Circumventing genetic restriction of protection against malaria with multigene DNA immunization: CD8+ cell-, interferon gamma-, and nitric oxide-dependent immunity.
Despite efforts to develop vaccines that protect against malaria by inducing CD8+ T cells that kill infected hepatocytes, no subunit vaccine has been shown to circumvent the genetic restriction inherent in this approach, and little is known about the interaction of subunit vaccine-induced immune effectors and infected hepatocytes. We now report that immunization with plasmid DNA encoding the plasmodium yoelii circumsporozoite protein protected one of five strains of mice against malaria (H-2d, 75%); a PyHEP17 DNA vaccine protected three of the five strains (H-2a, 71%; H-2k, 54%; H-2d, 26%); and the combination protected 82% of H-2a, 90% of H-2k, and 88% of H-2d mice. Protection was absolutely dependent on CD8+ T cells, INF-gamma, or nitric oxide. These data introduce a new target of protective preerythrocytic immune responses, PyHEP 17 and its P. falciparum homologue, and provide a realistic perspective on the opportunities and challenges inherent in developing malaria vaccines that target the infected hepatocyte.
Doolan
D L
DL
Malaria Program, Naval Medical Research Institute, Bethesda, Maryland 20889-5607, USA.
Sedegah
M
M
Hedstrom
R C
RC
Hobart
P
P
Charoenvit
Y
Y
Hoffman
S L
SL
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016054:DNA, Protozoan / Q000627:therapeutic use*; D005260:Female; D017125:Genes, Protozoan; D007109:Immunity / Q000235:genetics; D007114:Immunization; D007371:Interferon-gamma; D008212:Lymphocyte Depletion; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000627:therapeutic use*; D051379:Mice / Q000235:genetics; D009569:Nitric Oxide; D010957:Plasmids / Q000627:therapeutic use; D010967:Plasmodium yoelii / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology; D013045:Species Specificity; D014614:Vaccines, Synthetic / Q000627:therapeutic use*
D016054:DNA, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan; D009569:Nitric Oxide; D007371:Interferon-gamma