Abstract
Polymorphic parasite antigens are known targets of protective immunity to malaria, but this antigenic variation poses challenges to vaccine development. A synthetic MSP-1 Block 2 construct, based on all polymorphic variants found in natural Plasmodium falciparum isolates has been designed, combined with the relatively conserved Block 1 sequence of MSP-1 and expressed in E.coli. The MSP-1 Hybrid antigen has been produced with high yield by fed-batch fermentation and purified without the aid of affinity tags resulting in a pure and extremely thermostable antigen preparation. MSP-1 hybrid is immunogenic in experimental animals using adjuvants suitable for human use, eliciting antibodies against epitopes from all three Block 2 serotypes. Human serum antibodies from Africans naturally exposed to malaria reacted to the MSP-1 hybrid as strongly as, or better than the same serum reactivities to individual MSP-1 Block 2 antigens, and these antibody responses showed clear associations with reduced incidence of malaria episodes. The MSP-1 hybrid is designed to induce a protective antibody response to the highly polymorphic Block 2 region of MSP-1, enhancing the repertoire of MSP-1 Block 2 antibody responses found among immune and semi-immune individuals in malaria endemic areas. The target population for such a vaccine is young children and vulnerable adults, to accelerate the acquisition of a full range of malaria protective antibodies against this polymorphic parasite antigen.
Highlights
Antibody responses to polymorphic parasite antigens of Plasmodium falciparum are associated with protective immunity to malaria [1,2,3,4,5]
Expression and purification of Merozoite surface protein 1 (MSP-1) hybrid The DNA sequence of the MSP-1 hybrid was codon optimized for expression in E. coli
This paper reports the expression of a soluble recombinant protein (MSP-1 hybrid) which encompasses the sequence and antigenic diversity present within the majority of MSP-1 Block 2 alleles found within the P. falciparum parasite population
Summary
Antibody responses to polymorphic parasite antigens of Plasmodium falciparum are associated with protective immunity to malaria [1,2,3,4,5]. It seems likely that selective immune pressure on antigens which elicit antibodies most threatening to the parasite’s survival has driven the evolution and maintenance of this polymorphism [8]. In vitro ADCI assays with purified IgG3 from immune individuals (including antibodies to MSP-1 Block 2) have shown the importance of this subclass as an inhibitor of parasite growth [29,30], supporting the hypothesis that antigens that elicit IgG3 responses (such as MSP-1 Block 2 and MSP-2) are important targets of protective mechanisms [31,32]
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