ABSTRACT: The recombinant vesicular stomatitis virus–vectored Zaire Ebola virus glycoprotein (rVSVΔG-ZEBOV-GP) vaccine, while effective and well-tolerated, exhibits notable reactogenicity, manifesting in expected adverse events (AEs) such as fever, headache, and pain, along with rare, unexpected AEs like skin lesions, cutaneous vasculitis, and transient arthritis. The presence or absence of AEs following rVSVΔG-ZEBOV-GP vaccination is associated with a specific innate plasma signature. This study aims to elucidate in-vitro the tropism of the vaccine for different cell types derived from tissues previously reported to be involved in the unexpected AEs. Upon in-vitro infection with rVSVΔG-ZEBOV-GP, various cell types such as synoviocytes, fibroblast, keratinocytes and endothelial cells (except chondrocytes) demonstrate productive infection, which in dermal fibroblast triggered the release of many innate plasma signature markers, including keratinocytes’ proinflammatory and proapoptotic cytokines such as OSM and TRAIL. Infected monocytes from buffy coats, activated by infection, produce most innate plasma signature markers. In co-culture, rVSVΔG-ZEBOV-GP-infected monocytes serve as a source to synoviocytes infection, resulting in a distinct kinetics modulation in innate biomarkers (transcription and secretion) and upregulation of specific genes such as NEDD8 and SIGLEC-1, which have been associated with inflammatory arthritis in animal models. Altogether, our work based on in-vitro studies provide insights into the possible mechanisms of rVSVΔG-ZEBOV-GP observed reactogenicity by showing tropism of the vaccine for off target cells derived from AE affected compartments (skin, joints, vessels). Furthermore, in-vitro interaction with infected monocytes modulates the innate response of synoviocytes.
