Pre-clinical evaluation of a novel HIV vaccine based on an adeno-associated virus vector

In earlier work, we showed that a single dose of an SIV vaccine based on a serotype 2 recombinant adeno-associated virus vector (rAAV2/SIV) elicited durable immune responses that were similar to those observed in macaques experimentally infected with pathogenic SIV. In challenge studies, macaques immunized with rAAV2/SIV sustained significantly lower viral burdens than did controls after exposure to a pathogenic SIV challenge (SIVsm/ E660). Based on these data, our collaborative group (CCRI; Targeted Genetics Corporation, Seattle; and the International AIDS Vaccine Initiative, New York) has generated an HIV-1 Clade C vaccine for the developing world. As part of the pre-clinical evaluation leading up to human phase I trials, we inoculated 24 macaques over a dose range (3 · 109–3 · 1012 genomes) with the clinical HIV vaccine lot (manufactured by Targeted Genetics). Macaques received a single intramuscular injection (four dose groups, six per group) and immune responses were studied over 6 months. As we had seen in other studies, antibodies to the transgene product (in this case, HIV-1 Gag) rose slowly over time and were sustained through 6 months, regardless of dose. The magnitude of the response was clearly affected by dose. However, owing to the variability in individual monkeys, the observed differences in titer between the highest dose groups were not statistically significant at any time after 2 weeks. A similar stratification was observed in antigen-specific T cell responses. Overall, responses gradually rose through week 12 and persisted through 6 months. By 6 months, over 70% of animals in the two highest dose groups had persistent ELISPOT responses (to gag peptides). In two monkeys sacrificed at 20 weeks, vaccine vector genomes were detected by PCR at the site of injection. Importantly, no local (injection site) or systemic adverse reactions were noted over the 6 months of the study. These data confirm and extend our earlier observations with rAAV2/SIV vaccines in macaques and provide a foundation for phase I testing in humans.