The ongoing COVID-19 pandemic has highlighted the importance of vaccination as a critical public health tool against current and emerging pathogens. While vaccines have traditionally been delivered via needle-and-syringe injection, much work into alternative delivery systems has been conducted. The immunologically active microenvironment and the high density of antigen-presenting cells make the skin an attractive target for vaccination. The use of microarray patches to deliver vaccines directly these layers of the skin presents a promising alternative to traditional vaccine delivery mechanisms. One such microarray patch is the Vaxxas High-Density Microarray patch (HD-MAP). Delivery of vaccines via the HD-MAP has shown dramatic improvements in immunogenicity in terms of magnitude, breadth and quality of the immune response. We used newly available spatial transcriptomics tools to examine the immunological mechanisms underpinning the immune enhancement phenomena associated with HD-MAP vaccine delivery, including the nanoString GeoMx and 10x Genomics Visium and Xenium (single cell resolution). Using these techniques, we investigated the response to HD-MAPs at the transcriptome level in both mice and humans temporally and spatially in the skin. Analysis revealed the HD-MAP triggers a localized enhanced inflammatory state in the skin within 1 hour, characterized by TNF and IL-17 signaling, resulting in rapid infiltration of multiple immune cells. Distinct cell infiltrates into the epidermis and dermis were observed with the 10x Xenium platform. This work provides unprecedented detail into the precise transcriptional mechanisms following HD-MAP vaccination. These findings have implications for future microarray patch-delivered vaccine development and design.