Lymphocyte recirculation within the human body is essential for efficient pathogen detection and immune responses. So far, immune cell migration has been investigated largely using ovine and murine models, with little evidence in humans. Here, we analyzed peripheral blood of healthy individuals following primary vaccination with the Yellow Fever vaccine YF-17D. We found that the number of leukocytes was transiently and sharply reduced in blood as detected on day 7 after vaccine administration. The T cell drop was restricted to cells expressing the lymph node-homing chemokine receptor CCR7. Interestingly, the vaccine-induced drop positively correlated with the expression of CD69 by the T cells before vaccination. This suggests that CCR7 ⁺ T cells are being trapped within the lymph nodes through CD69-induced suppression of egress. Strikingly, we further found that the T cell drop negatively correlated with CD8 T cell activation and with production of neutralizing antibodies. In conclusion, early and transient T cell depletion in blood negatively correlated with protective immune response events induced by YF-17D vaccination. Our data highlight baseline CD69 expression and early drop in T cells as potential biomarkers of the Yellow Fever vaccine response.