Arthropod-borne flaviviruses include a number of medically relevant human pathogens such as the mosquito-borne
dengue (DEN), Zika, and
yellow fever (YF) viruses as well as tick-borne encephalitis virus (TBEV). All flaviviruses are antigenically related and anamnestic responses due to prior immunity can modulate antibody specificities in subsequent
infections or vaccinations. In our study, we analyzed the induction of broadly flavivirus cross-reactive
antibodies in
tick-borne encephalitis (TBE) and DEN patients without or with prior flavivirus exposure through TBE and/or YF vaccination, and determined the contribution of these
antibodies to TBE and dengue virus (DENV) neutralization. In addition, we investigated the formation of cross-reactive
antibodies in TBE-vaccination breakthroughs (VBTs). A TBEV
infection without prior YF or TBE vaccination induced predominantly type-specific
antibodies. In contrast, high levels of broadly cross-reactive
antibodies were found in samples from TBE patients prevaccinated against YF as well as in DEN patients prevaccinated against TBE and/or YF. While these cross-reactive
antibodies did not neutralize TBEV, they were effective in neutralizing DENV. This discrepancy points to structural differences between the two viruses and indicates that broadly cross-reactive
epitopes are less accessible in TBEV than in DENV. In TBE VBT
infections, type-specific
antibodies dominated the antibody response, thus revealing no difference from that of unvaccinated TBE patients. Our results emphasize significant differences in the structural properties of different flaviviruses that have an impact on the induction of broadly cross-reactive
antibodies and their functional activities in virus neutralization.