The split-virus influenza vaccine activates Fcγ receptors instead of Toll-like receptors (VAC2P.930)

Abstract

Abstract Seasonal influenza vaccination is the most common medical procedure targeting the immune system and yet the extent to which influenza vaccination activates innate immunity in humans is not fully understood. Currently, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles often prepared without any adjuvants. We sought to determine whether the unadjuvanted split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. A mass-cytometry (CyTOF) based proteomic profiling platform was developed and used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response in human whole-blood (ex vivo). This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a serum factor was necessary for vaccine-dependent immune activation. We found this serum factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza vaccine splitting inactivates any microbial adjuvants endogenous to influenza but potentially elicits a potent immune modulator by facilitating the rapid formation of immune complexes.