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The tick-borne encephalitis complex contains a number of flaviviruses that share close genetic homology, and are responsible for significant human morbidity and mortality with widespread geographical range. Although many members of this complex have been recognised for decades, licenced human vaccines with broad availability are only available for tick-borne encephalitis virus. While tick-borne encephalitis virus vaccines have been demonstrated to induce significant protective immunity, as determined by virus-neutralisation titres, vaccine breakthrough (clinical infection following complete vaccination), has been described. The aim of this study was to confirm the cross-neutralisation of tick-borne flaviviruses using mouse immune ascitic fluids, and to determine the magnitude of cross-neutralising antibody titres in sera from donors following tick-borne encephalitis vaccination, infection, and vaccine breakthrough. The results demonstrate that there is significant cross-neutralisation of representative members of the tick-borne encephalitis complex following vaccination and/or infection, and that the magnitude of immune responses varies based upon the exposure type. Donor sera successfully neutralised most of the viruses tested, with 85% of vaccinees neutralising Kyasanur forest disease virus and 73% of vaccinees neutralising Alkhumra virus. By contrast, only 63% of vaccinees neutralised Powassan virus, with none of these neutralisation titres exceeding 1:60. Taken together, the data suggest that tick-borne encephalitis virus vaccination may protect against most of the members of the tick-borne encephalitis complex including Kyasanur forest disease virus and Alkhumra virus, but that the neutralisation of Powassan virus following tick-borne encephalitis vaccination is minimal., Tick-borne encephalitis: One vaccine protects against multiple flaviviruses Prior exposure to tick-borne encephalitis virus confers immunity to distinct, but genetically related, significant human pathogens. The tick-borne encephalitis complex comprises multiple ‘flaviviruses’; however, a licensed vaccine only exists for one: tick-borne encephalitis virus (TBEV). Alexander McAuley, of the University of Texas Medical Branch, USA, and collaborators tested human serum samples from donors who had either received the TBEV vaccine, been infected with the virus naturally, or had contracted the virus despite prior vaccination. The team tested the sera against six genetically related flaviviruses, looking for antibodies that indicate viral immunity. The results showed that TBEV exposure induce production of antibodies that inhibit other flaviviruses, the efficacy of which decreases as the genetic variation from TBEV increases. Additionally, sera from infected individuals generated more antibodies than sera from vaccinated donors. This study provides an insight into the relationship between genetic similarity and vaccine cross-protection.