T-cell vaccines that elicit effective immune responses against HCV in chimpanzees may create greater immune pressure for viral mutation

A prime/boost vaccine strategy that transfects antigen-presenting cells using ligand-modified immunoliposomes to efficiently deliver plasmid DNA, followed by boosting with non-replicating recombinant advenovirus was used in chimpanzees to generate HCV-specific memory T-cells. Three chimpanzees (two vaccines, one control) were immunized with immunoliposomes complexed with DNA expressing NS3-NS5B or complexed with empty vector. Animals were boosted with adenovirus expressing NS3-NS5B, or non-recombinant adenovirus (control). Using liposome delivery we were able to obtain specific HCV responses following DNA priming in the chimpanzees. This data and mouse immunization studies confirm this as a more efficient delivery system than direct intramuscular inoculations with naked DNA. Subsequent to the adenovirus boost significant increases in peripheral HCV-specific T-cell responses and intrahepatic IFN-gamma and CD3 epsilon mRNA were also observed in the two vaccinated animals. Following challenge (100 CID50) both vaccinated animals showed immediate and significant control of viral replication (peak titers 3.7 x10(4) and 9 x 10(3) IU/mL at weeks 1 and 2), which coincided with increases in HCV-specific T-cell responses. Viral kinetics in the control animals were comparable to historical controls with exponenital increases in titer during the first several weeks. One vaccinated animal developed a low-level persistent infection (2 x 10(3) IU/mL) which correlated with a decrease in HCV-specific T-cell responses. Circulating virus isolated from both vaccinated animals showed similar to 2-fold greater nonsynonymous mutation rates compared to controls and the nonsynonymous/synonymous mutation rate ratio was indicative of positive selection. These data suggest that although T-cell vaccines can include immune responses capable of controlling HCV, they also induce high levels of immune pressure for the potential selection of escape mutants Published by Elsevier Ltd.