Longitudinal Profiling of CD4⁺ T Cell Responses Following de novo Yellow Fever Vaccination

The yellow fever 17D vaccine is one of the most successful live-attenuated viral vaccines, yet the cellular mechanisms underlying its long-term protection remain not fully understood. This study provides a longitudinal analysis of the human CD4+ T cell and IgG response following de novo yellow fever vaccination by focusing. Peripheral blood mononuclear cells (PBMCs) from 49 vaccinated individuals were stimulated with yellow fever (YF) and control peptide pools across four timepoints: pre-vaccination/baseline (D1), day 22 (D22), day 43 (D43), and one year (D365) post-vaccination. Activation-induced marker (AIM) assays confirmed robust activation of CD4+ T cells following yellow fever peptide stimulation, peaking at day 22 post-vaccination and subsequently declining. T-cell receptor (TCR{beta}) sequencing of AIM-sorted CD4+ T cells showed a transient increase in clonal diversity at D22, consistent with broad epitope targeting and early polyclonal expansion. This was followed by repertoire contraction, which could indicate the persistence of a limited set of dominant clonotypes responsible for immune memory formation. TCR repertoires remained largely private over time, indicating a mostly individualized immune response. Next, serological analyses revealed a robust and highly yellow fever virus (YFV)-specific IgG response. Antibody levels peaked within the D22-D43 window and remained elevated at one year post-vaccination. Cross-reactivity toward other flaviviruses was limited, suggesting an antigen-specific humoral response. Together, these findings characterize the longitudinal dynamics of the CD4+ T cell and IgG response following de novo yellow fever vaccination and provide insights into the mechanisms contributing to durable antiviral immunity.