Plasmodium falciparum merozoite surface protein 3 is a target of allele-specific immunity and alleles are maintained by natural selection.
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.
Polley
Spencer D
SD
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Tetteh
Kevin K A
KK
Lloyd
Jennie M
JM
Akpogheneta
Onome J
OJ
Greenwood
Brian M
BM
Bojang
Kalifa A
KA
Conway
David J
DJ
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
D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C089133:merozoite surface protein 3, Plasmodium