T-cell responses are considered an important component of a successful HCV-vaccine. However, immunological markers that differentiate successful, vaccine-induced memory T-cells from regular memory T-cells induced during natural HCV infection have not been described.
Here, we mapped minimal T-cell epitopes, generated 6 MHC/peptide tetramers and performed a detailed multi-color flow cytometry analysis of HCV-specific memory T-cells of 5 chimpanzees, which were part of a previously published adenovirus/DNA-based HCV-NS3-5 vaccine trial (Nature Medicine 12:190, 2006). HCV-specific memory T-cells were detectable not earlier than week 11 after HCV-challenge in 2 non-vaccinated chimpanzees, whereas they were detectable immediately after vaccination in 3 vaccinated chimpanzees and their numbers increased as early as week 4 after HCV-challenge. However, irrespective of the chimpanzees’ vaccination status, HCV-specific memory T-cells wereabout 44% central memory (CCR7+CD45RA-) and 47% effector memory (CCR7-CD45RA-) cells.
At the time of their peak frequency, HCV-specific memorycells were maximally activated in non-vaccinated chimpanzees with high levels of CD38 and PD-1 expression. In contrast, HCV-specific memory cells were only modestly activated in vaccinated chimpanzees, and their activation status remained controlled even during HCV challenge. Consistent with these findings in the peripheral blood, the PD-1/CD8 mRNA ratio in the liver was higher for non-vaccinated chimpanzees than for vaccinated chimpanzees. The limited activation ofvaccine-induced T-cells was unexpected as these cells showed excellent functional responses (proliferation, IFN-g production) that were superior to those of memory T-cells induced in non-vaccinated chimpanzees during the natural course of HCV infection. Thus, vaccine-induced T-cellsappeared to achieve more (better effector function) with less effort (less activation).
Taken together, a successful T-cell vaccine induces effective T-cell immunity by optimal rather than maximal activation of HCV-specific CD8 T-cells.