title: Effect of the malaria vaccine Combination B on merozoite surface antigen 2 diversity.
abstract: Extensive genetic polymorphism is generally found in Plasmodium falciparum surface antigens. This poses a considerable obstacle to the development of a malaria vaccine. In order to assess possible effects of a polymorphic vaccine, we have analyzed the genetic diversity of parasites collected in the course of a phase 2b field trial of the blood stage vaccine Combination B in Papua New Guinea. The full-length 3D7 allele of the merozoite surface protein 2 (MSP2) was included in Combination B as one of three subunits. Vaccinees had a lower prevalence of parasites carrying a 3D7-type allele (corresponding to that in the vaccine) and selection appeared to favour the alternative FC27-type alleles resulting in a higher incidence of morbid episodes associated with FC27-type parasites. We sequenced MSP2 alleles detected in study participants after vaccination to identify breakthrough genotypes. Extensive genetic diversity of MSP2 was observed in both the repetitive and family-specific domains, but alleles occurring in vaccine recipients were no different from those found in placebo recipients. A phylogenetic analysis showed no clustering of 3D7-type breakthrough infections from vaccine recipients. The repeat unit present in the vaccine molecule occurred in a number of alleles from the trial area and was also observed in vaccinated individuals. Thus the anti-repeat immune response did not lead to elimination of parasites carrying the same repeat unit. We conclude that the conserved epitopes in the family-specific domain were the most important determinants of the vaccine effect against new 3D7-type infections and that the hypervariable domains were not subject to selective effects of the vaccine.
authors.affiliation: Swiss Tropical Institute, Socinstrasse 57, Postfach, CH 4002 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Flück
authors.forename: Sonja
authors.initials: S
authors.lastname: Schöpflin
authors.forename: Tom
authors.initials: T
authors.lastname: Smith
authors.forename: Blaise
authors.initials: B
authors.lastname: Genton
authors.forename: Michael P
authors.initials: MP
authors.lastname: Alpers
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Beck
authors.forename: Ingrid
authors.initials: I
authors.lastname: Felger
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D014644:Genetic Variation / Q000187:drug effects*; D006801:Humans; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000276:immunology; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000276:immunology; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014614:Vaccines, Synthetic / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C065974:merozoite surface protein 2, Plasmodium