Pre-Clinical Assessment of Novel Multivalent MSP3 Malaria Vaccine Constructs

Abstract

BackgroundMSP3 has been shown to induce protection against malaria in African children. The characterization of a family of Plasmodium falciparum merozoite surface protein 3 (MSP3) antigens sharing a similar structural organization, simultaneously expressed on the merozoite surface and targeted by a cross-reactive network of protective antibodies, is intriguing and offers new perspectives for the development of subunit vaccines against malaria.MethodsEight recombinant polyproteins containing carefully selected regions of this family covalently linked in different combinations were all efficiently produced in Escherichia coli. The polyproteins consisted of one monovalent, one bivalent, one trivalent, two tetravalents, one hexavalent construct, and two tetravalents incorporating coiled-coil repeats regions from LSA3 and p27 vaccine candidates.ResultsAll eight polyproteins induced a strong and homogeneous antibody response in mice of three distinct genotypes, with a dominance of cytophilic IgG subclasses, lasting up to six months after the last immunization. Vaccine-induced antibodies exerted a strong monocyte-mediated in vitro inhibition of P. falciparum growth. Naturally acquired antibodies from individuals living in an endemic area of Senegal recognized the polyproteins with a reactivity mainly constituted of cytophilic IgG subclasses.ConclusionsCombination of genetically conserved and antigenically related MSP3 proteins provides promising subunit vaccine constructs, with improved features as compared to the first generation construct employed in clinical trials (MSP3-LSP). These multivalent MSP3 vaccine constructs expand the epitope display of MSP3 family proteins, and lead to the efficient induction of a wider range of antibody subclasses, even in genetically different mice. These findings are promising for future immunization of genetically diverse human populations.

Allelic Diversity and Geographical Distribution of the Gene Encoding <i>Plasmodium falciparum</i> Merozoite Surface Protein-3 in Thailand

“…Regardless, this information is very crucial for the design of MSP-3 based vaccine. If the full-length MSP-3 molecule was to be developed as a vaccine, it would be preferable to incorporate both the K1 and 3D7 alleles that match the msp -3 allele frequency for each parasite population, as such a multivalent vaccine would have more long-term usefulness for induction of protective immunity [ 40 ].…”

Surface Engineering of the RNA Coliphage Q? to Display Plasmodium Falciparum Derived Asexual Blood Stage Antigens UB05 and Merozoite Surface Protein 3

“…In this study we genetically engineered the malaria blood stage immunogens UB05, MSP3 and their chimera UB05-MSP3 upon the surface of the RNA coliphage β, then used the ensuing recombinant phages to assess semi immunity to malaria in children in a high malaria transmission region of Cameroon. Recombinant chimera βUB05-MSP3 becomes necessary since malaria vaccines containing more than one fusion antigen have been demonstrated to induce effective immunity [24] resulting to protection against clinical malaria in African children [26][27][28]. Since anti-UB05 and anti-MSP3 antibodies have each been incriminated with protection against malaria this new antigen combinations might more reliably detect antibody responses which are predictive of protective ability of the immune system from clinical malaria.…”

Plasmodium vivax Merozoite Surface Protein-3 (PvMSP3): Expression of an 11 Member Multigene Family in Blood-Stage Parasites

“…Like PfMSP3 [29], [48], they may also function to elicit antibody-dependent cellular inhibition (ADCI) activity as a means to control the rise in parasitemia. This mechanism has not yet been demonstrated in P. vivax, though it largely forms the basis of developing effective PfMSP3 vaccines [24], [25], [49], [50].…”

“…Diversity studies with isolates from around the world continue to show extensive polymorphism in these genes and the encoded proteins, and the pvmsp 3 alleles have therefore become highly regarded as genetic tools to distinguish different parasite isolates and study population dynamics [23]. They have also been regarded as potential vaccine candidates, following in the path of PfMSP3 [24], [25]. Immune response studies carried out to date in Brazil assessing naturally acquired immunity to PvMSP3-α show the presence of broadly recognized B cell epitopes from the central region of PvMSP3α, IgG1 and IgG3 antibody subclasses associated with increased exposure to the parasite, and the association of HLA types with such responses [26], [27].…”