Research Project
8318266
Summary Statement Given the very high burden malaria imposes on many developing countries, the overall objective of this proposal is to develop a P. falciparum malaria-specific immunogen that may be useful as an affordable and effective vaccine to prevent malaria. The current most effective malaria vaccine candidate (RTS,S/AS02A) is based on the use of a particulate carrier platform (the HBsAg) fused to malaria circumsporozoite (CS)-specific T and B cell epitopes. Current limitations of the RTS,S vaccine have been a requirement for reactogenic adjuvants and transient protection. A further potential complication is that the carrier is derived from a human pathogen, the hepatitis B virus (HBV). To circumvent these problems a non-human pathogen-derived carrier platform has been developed, specifically the core protein from the woodchuck hepadnavirus (WHcAg). Modified WHcAg particles will be used as the vaccine platform for several reasons: CS-WHcAg hybrid particles elicit extremely high levels of anti-CS antibodies; the immune tolerance to HBcAg and HBsAg in HBV chronic carriers (400 million worldwide) can be circumvented by the use of the WHcAg platform; and because CS- WHcAg hybrid particles can be made in bacteria, production of a vaccine will be relatively inexpensive. A preliminary CS-WHcAg hybrid particle has been developed that contains two neutralizing CS repeat epitopes inserted into the loop region (the insertion site that raises the highest titer anti-insert antibodies) and two universal malaria-specific T cell domains fused to the C-terminus. This CS-WHcAg hybrid particle is very immunogenic in mice and is capable of eliciting neutralizing anti-CS repeat antibodies that prevent P. falciparum/P. berghei hybrid sporozoite liver infection in vivo, therefore it is an ideal basis from which to develop a vaccine for human use. The strategy for developing an optimal malaria vaccine is divided into four aims: 1) incorporation of additional CS-derived B cell and T cell neutralizing epitopes; 2) testing the protective efficacy of the vaccine candidates in a hybrid P. falciparum/P. berghei sporozoite model and developing the model to encompass additional P. falciparum epitopes; 3) test recombinant and chemically linked molecular adjuvants for their ability to improve protective efficacy of the vaccine particles; and 4) determine optimal formulation, route and dosing of the chosen vaccine candidates. The combination of these two powerful technologies, the WHcAg-carrier platform and the P. falciparum/P. berghei hybrid sporozoite challenge model, will enable the production of a variety of CS-WHcAg hybrid particle immunogens that can be tested for protective efficacy in an in vivo infectious model system specific for P. falciparum malaria.
