Tick borne encephalitis (TBE) virus is a major human pathogenic flavivirus and closely related to yellow fever (YF), dengue, Japanese encephalitis (JE) and West Nile (WN) viruses. Antibodies induced by infection or vaccination protecting from disease mainly target the major viral envelope protein E. It tightly covers the virion surface in a herringbone like arrangement and contains three structural domains: DI, DII and DIII.
In this study, we dissected the antibody response to different structural parts of the virus surface in 43 TBE patients and 38 vaccinees, the functional properties of these antibody subsets as well as individual specific differences thereof. We produced recombinant TBE virus antigens representing isolated domains of E or combinations thereof, as well as the smaller surface protein prM (found in immature virions) and protein E of the related WN virus to detect antibodies cross reactive with both viruses. Using these tools, we established new in vitro assays to study the fine specificities of antibody responses. Analyses of sera with the different antigens showed a high degree of individual variation concerning the magnitude of the response, but also the relative proportions of different antibody subsets. Quantification of these portions and their contribution to virus neutralization was achieved by depletion of specific antibody subsets with our antigens from serum pools as well as individual sera. In both groups, the neutralizing determinants were confined to epitopes in the dimeric E protein but the involvement of more complex quaternary epitopes present at the virion surface only cannot be totally excluded. The response is dominated by antibodies to DII and/or its junction to DI, whereas DIII - immunodominant in mice - appears to be immunologically silent in humans.
In post infection sera, but not post vaccination sera, 25% of the virion response was directed to prM,without contributing to neutralization.
Antibodies cross reactive with WN virus E were found to be present to a low extent mainly in post vaccination sera and to target DII.
The results of our study provide new insights into the fine specificity and functional properties of antibodies elicited in the course of TBE virus infection and vaccination. Despite high individual variations, the main neutralizing determinants appear to be similar when the virus is encountered by the immune system either as replicating agent or in an inactivated form adsorbed to aluminum hydroxide. These findings can help to improve structure based strategies for the development of new vaccines also to other human pathogenic flaviviruses.