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Strategy for development of a pre-erythrocytic Plasmodium falciparum DNA vaccine for human use
S L Hoffman1, D L Doolan, M Sedegah
1Malaria Program, Naval Medical Research Institute, Bethesda, MD 20889-5607, USA. hoffman@mail2.nmri.nnmc.navy.mll
Insights
DNA vaccines targeting Plasmodium yoelii circumsporozoite protein (PyCSP) and other antigens induced protective CD8+ T cell responses. Combining these vaccines enhanced protection against malaria parasites.
Area of Science:
- Immunology
- Vaccinology
- Parasitology
Background:
- Plasmodium yoelii rodent model used to study malaria vaccine candidates.
- CD8+ T cell responses are crucial for protection against infected hepatocytes.
Purpose of the Study:
- To evaluate DNA vaccines encoding Plasmodium yoelii antigens for inducing protective immunity.
- To explore the potential of multi-gene DNA vaccines for human malaria prevention.
Main Methods:
- Plasmid DNA vaccines encoding PyCSP, PyHEP17, and PySSP2 were administered to mice.
- Immunogenicity and protective efficacy of single and mixed plasmid vaccines were assessed.
- Homologous genes from Plasmodium falciparum were selected for human vaccine development.
Main Results:
- Vaccines encoding PyCSP and PyHEP17 potently induced CD8+ T cell responses against infected hepatocytes.
- A mixture of PyCSP and PyHEP17 DNA vaccines circumvented genetic restrictions and provided additive protection.
- A third DNA vaccine encoding PySSP2 also demonstrated protective capacity.
Conclusions:
- Multi-gene DNA vaccines targeting Plasmodium antigens can induce robust CD8+ T cell-mediated protection.
- Further development and clinical trials are necessary for optimizing P. falciparum DNA vaccines for human use.
Abstract:
Data generated in the Plasmodium yoelii rodent model indicated that plasmid DNA vaccines encoding the P.yoelii circumsporozoite protein (PyCSP) or 17 kDa hepatocyte erythrocyte protein (PyHEP17) were potent inducers of protective CD8+ T cell responses directed against infected hepatocytes. Immunization with a mixture of these plasmids circumvented the genetic restriction of protective immunity and induced additive protection. A third DNA vaccine encoding the P. yoelii sporozoite surface protein 2 (PySSP2) also induced protection. The P. falciparum genes encoding the homologues of these three protective P. yoelii antigens as well as another P. falciparum gene encoding a protein that is expressed in infected hepatocytes have been chosen for the development of a human vaccine. The optimal plasmid constructs for human use will be selected on the basis of immunogenicity data generated in mice and nonhuman primates. We anticipate that optimization of multi-gene P. falciparum DNA vaccines designed to protect against malaria by inducing CD8+ T cells that target infected hepatocytes will require extensive clinical trials during the coming years.