Malaria is one of the most widespread infectious diseases, prevalent in over 100 countries worldwide. Half of the human population is living in areas with risk of transmission. Plasmodium vivax is the most prevalent of the human malaria parasites outside Africa with an estimated 80% of the cases in South and Southeast Asia and 70% in the Americas. According to the World Health Organization malaria parasites are responsible for over 3% of the years of life lost. The economic impact is also enormous with an estimated average loss of 1.3% of annual economic growth in high transmission areas. The development of effective vaccines, anti-malaria drugs and the implementation of anti-vector measures are global health priorities to control the disease. The overall goal of this research proposal is to develop an effective multi-stage P. vivax vaccine. We have recently shown that a hybrid protein vaccine designed by genetic fusion of pre-erythrocytic and erythrocytic stage components induced a robust protective immune response in a very sensitive rodent system. Functional antibodies and CD4+ T cells are required for protection. We have also used a novel chimeric adenovirus vector to deliver such protective antigen and have confirmed that heterologous immunization regimens enhanced vaccine potency. The corresponding orthologous sequences in P. vivax have also been expressed as chimeric recombinant proteins. A critical biological feature of P. vivax is the development of dormant forms in the liver that cause subsequent blood infections known as relapses. We hypothesize that the multi-stage P. vivax vaccine proposed here will have a significant impact on malaria relapses. To test this hypothesis, we will conduct in vitro and in vivo studies with P. cynomolgi, a simian malaria parasite that reproduces the biological and clinical features of the human parasite P. vivax. The studies proposed are aimed at: (1) developing multi-stage P. cynomolgi experimental vaccine constructs, (2) assessing the safety, immunogenicity and efficacy of the P. cynomolgi multi-stage constructs in rhesus macaques and (3) optimizing a P. vivax multi-stage vaccine candidate and evaluating efficacy in non-human primates (Saimiri boliviensis). This rigorous testing, using two unique and complementary non-human primate models, will determine if the approach is promising and will offer the potential for subsequent clinical pathway development. Given the dramatic impact of malaria with increasing attention on the widespread and severe nature of P. vivax and the urgent need of novel control measures, our proposal is both significant and timely.
Malaria caused by P. vivax is a major worldwide health problem with likely annual infections estimated at 132 to 391 million cases. P. vivax is characterized by its wider geographic distribution than P. falciparum with 2.6 billion people at risk of infection, and P. vivax malaria, which is resurging, now represents a serious threat in areas where it had been eradicated. 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.
|Fonseca, Jairo A; McCaffery, Jessica N; Caceres, Juan et al. (2018) Inclusion of the murine IgG? signal peptide increases the cellular immunogenicity of a simian adenoviral vectored Plasmodium vivax multistage vaccine. Vaccine 36:2799-2808|
|Fonseca, Jairo A; McCaffery, Jessica N; Kashentseva, Elena et al. (2017) A prime-boost immunization regimen based on a simian adenovirus 36 vectored multi-stage malaria vaccine induces protective immunity in mice. Vaccine 35:3239-3248|
|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|
|Fonseca, Jairo Andres; Cabrera-Mora, Monica; Singh, Balwan et al. (2016) A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119. Sci Rep 6:34527|
|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|
|Cabrera-Mora, Monica; Fonseca, Jairo Andres; Singh, Balwan et al. (2015) Induction of Multifunctional Broadly Reactive T Cell Responses by a Plasmodium vivax Circumsporozoite Protein Recombinant Chimera. Infect Immun 83:3749-61|
|Moreno, Alberto; Joyner, Chester (2015) Malaria vaccine clinical trials: what's on the horizon. Curr Opin Immunol 35:98-106|