RECOMBINANT BCG MALARIA VACCINES

DESCRIPTION: (Adapted from Applicant's Abstract) Malaria is a major global health burden with annual incidences of 300 to 500 million cases and 1.5 to 2.7 million deaths per year. Development of a vaccine represents an essential goal for an effective control strategy. However, for a vaccine to have a significant impact it would need to be safe, easy to administer, effective in children and affordable in Africa. This laboratory has developed the systems to engineer BCG, the widely used tuberculosis vaccine into a recombinant BCG (rBCG) vaccine vector capable of expressing foreign antigens. Immunization with rBCG expressing viral, bacterial, or parasitic foreign antigens elicits antibody as well as CD4 and CD8 T cell responses to the foreign antigens in mice and monkeys. Recombinant BCG represents an attractive vaccine delivery system for Africa as BCG is a safe, inexpensive vaccine that is already administered to the majority of children at birth throughout Africa and the developing world. Previous studies have shown that immunization with the conserved antigen MSP-1 from a variety of Plasmodium species protects against challenge with the homologous Plasmodium species in mouse and monkey models. We have obtained expression of the conserved portion of the Plasmodium falciparum blood stage antigen MSP-1 on the surface of BCG. These expression constructs have been engineered into vectors that contain a gene that complements novel auxotrophic deletion mutations of BCG, to provide a selection system to maintain the plasmids when grown in mammalian hosts. We intend to express MSP-1 antigens of P. yoelii and P. knowlesi in these systems and then test the ability of all of the rBCG constructs to protect against malaria in mice, Aotus monkeys, and Rhesus monkeys. The immunization studies are designed to test the recombinant BCG's expressing MSP-1 for protection and their abilities to induce a priming immunization that can confer protection upon infection with the malarial parasites.