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Toward the rational design of a malaria vaccine construct using the MSP3 family as an example: contribution of
Lena-Juliette Daher1, Corine G Demanga, Eric Prieur
1Biomedical Parasitology Unit, Institut Pasteur, 75724 Paris Cedex 15, France.
Abstract:
Plasmodium falciparum merozoite surface protein 3 (MSP3), the target of antibodies that mediate parasite killing in cooperation with blood monocytes and are associated with protection in exposed populations, is a vaccine candidate under development. It belongs to a family of six structurally related genes. To optimize immunogenicity, we attempted to improve its design based on knowledge of antigenicity of various regions from the conserved C terminus of the six proteins and an analysis of the immunogenicity of "tailored" constructs. The immunogenicity studies were conducted in BALB/c and C57BL/6J mice, using MSP3 (referred to here as MSP3-1) as a model. Four constructs were designed in order to assess the effect of sequences flanking the 69-amino-acid region of MSP3-1 previously shown to be the target of biologically active antibodies. The results indicate major beneficial effects of removing (i) the subregion downstream from the 69-amino-acid sequence, since antibody titers increased by 2 orders of magnitude, and (ii) the upstream subregion which, although it defines a T-helper cell epitope, is not the target of antibodies. The construct, excluding both flanking sequences, was able to induce Th1-like responses, with a dominance of cytophilic antibodies. This led to design a multigenic construct based on these results, combining the six members of the MSP3 family. This new construction was immunogenic in mice, induced antibodies that recognized the parasite native proteins, and inhibited parasite growth in the functional antibody-dependent cellular inhibition assay, thus satisfying the preclinical criteria for a valuable vaccine candidate.
Insights
Optimizing Plasmodium falciparum merozoite surface protein 3 (MSP3) vaccine design by removing flanking sequences significantly boosted antibody responses. A multigenic construct combining MSP3 family members proved immunogenic and inhibited parasite growth, meeting vaccine candidate criteria.
Area of Science:
- Malariology and Vaccinology
- Immunology and Parasitology
Background:
- Plasmodium falciparum merozoite surface protein 3 (MSP3) is a key vaccine candidate targeting parasite killing.
- MSP3 belongs to a family of six related genes, offering potential for multigenic vaccine strategies.
Purpose of the Study:
- To optimize MSP3 immunogenicity by analyzing antigenicity and tailoring construct design.
- To evaluate the impact of flanking sequences on MSP3-1 immunogenicity and antibody responses.
Main Methods:
- Immunogenicity studies were performed in BALB/c and C57BL/6J mice using modified MSP3-1 constructs.
- Four tailored constructs were designed to assess the role of flanking sequences on the immunogenic 69-amino-acid region.
- A multigenic construct combining all six MSP3 family members was created based on optimized design.
Main Results:
- Removing downstream flanking sequences increased antibody titers by two orders of magnitude.
- Removing upstream flanking sequences, while containing a T-helper epitope, further improved antibody responses.
- The optimized construct induced Th1-like responses with predominantly cytophilic antibodies and recognized native parasite proteins.
Conclusions:
- Tailoring MSP3 construct design by removing specific flanking sequences significantly enhances immunogenicity.
- A multigenic MSP3 construct is a promising preclinical vaccine candidate, demonstrating immunogenicity and functional parasite inhibition.
