title: Plasmodium falciparum merozoite surface protein 3 is a target of allele-specific immunity and alleles are maintained by natural selection.
abstract: BACKGROUND
  Plasmodium falciparum merozoite surface protein (MSP) 3 is an asexual blood-stage malaria vaccine candidate antigen. Sequence polymorphisms divide alleles into 2 major types, but the adaptive and immunological significance of the types has not been defined.
  
  
  METHODS
  One hundred one msp3 allele sequences were sampled from 2 populations living in areas where malaria is endemic and were analyzed for evidence of natural selection. Recombinant antigens representing full-length sequences of different allelic types and a relatively conserved C-terminal region were produced, to evaluate immunization-induced antibody responses in mice and protective associations for naturally acquired antibodies in a cohort of 319 Gambian children under surveillance for malaria.
  
  
  RESULTS
  Frequency-based statistical analyses indicated that polymorphisms are maintained by balancing selection in each of the 2 populations studied. Immunization of mice with full-length MSP3 antigens induced predominantly type-specific antibodies, and a large proportion of naturally acquired antibodies to MSP3 in humans also discriminated between the alleles. Among Gambian children, antibodies to allele-specific and conserved epitopes in MSP3 were associated prospectively with protection from clinical malaria, even after adjustment for age and for the presence of antibodies to other merozoite antigens.
  
  
  CONCLUSIONS
  A vaccine incorporating both major allelic types of this promising candidate antigen could be particularly useful for induction of protective immunity in infants and young children.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Polley
authors.forename: Kevin K A
authors.initials: KK
authors.lastname: Tetteh
authors.forename: Jennie M
authors.initials: JM
authors.lastname: Lloyd
authors.forename: Onome J
authors.initials: OJ
authors.lastname: Akpogheneta
authors.forename: Brian M
authors.initials: BM
authors.lastname: Greenwood
authors.forename: Kalifa A
authors.initials: KA
authors.lastname: Bojang
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
mesh_terms: D000483:Alleles; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood* / Q000276:immunology; D000918:Antibody Specificity; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005714:Gambia; D006801:Humans; D007114:Immunization; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008969:Molecular Sequence Data; D009549:Nigeria; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D013785:Thailand
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C089133:merozoite surface protein 3, Plasmodium