I will discuss our efforts to define the features of vaccine-induced T cell responses that underlie protection and long-term immunity by integrating functional, phenotypic, and clonotypic analyses across human vaccine studies.
I will share our work in progress analyzing radiation-attenuated Plasmodium falciparum sporozoite (SPZ) vaccination, where we identify CD4⁺ T cell responses associated with sterile protection in a human challenge trial. I will show how protected individuals maintain higher frequencies of SPZ-reactive CD4⁺ T cells at the time of challenge, with a bias toward IFNγ-producing responses and how we confirmed the antigen-specificity of these responses. I’ll also discuss the use of single-cell RNA sequencing paired with TCR sequencing to show that these cells are predominantly Th1 with cytotoxic features, which contrasts profiles of SPZ-specific CD4 responses observed in donors with repeated natural malaria exposure.
I will also describe our work on HIV vaccination, focusing on the clonal architecture and longitudinal dynamics of vaccine-induced T cell responses. Using a high-throughput approach for antigen-specific TCR identification, we generated large libraries of HIV Env- and Gag-specific clonotypes and tracked their evolution over time. I will discuss how these analyses reveal distinct kinetic patterns across CD4 and CD8 T cells and between antigen targets, including expansion of short-lived effector clones and persistence of stable memory populations, which we can also link to single cell phenotypic profiles. I will also show how clustering of TCR trajectories can identify additional vaccine-responsive clonotypes not captured by conventional functional assays.
Overall, I’ll describe how integrating phenotypic, functional and clonotypic data provides a more complete framework for understanding vaccine-induced immunity. I will highlight how these approaches can be used to identify features associated with protection and durability and outline their broader applications for immune monitoring, biomarker discovery, and TCR-based therapeutic development.