TCR bias drives development of dominant vaccine-induced CD8+ T cell responses which can be redirected toward cellular...

The yellow fever (YF) vaccine is known to elicit strong CD8+ T cell immune responses, predominantly targeting an HLA-A2-restricted immunodominant epitope within the NS4B protein. We aimed to characterize these cells and explore their functional utility when redirected to a target unrelated to YF. We performed single-cell TCR and mRNA sequencing on YF-specific CD8+ T cells from five vaccinated donors, 21 days post-vaccination to characterize their clonal diversity and transcriptional profiles. An HLA-restricted bispecific T cell engager, Redirector of Vaccine-induced Effector Responses (RoVER), was used to redirect YF-specific CD8+ T cells toward target cells including HIV-1-infected CD4+ T cells and CD19+ B cells. The vaccine elicited a robust CD8+ T cell response characterized by a diverse set of differentiated YF-specific cells spanning activated naïve-like, memory and effector phenotypes. Despite biases in the TCR repertoires, antigen-specificity did not promote the development of unique phenotypes following vaccination. Our findings suggest phenotypic overlap causing redundancy in CD8+ T cell immunity across YF epitopes. Using the recombinant RoVER, YF-specific CD8+ T cells could be redirected toward other target cells, leading to efficient target cell elimination. Together, this study enhances our understanding of the cytotoxic T cell response to viral infections and its implications for vaccine development, while also supporting the development of personalised immunotherapies tailored to individual HLA alleles.