Abstract
MSP2 is an intrinsically disordered protein that is abundant on the merozoite surface and essential to the parasite Plasmodium falciparum. Naturally-acquired antibody responses to MSP2 are biased towards dimorphic sequences within the central variable region of MSP2 and have been linked to naturally-acquired protection from malaria. In a phase IIb study, an MSP2-containing vaccine induced an immune response that reduced parasitemias in a strain-specific manner. A subsequent phase I study of a vaccine that contained both dimorphic forms of MSP2 induced antibodies that exhibited functional activity in vitro. We have assessed the contribution of the conserved and variable regions of MSP2 to the generation of a strain-transcending antibody response by generating MSP2 chimeras that included conserved and variable regions of the 3D7 and FC27 alleles. Robust anti-MSP2 antibody responses targeting both conserved and variable regions were generated in mice, although the fine specificity and the balance of responses to these regions differed amongst the constructs tested. We observed significant differences in antibody subclass distribution in the responses to these chimeras. Our results suggest that chimeric MSP2 antigens can elicit a broad immune response suitable for protection against different strains of P. falciparum.
Highlights
Anti-merozoite surface protein 2 (MSP2) antibodies are generated following natural infections and correlate with the age-dependent protection observed in adults and children over the age of 5 years[20,21]
We designed a set of chimeric antigens (Fig. 1B) consisting of different regions of 3D7 and FC27 MSP2 in order to address two issues: 1) could chimeric MSP2 constructs induce effective antibody responses to both 3D7 and FC27 forms of MSP2, and 2) what impact did the conserved regions have on the immunogenicity and aggregation propensity of MSP2
We name these constructs using a scheme in which the NTR and CTR are denoted as N and C, respectively, and the VR of 3D7 and FC27 are denoted as V3D7 and VFC27, respectively
Summary
Anti-MSP2 antibodies are generated following natural infections and correlate with the age-dependent protection observed in adults and children over the age of 5 years[20,21]. A subsequent phase I trial of a combination of 3D7 and FC27 alleles of full-length MSP2, adjuvanted in Montanide ISA72024, exhibited functional activity in vitro that included ADCI24 and complement-mediated inhibition of parasite growth[22] These trials suggested that MSP2 vaccines can induce functional responses that may mediate in vivo protection, but highlighted the need to evaluate the benefits of including the VR from both alleles, as well as the conserved NTR and CTR. A series of MSP2 constructs was designed to accommodate both allelic forms of the protein as well as permutations in their conserved, polymorphic and repeat regions These chimeras allowed us to test whether, by manipulating the composition of these chimeras, we could enhance the immune response, target it toward potentially protective epitopes, remove the propensity of MSP2 for aggregation, and modulate the IgG subclass distribution elicited by MSP2
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