Non-cytolytic re-engineering of a viral vaccine vector enables durable effector-memory T cell immunity by reinforcing type I IFN induction

Replication-deficient viral vector systems hold promise for CD8 T cell-based vaccination, but the molecular mechanisms accounting for platform-specific differences in immunogenicity remain ill-defined. When comparing prototypic single-cycle vaccine delivery platforms, we found that lymphocytic choriomeningitis virus (rLCMV)-based vectors, which are non-cytolytic, elicited more durable and effector-memory-differentiated CD8 T cell responses than vectors based on cytolytic vesicular stomatitis virus (rVSV). Hence, we re-engineered rVSV to be non-cytolytic (rVSVMq). This vector induced more durable and effector-differentiated CD8 T cell memory than the parental rVSV, and it afforded superior protection against <i>Listeria</i> challenge. Improved CD8 T cell responses of non-cytolytic rVSVMq were driven by a reinforced type I interferon (IFN-I) response and its direct sensing by vaccination-induced CD8 T cells. Many vector cargo-specific CD8 T cells in the splenic marginal zone of rVSVMq- or rLCMV-vaccinated mice were in contact with vector cargo-expressing cells that co-expressed IFN-I. In contrast, rVSV-vectored cargo-expressing contacts of specific CD8 T cells were largely IFN I-negative. Thereby, vaccination with non-cytolytic viral vectors offered an opportunity for CD8 T cells to integrate peptide-MHC (major histocompatibility complex) and IFN-I signals during priming. These mechanistic insights should help to refine vaccines aimed at eliciting durable and protective effector-memory CD8 T cell immunity.