TBE vaccine and post TBE disease Abs drive antibody dependent enhancement of Zika infection

Tick-borne encephalitis (TBE) virus belongs to the Flaviviruses, such as Zika, Dengue, Yellow fever viruses (YFV), etc. Antibody dependent enhancement (ADE) was first described between Dengue 1textendash4 viruses. Recently the ADE phenomenon was extended to include additional Flaviviruses that are phylogenetically close to Dengue: Zika and YFV. All arthropod borne Flaviviruses are antigenically related, however, the existence and extent of ADE between mosquito-borne and tick-borne Flaviviruses were never addressed. In order to explore ADE associated pathogenesis of sera cross-reactivity, we studied human sera from patients with acute TBE (n=30), vaccinated against TBE (n=76) and a control group without antibodies (Abs) to Flaviviruses (n=30). ELISA assays were used to profile the IgG and IgM serological repertoires to TBE and cross-reactivity to Zika antigen (Ag). Viral plaque assays (VPA) were used to test if TBE Abs cause ADE during infection with Zika virus. Flow cytometry (FACS) was used to measure ADE of Zika infection in U937 cells in the presence of the sera with TBE Abs. We found that 257reactive Abs to Zika Ag in ELISA. Furthermore, serum from 37/40 (92 TBE positive subjects caused ADE in the VPA assay and 58/60 (96 caused ADE using the FACS assay. The magnitude of Zika ADE correlated with the titer of TBE Abs. Thereby we demonstrate, that previous vaccination or infection with TBE significantly increases the risk of ADE upon a secondary infection with Zika virus. These results highlight that presence of cross-reactive Abs induced by previous exposure even to a very distantly related Flaviviruses by vaccination or infection dictates the risk of ADE upon secondary infection.