Upregulated Intrathecal Expression of VEGF-A and Long Lasting Global Upregulation of Proinflammatory Immune Mediators in Vaccine Breakthrough Tick-Borne Encephalitis.

Although anti-TBE vaccines are highly effective, vaccine breakthrough (VBT) cases have been reported. With increasing evidence for immune system involvement in TBE pathogenesis, we characterized the immune mediators reflecting innate and adaptive T and B cell responses in neurological and convalescent phase in VBT TBE patients. At the beginning of the neurological phase, VBT patients have significantly higher serum levels of several innate and adaptive inflammatory cytokines compared to healthy donors, reflecting a global inflammatory state. The majority of cytokines, particularly those associated with innate and Th1 responses, are highly concentrated in CSF and positively correlate with intrathecal immune cell counts, demonstrating the localization of Th1 and proinflammatory responses in CNS, the site of disease in TBE. Interestingly, compared to unvaccinated TBE patients, VBT TBE patients have significantly higher CSF levels of VEGF-A and IFN-β and higher systemic levels of neutrophil chemoattractants IL-8/CXCL8 and GROα/CXCL1 on admission. Moreover, serum levels of IL-8/CXCL8 and GROα/CXCL1 remain elevated for two months after the onset of neurological symptoms, indicating a prolonged systemic immune activation in VBT patients. These findings provide the first insights into the type of immune responses and their dynamics during TBE in VBT patients. An observed systemic upregulation of neutrophil derived inflammation in acute and convalescent phase of TBE together with highly expressed VEGF-A could contribute to BBB disruption that facilitates the entry of immune cells and supports the intrathecal localization of Th1 responses observed in VBT patients.

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Copyright © 2021 Pavletič, Korva, Knap, Bogovič, Lusa, Strle, Nahtigal Klevišar, Vovko, Tomažič, Lotrič-Furlan, Strle and Avšič-Županc.

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PB served on the scientific advisory board for Pfizer on TBE CEE expert meeting 2020. KS served on the scientific advisory board for Roche for development of Lyme disease serological diagnostics received support by grant from MGH-ECOR. FS served on the scientific advisory board for Roche on Lyme disease serological diagnostics and the scientific advisory board for Pfizer on TBE CEE expert meeting 2020, has been a member of Pfizer Lyme Vaccine Licensure Advisory Board, received research support from the Slovenian Research Agency [grant number P3-0296], and is an unpaid member of the steering committee of the ESCMID Study Group on Lyme Borreliosis/ESGBOR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.