Pre-existing yellow fever immunity impairs and modulates the antibody response to tick-borne encephalitis vaccination.

Flaviviruses have an increasing global impact as arthropod-transmitted human pathogens, exemplified by Zika, dengue, yellow fever (YF), West Nile, Japanese encephalitis, and tick-borne encephalitis (TBE) viruses. Since all flaviviruses are antigenically related, they are prone to phenomena of immunological memory (‘original antigenic sin’), which can modulate immune responses in the course of sequential infections and/or vaccinations. In our study, we analyzed the influence of pre-existing YF vaccine-derived immunity on the antibody response to TBE vaccination. By comparing samples from YF pre-vaccinated and flavivirus–naive individuals, we show that YF immunity not only caused a significant impairment of the neutralizing antibody response to TBE vaccination but also a reduction of the specific TBE virus neutralizing activities (NT/ELISA-titer ratios). Our results point to a possible negative effect of pre-existing cross-reactive immunity on the outcome of flavivirus vaccination that may also pertain to other combinations of sequential flavivirus infections and/or vaccinations. Flaviviruses, such as Yellow Fever (YF) virus and Tick-borne encephalitis (TBE) virus, share a certain level of antigenic relatedness, meaning that pre-existing immunity to one flavivirus species can impact the antibody response to a second — a phenomenon known as ‘original antigenic sin’. A team led by Franz X. Heinz at the Medical University of Vienna investigate the impact of pre-vaccination with the YF vaccine (a minimum of one year earlier) on subsequent vaccination against TBE. Overall, YF pre-immunity significantly reduced generation of TBE neutralizing antibodies compared to flavivirus-naive individuals, but there was a striking level of inter-individual variation. Although even the YF-vaccinated individuals produced sufficient TBE neutralizing titers to be considered potentially protective, these findings suggest that the influence of ‘original antigenic sin’ might need to be taken into account for flavivirus vaccination protocols.