Roßbacher et al.
Effect of previous heterologous flavivirus vaccinations on human antibody responses in tick-borne encephalitis and dengue virus infections
J Med Virol. 2023;95(11):e29245. doi: 10.1002/jmv.29245

Sequential exposure to distantly related flaviviruses can elicit anamnestic responses and boosting of cross-reactive antibodies of conserved elements within the glycoprotein E, e.g. the otherwise buried fusion loop (FL). FL antibodies have been described to be not or only weakly neutralizing.

A study has been carried out in individuals to investigate the effects and anamnestic responses on antibody formation in TBE and Dengue patients with and without a history of yellow fever and/or TBE vaccination. Among 41 TBE patients, 30 patients had no TBE or YF vaccination and 11 patients had a previous YF vaccination. Of 27 DEN patients, 5 had been infected by DEN virus serotype 1 and 22 by serotype 2, and all DEN patients had a flavivirus vaccination, either TBE, YF or both.

TBE virus infection in non-vaccinated patients induced only low levels of cross-reactive antibodies. In YF-prevaccinated patients, the induction of cross-reactive antibodies was higher. A pre-existing YF immunity in TBE patients resulted in significantly higher antibodies that are skewed towards cross-reactive epitopes. The pre-existing YF immunity did not affect the induction of neutralizing TBE antibodies. Cross-reactive antibodies are not involved in virus neutralization.

TBE- and/or YF –prevaccinated DEN patients had significantly higher levels of cross-reactive antibodies than YF-prevaccinated TBE patients. DEN virus infections with prior heterologous immunity might be prone to elicit cross-reactive antibodies, most likely to the FL region.

These results indicate differences in the structural properties of different flaviviruses which have an impact on the induction of cross-reactive antibodies and their functional activities in virus neutralization.

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