A plasmid encoding murine granulocyte-macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine.
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-gamma 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.
Weiss
W R
WR
Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889, USA.
Ishii
K J
KJ
Hedstrom
R C
RC
Sedegah
M
M
Ichino
M
M
Barnhart
K
K
Klinman
D M
DM
Hoffman
S L
SL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008288:Malaria / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000276:immunology* / Q000494:pharmacology; D010967:Plasmodium yoelii / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*
D016207:Cytokines; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D019444:Vaccines, DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor