Abstract
Background: System vaccinology identified an early innate signature associated with vaccine-mediated protection whose induction is likely to involve both immune and non-immune cells. Methods: To dissect muscle and stromal cell contribution, we simulated in vitro anti-COVID19 BNT162b2 mRNA vaccine intramuscular administration in human primary cell systems composed of 3D muscle-like tissue (3D-MT), fibroblasts, and peripheral blood mononuclear cells (PBMC). Results: BNT162b2 vaccine was recognized by all cell types, although fibroblasts only translated the spike antigen. Factors from vaccine-injected 3D-MT stimulated monocyte and macrophage recruitment and promoted inflammatory macrophage activation, while stromal factors improved dendritic cell frequency and activation. Conditioned media from vaccine-exposed 3D-MT and fibroblasts elicited in PBMC the expression of an early innate immune module previously associated with protective responses in BNT162b2 vaccinees. Conclusion: Thus, models combining human PBMC, stromal and muscle cells could be employed for the in vitro validation of system vaccinology findings and non-animal vaccine pre-clinical testing.