We describe two adolescents (13 and 16 years old) with severe tick-borne encephalitis (TBE) and vaccination breakthrough (VBT). Both suffer from severe persistent neurologic sequelae. Both patients had high TBE-IgG-titers after vaccination at the beginning of the infection and a low or missing TBE-IgM response (Type 2 vaccine failure). Neutralization tests show low titers against the respective infecting TBE virus strain and higher titers against the vaccine strain at the beginning of the infection implying an individual weak or impaired immune response to the respective virus as possible cause of TBE vaccine failure. We do not know of any similar observation or explanation for the phenomenon and at the moment can only speculate of a severe course correlated to highly mismatched IgG. This constellation of high TBE IgGs, the lack of immune response and a severe course strongly resembles the severe TBE courses that occurred in the past after TBE immunoglobulin administration. To our knowledge differentiation between structural and functional antibodies by neutralization tests with a) the affecting TBE virus strain and b) the vaccine virus strain in TBE vaccine failures has never been described before. We conclude (1) to consider a TBE virus infection also in vaccinated children presenting with meningoencephalitis, (2) to perform a broad immunological work-up in severe TBE especially after VBT, (3) to further study if high mismatch IgG's are a possible reason for vaccine failure.