title: Global genetic diversity of the Plasmodium vivax transmission-blocking vaccine candidate Pvs48/45.
abstract: BACKGROUND
  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-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.
  
  
  METHODS
  Plasmodium 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.
  
  
  RESULTS
  Nine 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.
  
  
  CONCLUSIONS
  There 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.
authors.affiliation: Malaria Vaccine and Drug Development Center, Cali, Colombia.
authors.forename: Andres F
authors.initials: AF
authors.lastname: Vallejo
authors.affiliation: Malaria Vaccine and Drug Development Center, Cali, Colombia.
authors.forename: Nora L
authors.initials: NL
authors.lastname: Martinez
authors.affiliation: Malaria Vaccine and Drug Development Center, Cali, Colombia.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Tobon
authors.affiliation: Facultad de Ciencias Médicas, Hospital Escuela Universitario, Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras.
authors.forename: Jackeline
authors.initials: J
authors.lastname: Alger
authors.affiliation: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Lacerda
authors.affiliation: Centre de Recherches Biochimie Macromoléculaire (CRBM), Institut de Biologie Computationnelle (IBC), CNRS, University of Montpellier, Montpellier, France.|Institute of Bioengineering, University ITMO, Saint Petersburg, Russia.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kajava
authors.affiliation: Caucaseco Scientific Research Center, Cali, Colombia.|School of Health, Universidad del Valle, Cali, Colombia.
authors.forename: Myriam
authors.initials: M
authors.lastname: Arévalo-Herrera
authors.affiliation: Caucaseco Scientific Research Center, Cali, Colombia. sherrera@inmuno.org.
authors.forename: Sócrates
authors.initials: S
authors.lastname: Herrera
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology*; D016645:Aotidae; D014644:Genetic Variation; D006239:Haplotypes; D000071497:Immunogenicity, Vaccine; D017780:Malaria Vaccines / Q000235:genetics* / Q000276:immunology; D016780:Malaria, Vivax / Q000517:prevention & control; D051379:Mice; D010966:Plasmodium vivax / Q000235:genetics* / Q000276:immunology*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins