SBIR-STTR Award

Pre-erythrocytic stage malaria vaccines aim to block hepatocyte entry by sporozoites and/or release of merozoites into the blood stream, thereby circumventing the disease process and rendering the host non- infectious. The primary target of this class of vaccines is the circumsporozoite protein (CS), which is a major constituent of the sporozoite coat when it enters the host. Pre-erythrocytic immunity has been demonstrated by immunization with the CS-NANP repeat epitope, passive transfer of antibodies specific for anti-NANP repeat epitope, and immunization with irradiated sporozoites. In animal models the immunodominant CS-repeat epitope from either P.bergeii or P.yoelli, displayed on hepatitis B core particles, successfully protected >90% of animals against infection. Preliminary studies of HBc particles engineered to deliver the CS-repeat from the human parasite P.falciparum are promising, but in need of optimization. The focus of this work is to optimize the immunogenicity of the P.falciparum particle to attain the high immunogenicity and absence of genetic restriction observed with P.bergeii and P.yoelli particles. This will be achieved by optimizing the presentation of the NANP repeat epitope at the surface of HBc and incorporating a universal malaria- specific T cell epitope. Once identified, this vaccine candidate will be the subject of clinical testing during phase II. PROPOSED COMMERCIAL APPLICATION: Malaria is by far the world's most important tropical parasitic disease, and kills more people than any other communicable disease, with the exception of tuberculosis. Malaria is a public health problem in more than 90 countries, inhabited by a total of 2.4 billion people - 40% of the world's population. Mortality due to malaria is estimated to be in the range of 1.5 to 2.7 million deaths each year, according for one person every 12 seconds. There are 7 million travelers from the U.S. each year to endemic areas.

Public Health Relevance Statement:
Terms: vaccine development; circumsporozoite protein; SDS polyacrylamide gel electrophoresis; malaria vaccines; nonhuman therapy evaluation; Plasmodium falciparum; Plasmodium berghei; Plasmodium; virus protein; antigen presentation; antigen antibody reaction; immunofluorescence technique; epitope mapping; enzyme linked immunosorbent assay; passive immunization; cellular immunity; drug screening /evaluation; cytotoxic T lymphocyte; B lymphocyte; laboratory mouse

Phase I work has resulted in the successful development of a candidate P.falciparum malaria vaccine. The vaccine is composed of well- characterized neutralizing B cell epitopes and a universal human T cell epitope delivered on a highly immunogenic particulate carrier protein that effectively delivers 240 copies of each epitope on each particle. When formulated in alum, the vaccine candidate is a potent immunogen in mice eliciting unprecedented titers of sporozoite-neutralizing antibody. A universal CS-derived T cell epitope, incorporated into the vaccine candidate during phase I, facilitates a significant reduction in parasite load in the P.yoelii rodent system and effectively stimulates human T cells in vitro. The cell-mediated immunity afforded by the vaccine candidate should facilitate boosting of anti-sporozoite antibody titers in endemic regions, as well as the direct targeting of infected hepatocytes. The vaccine candidate has been produced in abundant quantities in E.coli using newly developed expression and purification methods that are fully scalable. Phase II work will focus on three areas: 1) completion of small animal studies of the vaccine candidate, 2) pre-clinical development of the vaccine candidate in preparation for human clinical trials, and 3) Phase I humans clinical trials. PROPOSED COMMERCIAL APPLICATION: Malaria is by far the world's most important tropical parasitic disease, and kills more people than any other communicable disease, with the exception of tuberculosis. Malaria is a public health problem in more than 90 countries, inhabited by a total of 2.4 billion people - 40% of the world's population. Mortality due to malaria is estimated to be in the range of 1.5 to 2.7 million deaths each year, accounting for one person every 12 seconds. There are 7 million travelers from the U.S. each year to endemic areas.

Public Health Relevance Statement:
Terms: vaccine development; clinical research; clinical trial phase I; circumsporozoite protein; SDS polyacrylamide gel electrophoresis; malaria vaccines; nonhuman therapy evaluation; Plasmodium falciparum; Plasmodium berghei; Plasmodium; virus protein; antigen presentation; antigen antibody reaction; epitope mapping; enzyme linked immunosorbent assay; passive immunization; cellular immunity; human subject; drug screening /evaluation; cytotoxic T lymphocyte; B lymphocyte; laboratory mouse