Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon vaccination

Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naive T cells with high specificity to expand and differentiate into memory T cells that allow for a quick and robust T cell response upon exposure to the pathogen or re-exposure to the vaccine antigen. This is why the induction of memory T cells is a key feature in vaccine development. However, it has become increasingly evident that antigen-specific memory CD4 and CD8 T cells exist in unexposed antigen-naive hosts and it is likely that exposure to one antigen might alter the TCR repertoire of memory T cells to a different unrelated antigen. In this study, we utilize high-throughput sequencing to profile the memory CD4 TCRβ repertoire and track vaccine-specific TCRβ clonotypes following the de novo administration of hepatitis B (HepB) vaccine in healthy HepB-naive individuals and show that vaccinees with preexisting vaccine-specific memory CD4 T cell clonotypes elicited earlier and higher antibody concentrations and mounted a more robust CD4 T cell response to the vaccine. We further identify vaccine-specific TCRβ sequence patterns that can be used to predict which individuals will have an early and more vigorous vaccine-elicited immunity to HepB vaccine. Moreover, we find that an expansion of 4-1BB+ memory TREG is a prominent feature in individuals with delayed and modest vaccine-induced immunity. Our approach shows that modeling pre-vaccination TCRβ repertoire enables prediction of both antibody and CD4 responses to vaccines.