Effect of the malaria vaccine Combination B on merozoite surface antigen 2 diversity.
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.
Flück
Christian
C
Swiss Tropical Institute, Socinstrasse 57, Postfach, CH 4002 Basel, Switzerland.
Schöpflin
Sonja
S
Smith
Tom
T
Genton
Blaise
B
Alpers
Michael P
MP
Beck
Hans-Peter
HP
Felger
Ingrid
I
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
D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C065974:merozoite surface protein 2, Plasmodium