med Hyg. 2012 May;86(5):775-81
references.pmid: 22556073
references.citation: Parasite Immunol. 2009 Sep;31(9):582-6
references.pmid: 19691561
references.citation: J Histochem Cytochem. 1990 Apr;38(4):475-81
references.pmid: 2181019
references.citation: Genetics. 1992 Oct;132(2):583-9
references.pmid: 1427045
references.citation: Nat Methods. 2012 Mar 04;9(4):357-9
references.pmid: 22388286
references.citation: Int J Parasitol. 2007 Jan;37(1):77-85
references.pmid: 17046771
references.citation: Clin Microbiol Rev. 2013 Jan;26(1):36-57
references.pmid: 23297258
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):814-9
references.pmid: 15640359
references.citation: Nature. 2000 Sep 28;407(6803):513-6
references.pmid: 11029002
references.citation: J Exp Med. 1990 Jul 1;172(1):379-82
references.pmid: 1694225
references.citation: Am J Trop Med Hyg. 1999 Mar;60(3):350-6
references.pmid: 10466960
references.citation: Lancet Infect Dis. 2009 Sep;9(9):555-66
references.pmid: 19695492
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15523-8
references.pmid: 16227436
references.citation: Infect Genet Evol. 2010 Mar;10(2):298-303
references.pmid: 20097310
references.citation: J Virol. 2007 Jun;81(12):6643-51
references.pmid: 17428864
references.citation: J Comput Biol. 2002;9(5):687-705
references.pmid: 12487758
references.citation: Am J Trop Med Hyg. 2005 Jun;72(6):694-701
references.pmid: 15964952
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13040-5
references.pmid: 9371796
references.citation: Malar J. 2012 Jun 18;11:206
references.pmid: 22709605
references.citation: PLoS One. 2009;4(5):e5568
references.pmid: 19440377
references.citation: J Mol Evol. 2004 Oct;59(4):528-35
references.pmid: 15638464
references.citation: Malar J. 2009 Mar 12;8:42
references.pmid: 19284634
references.citation: J Infect Dis. 2002 Mar 15;185(6):820-7
references.pmid: 11920300
references.citation: J Clin Microbiol. 2012 Apr;50(4):1449-51
references.pmid: 22205791
references.citation: J Immunol. 2005 Sep 15;175(6):3935-9
references.pmid: 16148140
references.citation: J Exp Med. 1997 Nov 17;186(10):1689-99
references.pmid: 9362529
references.citation: Exp Parasitol. 2007 Jan;115(1):32-40
references.pmid: 16797008
references.citation: Nat Rev Microbiol. 2004 Jan;2(1):15-22
references.pmid: 15035005
references.citation: PLoS Clin Trials. 2006 May;1(1):e5
references.pmid: 16871327
references.citation: Am J Trop Med Hyg. 2013 Jan;88(1):24-8
references.pmid: 23243112
references.citation: Bioinformatics. 2004 Jan 22;20(2):289-90
references.pmid: 14734327
references.citation: Vaccine. 2003 Mar 7;21(11-12):1033-43
references.pmid: 12559776
references.citation: Genetics. 1989 Nov;123(3):585-95
references.pmid: 2513255
references.citation: J Immunol. 1992 Jun 15;148(12):3986-90
references.pmid: 1376347
references.citation: N Engl J Med. 2013 Mar 21;368(12):1111-20
references.pmid: 23514288
references.citation: Acta Trop. 2007 Apr;102(1):38-46
references.pmid: 17397788
references.citation: Mem Inst Oswaldo Cruz. 2006 Aug;101(5):547-50
references.pmid: 17072460
references.citation: Gene. 2013 Apr 15;518(2):381-7
references.pmid: 23333606