Despite the availability of tick-borne encephalitis virus (TBEV) vaccines, the number of TBE cases continues to rise, necessitating further research into the immune response to TBEV infection to enable the development of therapeutics. Our research addresses a critical knowledge gap concerning the nature of polyclonal human responses to TBEV infection, and how these compare to the effects of neutralizing monoclonal antibodies (mabs). Currently, we do not know whether the neutralizing mechanisms of antibodies in the polyclonal repertoire are the same as those of mabs that have been characterized to date. A new aspect of our studies will be an electron microscopy-based polyclonal epitope mapping-approach to analyze polyclonal responses against TBEV, followed by in detail characterization of selected mabs. In addition, we will carry out asymmetric and sub-particle reconstructions to determine the structures of virus-antibody complexes. Combining structural biology with immunological and biochemical assays will provide new insights into antibody-mediated TBEV neutralization.