Circumventing genetic restriction of protection against malaria with multigene DNA immunization: CD8(+) T 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 od five strains of mice against malaria (H-2(d), 75%); a PyHEP17 DNA vaccine protected three of the five strains (H-2(a), 71%; H-2(k), 54%; H-2(d), 26%); and the combination protected 82% of H-2(a), 90% of H-2(k), and 88% of H-2(d) mice. Protection was absolutely dependent on CD8(+) T cells, IFN-gamma, or nitric oxide. These data introduce a new target of protective preerythrocytic immune responses, PyHEP17 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.