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*
Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889;
Section of Retroviral Immunology, Division of Viral Products, Center for Biologics Research and Evaluation, Food and Drug Administration, Bethesda, MD 20892;
University of Maryland, Baltimore, MD 21201; and
§
Vical, Inc., San Diego, CA 92121
Using the murine parasite Plasmodium yoelii (Py) as
a model for malaria vaccine development, we have previously shown that
a DNA plasmid encoding the Py circumsporozoite protein (PyCSP) can
protect mice against sporozoite infection. We now report that mixing a
new plasmid PyCSP1012 with a plasmid encoding murine
granulocyte-macrophage colony-stimulating factor (GM-CSF) increases
protection against malaria, and we have characterized in detail the
increased immune responses due to GM-CSF. PyCSP1012 plasmid
alone protected 28% of mice, and protection increased to 58% when
GM-CSF was added (p < 0.0001). GM-CSF plasmid
alone did not protect, and control plasmid expressing inactive GM-CSF
did not enhance protection. GM-CSF plasmid increased Abs to PyCSP of
IgG1, IgG2a, and IgG2b isotypes, but not IgG3 or IgM. IFN-
responses of CD8+ T cells to the PyCSP 280–288 amino acid
epitope increased but CTL activity did not change. The most dramatic
changes after adding GM-CSF plasmid were increases in Ag-specific IL-2
production and CD4+ T cell proliferation. We hypothesize
that GM-CSF may act on dendritic cells to enhance presentation of the
PyCSP Ag, with enhanced IL-2 production and CD4+ T cell
activation driving the increases in Abs and CD8+ T cell
function. Recombinant GM-CSF is already used in humans for medical
purposes, and GM-CSF protein or plasmids may be useful as enhancers of
DNA vaccines.
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