| Popis: |
To develop a multi-stage, multi-antigen, multi-immune response-inducing vaccine against malaria we have focused on DNA vaccines because of their simplicity of construction and modification, ease of mixing, and effectiveness in inducing CD8+ T cell responses. DNA malaria vaccines induce CD8+ T cell dependent protection in mice and CD8+ CTL in rhesus monkeys and humans after intramuscular needle administration. Clinical trials in normal, healthy humans are in progress or planned, assessing alternative methods and routes of administration, and the capacity of a plasmid expressing human GM-CSF to enhance the protective efficacy of a five-gene liver-stage malaria vaccine. In mice, we have demonstrated that priming with the combination of DNA plasmids encoding a Plasmodium yoelii protein and murine GM-CSF and boosting with recombinant poxvirus expressing the same P. yoelii protein induces a 30-fold increase in antigen-specific antibodies, a 10-fold increase in antigen-specific IFN-gamma spot forming cells, a significant (p0.05) increase in protection, and the capacity to reduce the dosage of DNA by 10-100 fold, compared to immunizing with DNA alone. In Aotus monkeys priming with DNA and boosting with recombinant protein in adjuvant is more protective than homologous priming and boosting with either DNA or recombinant protein in adjuvant. Clinical trials are now planned using these immunization strategies. Because of the complexity and cost of the heterologous regimens, we are working to make DNA vaccination alone as immunogenic and protective as the prime-boost approach. Our most encouraging findings have resulted from altering codon usage from the highly A+T rich P. falciparum native sequence to that more closely resembling mammalian sequences. Although much progress is required for the development of a vaccine that provides sustainable protective immunity against malaria, a strategy using DNA vaccine technology as a core component of such a vaccine is promising. |
