title: Molecular basis of allele-specific efficacy of a blood-stage malaria vaccine: vaccine development implications.
abstract: The disappointing efficacy of blood-stage malaria vaccines may be explained in part by allele-specific immune responses that are directed against polymorphic epitopes on blood-stage antigens. FMP2.1/AS02(A), a blood-stage candidate vaccine based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, had allele-specific efficacy against clinical malaria in a phase II trial in Malian children. We assessed the cross-protective efficacy of the malaria vaccine and inferred which polymorphic amino acid positions in AMA1 were the targets of protective allele-specific immune responses. FMP2.1/AS02(A) had the highest efficacy against AMA1 alleles that were identical to the 3D7 vaccine-type allele at 8 highly polymorphic amino acid positions in the cluster 1 loop (c1L) but differed from 3D7 elsewhere in the molecule. Comparison of the incidence of vaccine-type alleles before and after vaccination in the malaria vaccine and control groups and examination of the patterns of allele change at polymorphic positions in consecutive malaria episodes suggest that the highly polymorphic amino acid position 197 in c1L was the most critical determinant of allele-specific efficacy. These results indicate that a multivalent AMA1 vaccine with broad efficacy could include only a limited set of key alleles of this extremely polymorphic antigen.
authors.affiliation: Malaria Research and Training Center,  University of Sciences, Techniques and Technology, Bamako,  Mali.
authors.forename: Amed
authors.initials: A
authors.lastname: Ouattara
authors.forename: Shannon
authors.initials: S
authors.lastname: Takala-Harrison
authors.forename: Mahamadou A
authors.initials: MA
authors.lastname: Thera
authors.forename: Drissa
authors.initials: D
authors.lastname: Coulibaly
authors.forename: Amadou
authors.initials: A
authors.lastname: Niangaly
authors.forename: Renion
authors.initials: R
authors.lastname: Saye
authors.forename: Youssouf
authors.initials: Y
authors.lastname: Tolo
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.forename: D Gray
authors.initials: DG
authors.lastname: Heppner
authors.forename: Lorraine
authors.initials: L
authors.lastname: Soisson
authors.forename: Carter L
authors.initials: CL
authors.lastname: Diggs
authors.forename: Johan
authors.initials: J
authors.lastname: Vekemans
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.forename: Tina
authors.initials: T
authors.lastname: Dube
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Laurens
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Plowe
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions / Q000276:immunology; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D007223:Infant; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology; D016778:Malaria, Falciparum / Q000517:prevention & control*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*
chemical_list: D000953:Antigens, Protozoan; D000939:Epitopes; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium