Plasmodium vivax is the most widely distributed human malaria parasite responsible for 80% of the clinical cases in South and Southeast Asia and 70% in the Americas. The wider geographic distribution of P. vivax in comparison to P. falciparum is explained by the unique biological features of this parasite. Although the implementation of transmission control measures has had a significant impact on morbidity and mortality, the emergence and spread of drug-resistant parasites is a growing concern. The development of novel tools to control the disease is therefore a global priority. This proposal wil build on our experience developing chimeric recombinant proteins and recombinant adenovirus vectors to develop a coadministration vaccination regimen that combines these two vaccine platforms. The overall goal of this research proposal is to simplify the immunization schedule by reducing the need for boosting at regular intervals. We will modify existing adenovirus vectors that express a Plasmodium multi-stage protective antigen as a transgene by insertion of a promiscuous T cell epitope within the capsid structure. We hypothesize that the high copy number of T cell epitopes displayed by capsid incorporation will significantly enhance the immune responses to the chimeric transgene product. The optimized capsid modified vectors will then be used for coadministration with the multi- stage protective antigen expressed as recombinant protein.
The specific aims are to: 1. Characterize and compare the effect of the insertion of T cell epitopes within the capsid on the immunogenicity of recombinant adenovirus vectors. 2. Determine the immunogenicity and protective efficacy of a coadministration regimen using the P. yoelii model. 3. Assess the immunogenicity of a coadministration regimen tailored for P. vivax. We will use adenovirus serotype 5 (Ad5) and the chimeric Ad5/3 vectors for capsid modification. Viable vectors will be used for comparative experiments in mice. The successful outcome of comparative proof-of-principle experiments with the rodent malaria parasite will guide the design of a novel P. vivax vaccination regimen. We envision that our studies will provide valuable data to improve protective immune response induced by protein- based vaccines.
Malaria caused by Plasmodium vivax is a major public health problem worldwide with the number of annual infections estimated to be between 132 and 391 million. The emergence and spread of P. vivax drug resistant strains has brought increased emphasis to the need for alternative prophylactic and therapeutic strategies to control this infection. We aim to develop an effective vaccine able to induce long lasting protection using a simplified immunization schedule.
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|Cabrera-Mora, Monica; Fonseca, Jairo Andres; Singh, Balwan et al. (2016) A Recombinant Chimeric Ad5/3 Vector Expressing a Multistage Plasmodium Antigen Induces Protective Immunity in Mice Using Heterologous Prime-Boost Immunization Regimens. J Immunol 197:2748-61|
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|Fonseca, Jairo Andres; Cabrera-Mora, Monica; Kashentseva, Elena A et al. (2016) A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine. PLoS One 11:e0154819|
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|Ferreira, Amanda Ribeiro; Singh, Balwan; Cabrera-Mora, Monica et al. (2014) Evaluation of naturally acquired IgG antibodies to a chimeric and non-chimeric recombinant species of Plasmodium vivax reticulocyte binding protein-1: lack of association with HLA-DRB1*/DQB1* in malaria exposed individuals from the Brazilian Amazon. PLoS One 9:e105828|