Tick-borne meningoencephalitis (TBE) is a viral disease of the central nervous system (CNS) caused by tick-borne encephalitis virus (TBEV). The most effective protection against TBE is vaccination, however, despite highly immunogenic vaccine, vaccine breakthrough (VBT) infections still occur. VBT TBE patients are usually older, develop a monophasic disease and more severe symptoms compared to unvaccinated TBE patients. In contrast to unvaccinated TBE patients, VBT TBE patients are older and more often develop monophasic disease with more severe clinical symptoms. With growing evidence on pathological involvement of immune system in TBE, we aimed to investigate the functionality of Toll-like receptors (TLRs) 3, 7 and 8 and the activation of the immune system in VBT TBE patients. Genotyping of single nucleotide polymorphisms (SNPs) associated with TLR functionality showed that the frequency of the wild allele for TLR8 was higher in vaccinated females with TBE than in unvaccinated females with TBE, therefore functional TLR8 receptor could represent a risk factor for VBT TBE in women. To recreate the events in the initial phase of TBE pathogenesis, we stimulated peripheral blood mononuclear cells (PBMC) from VBT TBE and unvaccinated TBE patients with TBEV in vitro. Vaccinated and unvaccinated TBE patients did not differ in the expression of activation molecules dendritic cells after stimulation with TBEV in vitro, however, significantly lower concentrations of IFN-α, IL-12p70 and IL-15 were measured in supernatants of stimulated PBMCs from VBT patients in early time points. This could lead to more extensive viral replication and impair the activation of other immune cells. On the other hand, an observed increased IL-6 expression in VBT patients in late stages of in vitro stimulation, could support the extensive inflammatory responses and contribute to the blood-brain barrier disruption. Additionally, in acute phase of the disease, VBT TBE patients had systemically elevated inflammatory cytokines, with majority of them concentrated in cerebrospinal fluid and positively correlating with immune cell counts, indicating a localized Th1 and inflammatory responses in the central nervous system. Markedly elevated VEGF-A could lead to an extensive disruption of the blood-brain barrier, supporting immune cells entry and the formation of an intrathecal inflammatory focus, therefore contributing to a more severe disease. Also, VBT TBE patients had systemically upregulated levels of IL-8/CXCL8 and GROα/CXCL1 up to two months after the onset of neurological symptoms, indicating long-term systemic immune activation, which could explain the need for longer hospitalization of VBT TBE patients. An observed more extensive and prolonged inflammatory response in VBT TBE patients suggests an involvement of the immune response in the onset and development of the disease. However, additional studies are needed to better understand the mechanism behind vaccination breakthrough infections.
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