SBIR-STTR Award

Current estimates of mortality and morbidity due to malaria have given evidence of the decreasing effectiveness of both vector control and chemoprophylaxis and chromotherapy. The present focus is to develop vaccines against one more of the developmental forms of the Plasmodium parasite. One such approach utilizes a plasmid DNA expression, the circumsporozite protein (CSP). We propose to incorporate the pDNA into a low molecular weight, biocompatible-hydrolytically lable (absorbable) poly(d,l-lactide-co-glycolide) by a proprietary protocol, which eliminates both the shear stresses of emulsification and also contact of the pDNA with potentially denaturing solvents. An open-celled polymeric foam, prepared by lyophilization (~ 95% void volume), is impregnated with an aqueous solution of the plasmid. After a second lyophilization to remove the water, the matrix is compressed and cryogenically ground to a particle size suitable for injection. Plasmid content of the matrix and in vitro release profiles will be determined. The microparticulate formulation is anticipated to enhance the immune response. Samples will be submitted to the Naval Medical Research Center for evaluation in mice to determine Phase I feasibility as shown by development of titers suggestive of malarial protection.This work is practical as a means to lay the groundwork for the development of an efficacious, economical, DNA-based vaccine that would be of relatively low cost, stable, and circumvent the need for repeated inoculations. Each year approximately 300-500 million people are infected with malaria and each year 1.5 to 2.7 million people die from this disease. An effective vaccine for malaria would clearly be advantageous to people in the developing world, as well as to the individual U.S. military personnel who must enter malaria-infected areas. Commercialization by Cambridge Scientific, Inc., with our proven and patented technology under DoD sponsorship, will thus provide broad benefits to mankind.

Keywords:
Malaria, Vaccine, Controlled Release, Dna, Poly(D,L-Lactide-Co-Glycolide)

The goal of the Phase II project will be to optimize a PLGA form for clinical trials based on characterization of the dose/response of the particulate in small and large animal models. The particular challenge in moving a DNA/PLGA formulation through the preclinical stages to clinical trials lies in the translation of dose/response information from a very small animal model (rodent) to a larger animal model (primate). However, the attractive of particulate PLGA dose forms is based on their capacity to elicit immune responses based on their long-term persistence in the neighborhood of antigen presenting cells. Therein lies the thrust of optimization for vaccine efficacy-titration of the dose/response behavior of PLGA particulates. Phase II work will utilize the team structure established in Phase I. NMRC will produce and purify a candidate DNA plasmid for supply to Cambridge Scientific, Inc. (CSI). CSI will produce and characterize DNA/PLGA vaccines under Good Laboratory Practices (GLP). CSI will fully characterize the dose forms based on plasmid loading, release, and integrity. CSI will optimize the dose/response in mice, then demonstrate immunogenicity and in some cases protective efficacy in non-human primates. The workplan will be carried out under strict documentation clauses so that the candidate DNA/PLGA formulation can be finalized in a prototype system that can be transitioned to clinical testing in Phase III and eventual commercialization. This documentation will be supportive of regulatory standards to facilitate plans for transitioning to Good Manufacturing Practices (GMP) production, conducting pre-clinical safety studies, and submitting investigational new drug application (IND) to the FDA following the Phase II effort.

Keywords:
MALARIA, VACCINE, CONTROLLED RELEASE, DNA PLASMIDS, POLY(D,L-LACTIDE-CO-GLYCOLIDE)