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Dissertation
Design, production and evaluation of a Plasmodium falciparum merozoite surface protein 2-based vaccine for inclusion in a multivalent formulation targeting multiple parasite stages
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2019
DOI:
https://doi.org/10.17918/dhek-e084
Abstract
Development of a highly efficacious vaccine will be necessary for malaria elimination. Studies in Plasmodium falciparum endemic areas indicate that naturally acquired antibody responses to MSP2 are associated with resistance to malaria, making PfMSP2 an attractive vaccine candidate. To overcome challenges encountered with subunit malaria vaccines, we established that the use of highly immunogenic rPfMSP8 as a carrier protein for vaccine candidates rPfMSP119 and rPfs25 facilitated production, minimized antigenic competition and enhanced induction of functional antibodies. Here, we exploited the benefits of our rPfMSP8 fusion partner to optimize a rPfMSP2-based subunit vaccine. A synthetic PfMSP2 (3D7) codon harmonized gene was used to produce unfused rPfMSP2 or chimeric rPfMSP2/8 in E. coli. Purified, rPfMSP2 formed amyloid-like fibrils in vitro, however rPfMSP2/8 did not. Immunization of rabbits and mice with both rPfMSP2 antigens elicited high titer anti-PfMSP2 antibodies that recognized the major allelic variants of native PfMSP2. Competition assays revealed differences in antibody specificities induced by the two rPfMSP2-based vaccines, with evidence of epitope masking by rPfMSP2-associated fibrils. Immunogenicity studies in mice demonstrated that formulation of rPfMSP2 vaccines with GLA-SE, a synthetic TLR4 agonist, elicited cytophilic IgG isotypes and production of Th1-associated cytokines. T cell responses were specific for epitopes within PfMSP2 and PfMSP8 domains. The rPfMSP2/8 + GLA-SE formulation induced significantly higher antibody titers with superior durability and capacity to opsonize P. falciparum merozoites for phagocytosis. Immunization with a trivalent vaccine including PfMSP2/8, PfMSP1/8 and Pfs25/8 induced high levels of antigen-specific antibody, with no evidence of antigenic competition. These results are highly encouraging for the addition of rPfMSP2/8 as a component of an efficacious, multivalent, multistage malaria vaccine.
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Details
- Title
- Design, production and evaluation of a Plasmodium falciparum merozoite surface protein 2-based vaccine for inclusion in a multivalent formulation targeting multiple parasite stages
- Creators
- Jacqueline Schneider Eacret - DU
- Contributors
- James M. Burns Jr. (Advisor) - Drexel University (1970-)Elizabeth P. Blankenhorn (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvi, 229 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 9359; 991014632261804721