Session 17Oral Abstract Presentations HIV/SIV Vaccine Studies Session Day and Time: Wednesday 10 am - 12:30 pm Presentation Time: 11:45 Room: Ballroom B
83 Evolutionary Indicators of Vaccine Efficacy from the ALVAC Phase II Trials D. C. Nickle*1, K. Davis1, Y. Liu1, S. McLaughlin1, I. Genowati1, H. Zhao1, M. Pathmajeyan1, L. Rose1, G. H. Learn1, H. B. Sheppard2, C. Celum1, J. I. Mullins1 1Univ of Washington, Seattle and 2California Dept of Hlth Svcs, Richmond
Background: The ALVAC HIV-1 vaccine, designed to stimulate production of cytotoxic T-cells (CTL), is an attenuated canarypox vector genetically altered to contain copies of HIV-1 genes (e.g., gag and env). We studied vaccinees in AVEG and HIVNET trials of ALVAC who subsequently became infected with HIV-1, in an effort to detect molecular evolutionary evidence for vaccine impact.
Methods: We cloned and sequenced multiple full-length viral genomes from 4 vaccinees and 2 non-vaccinees. In addition, we assessed viral gp120 env sequences in 7 vaccinees, 4 placebo recipients, and 38 (unvaccinated) individuals infected while participating in the observational HIVNET Vaccine Preparedness Study. Genetic diversity across the viral genome and the amino acid genetic distance from the vaccine strain to the breakthrough infecting sequences were evaluated. We controlled for time of infection by separating the genetic distances into synonymous and non-synonymous distances, since synonymous mutations evolve at a constant rate, while non-synonymous mutations are more dynamic and are affected by selection.
Results: Initially, we found that the infecting viruses in the vaccinees had marginally greater amino acid distances from the vaccine strain than those found in non-vaccinees. However, when we controlled for time by separating the genetic distance into synonymous and nonsynonymous distances, synonymous distances were slightly smaller in vaccinees than in non-vaccinees, suggesting that differences in time had little or no effect. In contrast, infecting strains in vaccinees were significantly more distant from the vaccine strain than in non-vaccinees when the nonsynonymous distances were considered with respect to the synonymous distances (p = 0.02). Additionally, viruses infecting vaccinees had higher levels of diversity in the env gene early in infection than those infecting non-vaccinees.
Conclusions: These results suggest that either HIV-1 strains similar to the vaccine strain may have been blocked by limited sterilizing immunity, or prior immunity may have been more effective at suppressing variants within the infecting population that were most similar to the vaccine immunogen. This provides the first, though quite preliminary, evidence of an impact of HIV vaccination on the subsequent establishment of HIV-1 infection. Our results to date are strongly tempered by the small numbers of individuals studied.
