Human plasmacytoid dendritic cells at the crossroad of type I interferon-regulated B cell differentiation and antiviral response to tick-borne encephalitis virus

The Tick-borne encephalitis virus (TBEV) causes different disease symptoms varying from asymptomatic infection to severe encephalitis and meningitis suggesting a crucial role of the human host immune system in determining the fate of the infection. There is a need to understand the mechanisms underpinning TBEV-host interactions leading to protective immunity. To this aim, we studied the response of human peripheral blood mononuclear cells (PBMC) to the whole formaldehyde inactivated TBEV (I-TBEV), the drug substance of Encepur, one of the five commercially available vaccine. Immunophenotyping, transcriptome and cytokine profiling of PBMC revealed that I-TBEV generates differentiation of a sub-population of plasmacytoid dendritic cells (pDC) that is specialized in type I interferon (IFN) production. In contrast, likely due to the presence of aluminum hydroxide, Encepur vaccine was a poor pDC stimulus. We demonstrated I-TBEV-induced type I IFN together with Interleukin 6 and BAFF to be critical for B cell differentiation to plasmablasts as measured by immunophenotyping and immunoglobulin production. Robust type I IFN secretion was induced by pDC with the concerted action of both viral E glycoprotein and RNA mirroring previous data on dual stimulation of pDC by both S. aureus and influenza virus protein and nucleic acid that leads to a type I IFN-mediated sustained immune response. E glycoprotein neutralization or high temperature denaturation and inhibition of Toll-like receptor 7 signalling confirmed the importance of preserving the functional integrity of these key viral molecules during the inactivation procedure and manufacturing process to produce a vaccine able to stimulate strong immune responses. Author summary Though vaccination is generally considered effective in reducing tick-borne encephalitis (TBE) incidence, several studies have shown that the antibody response to TBEV vaccination declines with age resulting in more frequent TBE cases among 50+ year-old vaccinees. These observations together with the lack of a specific antiviral drug impose to pinpoint novel host- and pathogen-directed therapies and to improve the control of vaccine efficacy. Thus, we interrogated in vitro human PBMC, whose response to TBEV may provide a picture closer to what occurs in vivo in humans after vaccination or natural infection compared to animal models. The role of E glycoprotein and viral RNA in promoting antiviral and B cell-mediated responses was investigated. Thus, these key viral molecules should be considered, in future, for novel subunit vaccine formulations than the current whole inactivated TBEV-based vaccines, which require laborious manipulation in biosafety level-3 laboratory and animal testing for manufacturing and batch release.

Automated summary

The study showed that inactivated TBEV (I-TBEV) induced differentiation of a sub-population of plasmacytoid dendritic cells (pDC) specialized in type I interferon production in human PBMC. This was critical for B cell differentiation to plasmablasts, highlighting the importance of preserving key viral molecules during vaccine manufacturing process.