Intradermal influenza vaccination provides an ethical perturbation model for studying cutaneous inflammation in humans

Summary: Abstract Body: Comparisons of “snapshot” differences, i.e. cell type composition and cell state, among healthy control, non-lesional, and lesional skin constitute the foundation of known inflammatory skin pathophysiology, yet this design often fails to reveal the dynamical processes that drive disease. Additionally, a rich set of cutaneous stromal cells (keratinocytes, fibroblasts, and endothelial cells) acting as signal amplifiers and immune recruiters are increasingly recognized as critical to inflammatory skin disease pathology. Thus, to better understand the role of stromal cells and their coordinated induction and elicitation of immune responses in human skin so fundamental to inflammatory skin diseases, we have established an intradermal influenza vaccination model to ethically and systematically study the functionality and timing of coordinated immune activity. Through Xenium spatial transcriptomic profiling of skin biopsies from healthy individuals (N=38) before and after intradermally delivered flu vaccine or sham saline, we have identified a dynamic progression of local immune responses involving innate and adaptive immune cells, as well as distinct phenotypic shifts in stromal cell types at the local injection site over time. During early timepoints, there is an initial interferon-STAT1 signature in keratinocytes, fibroblasts, monocytes, endothelial cells and T-cells that rises as early as 2 hours, peaking at day 1 and continues to resolve by day 3. Even 28 days after vaccination, clinically normal appearing skin retains a preponderance of activated monocytes and perivascular T-cells with an effector memory phenotype in the reticular dermis not seen at baseline. This work provides a foundation for future applications in immune cell migration, tissue immune setpoints, and pathogenesis of cutaneous inflammatory disease. Andrew D. Johnston¹, Margaret MacGibeny², Jacob Kim¹, Christine Dien¹, Meirav Sela¹, Shoham Benmelech¹, Yona Lei¹, Siyi Chen¹, Anjali Jaiswal², Michal Kidacki², Matthew Vesely², Surender Khurana³, Hana Golding³, Andrew Martins¹, Inci Yildirim⁴, Rachel Sparks¹, John Tsang¹ 1. CSEI, Yale, New Haven, CT, United States. 2. Immunobiology, Yale, New Haven, CT, United States. 3. CBER, FDA, Silver Springs, MD, United States. 4. Pediatrics, Yale, New Haven, CT, United States. Clinical Research: Interventional Research