Modified Vaccinia Virus Boosts Immunogenicity
Of DNA Malaria Vaccine
WESTPORT, Mar 31 (Reuters) - In mice, a modified vaccinia virus boosted protection against malaria parasite challenge after plasmid DNA immunization to "unprecedented" levels.
Dr. Jorg Schneider of the University of Oxford and his team used DNA encoding pre-erythrocytic antigens of P. berghei in a series of immunization experiments in mice. The researchers, in Oxford and London, UK, found that "...priming with plasmid DNA followed by a single boost with a recombinant modified vaccinia virus Ankara...expressing the same antigen..." confers complete protection against the malaria parasite, Plasmodium berghei, in two strains of mice.
All of the mice immunized with this protocol were protected against infection at the first challenge, and the majority of them were also protected at a second challenge, 28 to 35 days later. All of the mice demonstrated "...very high levels of splenic peptide-specific interferon-gamma-secreting CD8+ T cells."
The findings in the "highly susceptible" C57BL/6 mice are "particularly encouraging," according to the investigators, since "...no vaccination protocol designed to induce strong cellular immune responses has previously protected this strain of mice against either P. berghei or P. yoelii."
When the vaccination protocol was administered in the reverse order--priming with the modified vaccinia virus Ankara and boosting with plasmid DNA encoding pre-erythrocytic antigen--protection against P. berghei was not achieved.
The mechanism underlying the efficacy of one immunization sequence but not the other "in unclear," Dr. Schneider and colleagues say, but they speculate on a possible mechanism. "The [modified vaccinia virus Ankara] vector appears more immunogenic than DNA for CD8+ T cell induction; however, because of the large number of viral genes that are co-expressed, the immune response to the malaria antigen or epitope may not be immunodominant, but priming with just the malaria antigen using plasmid DNA may produce sufficient primed CD8+ T cells to the malaria epitope to allow the recombinant [modified vaccinia virus Ankara]-induced response to focus on this rather than viral epitopes."
The protective effect of the P. berghei pre-erythrocytic antigen supports the idea that its P. falciparum homologue may represent a malaria vaccine candidate, the investigators report in the April issue of Nature Medicine. In fact, they have shown in follow-up experiments that the same protocol described above can be used to elicit high expression of CD8+ T cells to a P. falciparum epitope in chimpanzees.
The modified vaccinia virus Ankara "...appears to be an exceptionally safe live virus vector," and has the potential to be incorporated into ongoing human vaccine trials using plasmid DNA. Dr. Schneider and others also point out that the vaccinia virus alone may be effective in boosting a CD8+ T cell response in persons living in areas endemic to P. falciparum, who experience "...natural priming from infective mosquito bites."
Nat Med 1998;4:397-402.