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2 SIV Vaccines Based on Adeno-Associated Virus Vectors
P. Johnson*1, B. Schnepp1, D. Montefiori2, N. Letvin3, and R. Clark1
1Columbus Children's Res. Inst., OH, USA; 2Duke Univ., Durham, NC, USA; and 3Beth Israel Deaconess Med. Ctr., Boston, MA, USA
Background: Live-attenuated SIV vaccines are considered highly efficacious, but this approach for an HIV vaccine has met resistance because of safety concerns. Although the precise protective mechanism of live-attenuated SIV is not known, it can be argued that these vaccines allow for the persistence of viral antigens. Thus, it would seem prudent to mimic these properties in any HIV vaccine strategy.
Methods: We have adapted a novel viral vector system based on recombinant adeno-associated viruses (rAAV). Wild-type AAV is a replication-defective parvovirus that is entirely nonpathogenic in humans and animals. Packaged rAAV vectors lack any AAV genes and consist solely of the gene of interest and requisite expression elements. rAAV vectors have been shown to mediate long-term transgene expression in mice and nonhuman primates. These properties suggested that AAV vectors might: (i) direct long-term expression of SIV genes in animals; and (ii) elicit durable and effective immune responses. We have generated rAAV vectors expressing the major structural genes of SIV and used these to immunize macaques.
Results: We have easily detected CD8+ antigen-specific CTL responses (classic lysis assays) against multiple epitopes in macaques immunized intramuscularly with a single dose of rAAV/SIV. Importantly, these responses were detected not only shortly after immunization, but also more than 1 year later. Moreover, these same animals had persistent ELISA and neutralizing antibody titers over the same time period. Additional studies showed that genetically selected macaques had robust antigen-specific T-cell responses (tetramer staining) that were similar to responses observed in monkeys infected with pathogenic SIV. More recent studies have moved on to test the efficacy of rAAV/SIV vaccines in the SIV macaque challenge model. Preliminary results suggest that immunized macaques have significantly lower virus burdens at peak and set point after challenge than do controls.
Conclusions: These data suggest that rAAV vectors stimulate robust, durable, and effective immune responses against SIV. These findings provide the basis for moving forward with clinical trials of cognate rAAV/HIV vaccines in humans.
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