Several arthropod-borne flaviviruses cause severe human disease and have a global impact on public health. They are transmitted to humans by mosquitoes or ticks and include yellow fever (YF), dengue, West Nile, Japanese encephalitis, Zika and tick-borne encephalitis (TBE) viruses. Their potential of sudden emergence in previously unaffected geographical regions is exemplified by the introduction of West Nile virus into North America in 1999 and the recent Zika virus outbreak in South and Central America, starting in 2015. There are no specific antiviral drugs for the treatment of diseases caused by flaviviruses, but some very effective vaccines were developed for the prophylaxis of flavivirus infections. The attenuated live yellow fever vaccine has played a pioneering role in the history of vaccination and is one of the most successful vaccines ever produced. There is also a highly protective vaccine against tick-borne encephalitis virus, consisting of inactivated purified virus. Both vaccines are used not only in endemic regions (YF vaccine in parts of South America and Africa, and TBE vaccine in countries of Europe, Central and Eastern Asia) but also in travelers visiting regions that carry a risk of infection. 

All flaviviruses are antigenically related, and flavivirus infection and/or vaccination not only induces type-specific antibodies (which neutralize the virus and cause long-lived protection) but also antibodies that cross-react with other flaviviruses and are usually non-protective. In cases of sequential infections or vaccinations against different flaviviruses, this antigenic relatedness can cause phenomena of immunological memory that modulate the secondary immune responses in individuals with pre-existing flavivirus immunity. In our work at the Center for Virology, Medical University of Vienna, we investigated the effect of previous YF vaccination on the antibody response to TBE vaccination. Two major differences were observed between flavivirus-naïve and YF pre-immune individuals. First, TBE vaccination in YF pre-immunes caused a strong boost of YF-reactive antibodies, which, however did not result in an increase of YF neutralization. We showed that these antibodies were broadly flavivirus cross-reactive and specific for a conserved sequence in the viral envelope protein. Secondly, and most importantly, the neutralizing and protective antibody response to TBE virus was significantly impaired in the cohort with pre-existing YF immunity compared to the control group. This result suggested that the strong memory response to cross-reactive epitopes present both in YF and TBE viruses occurred at the expense of the formation of new antibody specificities capable of neutralizing TBE virus, a phenomenon designated as original antigenic sin.

Our work highlights the relevance of potentially negative effects of immunological memory in sequential flavivirus vaccinations. These are especially relevant in the context of recommendations for time schedules of booster vaccinations, which may require specific adjustments depending on the status of pre-existing flavivirus immunity. Future studies will be required to assess the generality of the effects observed in our study with other combinations of flavivirus vaccines and/or infections.