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Background Japanese encephalitis (JE) virus (JEV) causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV), which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses. Methods We conducted a single arm, open label clinical trial (registration: clinicaltrials.gov NCT01656200) to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue. Results Ten out of 16 (62.5%) participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb) titre was 18.5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87%) participants made T cell interferon-gamma (IFNγ) responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses. Conclusions JEV SA14-14-2 was more immunogenic for T cell IFNγ than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases. Trial Registration clinicaltrials.gov (NCT01656200), Author Summary The Flavivirus genus member Japanese encephalitis (JE) virus (JEV), causes severe brain disease in tens of thousands of children across Asia every year. JE is vaccine preventable, and the immune response to JEV plays a major role in disease outcome. However, the response to JEV is hard to study as JE affects young children in rural areas. Related flaviviruses, such as dengue virus (which has no good vaccine), can influence the outcome of JE, probably due to cross-reactive immune responses. T cells (a subset of white blood cells) respond to virus infections, but we know little about the timing and nature of T cell responses to JEV after infection and whether T cells are protective against JEV. We used the live JE vaccine SA14-14-2 as a model to study the immune response to JEV. We found T cell responses frequently after JE vaccination. In this small group of volunteers, many of whom were exposed to dengue virus, most of the T cell responses tested cross-reacted between JEV and dengue virus. However, only about two thirds of people made antibody responses to the vaccine. Studying these responses could help design new vaccines for use against JE and dengue in Asia.