Unit: Parasite Vaccinology
Director: LONGACRE, Shirley
The Laboratory of Anti-Parasite Vaccinology currently focuses on the two malaria parasite species responsible for most fatalities and morbidity in humans, Plasmodium falciparum and Plasmodium vivax. Recent work has concerned the development of sub-unit malaria vaccines, based on recombinant proteins produced in the baculovirus expression system, that target the merozoite in the blood stage of the parasite cycle, which is responsible for clinical disease.
LVP activities focus on the two components of subunit vaccines: recombinant protein antigens and novel immuno-stimulators with good potential for use in humans. While we have concentrated our efforts on antigens relevant to malaria vaccine(s), the approaches we have developed may be applicable to vaccines targeting other pathogens.
Recombinant antigens are produced in the baculovirus / insect cell expression system, which can reproduce proteins with complex native conformations and also reliably makes eukaryotic post-translational modifications such as signal sequence cleavage. Past efforts have focused on the C-terminal part of merozoite surface protein 1 (MSP1p19), a leading vaccine candidate for both Plasmodium falciparum and Plasmodium vivax malaria. PfMSP1p19 is currently undergoing process development for GMP manufacture prior to a phase 1 clinical trial sponsored by the Pasteur Institute. More recently the laboratory has been evaluating other baculovirus recombinant proteins, which have shown promise as vaccine candidates for both P. falciparum and P. vivax malaria.
Immuno-potentiators are needed to stimulate immune responses to the highly purified recombinant antigens required under increasingly stringent regulatory guidelines, which are generally poorly antigenic when administered alone. The LVP has recently been investigating two new approaches to augment the immunogenicity of the PfMSP1p19 antigen. (1) The baculovirus expression system can carry out glycosyl-phosphatidyl-inositol (GPI) modification using the GPI signal sequence on the C-terminus of the PfMSP1 protein, and preliminary results suggest that recombinant PfMSP1p19-GPI may have enhanced immunogenicity in mice. (2) Ideal vaccines targeting populations in the Third World, would confer long lasting efficacy after a single administration. Slow release delivery mechanisms allow the immune system to receive continued doses of the active principle over an extended period of time. A novel controlled-release technology uses a high-viscosity base component (approved as a food additive by the FDA) in combination with polymers, to provide prolonged release of active ingredients. Advantages include low cost of raw materials, ease of scalable manufacture and formulation, and high stability at ambient temperatures. Formulation of the PfMSP1p19 antigen using this approach induced a surprisingly good, long-lived antibody response in out-bred miceafter a single injection.
Keywords: Malaria, Plasmodium falciparum, Plasmodium vivax, merozoite surface proteins (MSP), vaccines, baculovirus