5 research outputs found
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