Optimization of chimeric multi-stage immunogens for malaria vaccine development

Objectives

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.