Although sterilizing immunity to
malaria can be elicited by irradiated sporozoite vaccination, no clinically practical
subunit vaccine has been shown to be capable of preventing the approximately 600,000 annual deaths attributed to this
infection.
DNA vaccines offer several potential advantages for a disease that primarily affects the developing world, but new approaches are needed to improve the immunogenicity of these
vaccines. By using a novel,
lipid-based adjuvant,
Vaxfectin, to attract immune cells to the immunization site, in combination with an
antigen-
chemokine DNA construct designed to target
antigen to immature dendritic cells, we elicited a humoral immune response that provided sterilizing immunity to
malaria challenge in a mouse model system. The
chemokine, MIP3αCCL20, did not significantly enhance the cellular infiltrate or levels of
cytokine or
chemokine expression at the immunization site but acted with
Vaxfectin to reduce liver stage
malaria infection by orders of magnitude compared to
vaccine constructs lacking the
chemokine component. The levels of protection achieved were equivalent to those observed with irradiated sporozoites, a candidate
vaccine undergoing development for further large scale clinical trial. Only vaccination with the combined regimen of adjuvant and
chemokine provided 80-100% protection against the development of
bloodstream infection. Treating the immunization process as requiring the independent steps of 1) attracting antigen-presenting cells to the site of immunization and 2) specifically directing
vaccine antigen to the immature dendritic cells that initiate the adaptive immune response may provide a rational strategy for the development of a clinically applicable
malaria DNA vaccine.