Improved memory CD8 T cell response to delayed vaccine boost is associated with a distinct molecular signature.

Although the prime/boost interval can impact vaccine responses, the criteria for deciding its time length are poorly defined. To address this, we examined CD8 T cell responsiveness to boost in a BALB/c mouse model of intramuscular (i.m.) vaccination by priming with HIV-1 gag-encoding Chimpanzee adenovector, and boosting with HIV-1 gag-encoding Modified Vaccinia virus Ankara. We found that boost was more effective at day(d)100 than at d30 post-prime, as evaluated at d45 post-boost by multi-lymphoid organ assessment of gag-specific CD8 T cell frequency, CD62L-expression (as a guide to memory status) and in vivo killing. RNA-sequencing of splenic gag-primed CD8 T cells at d100 revealed a quiescent, but highly responsive signature, that trended toward a central memory (CD62L+) phenotype. Interestingly, gag-specific CD8 T cell frequency selectively diminished in the blood at d100, relative to the spleen, lymph nodes and bone marrow. These results move forward the rational design of prime/boost intervals.