Dengue disease severity in humans is augmented by waning Japanese encephalitis virus immunity

Owing to increased global movement, vector-spread permissive climate change, and increased vaccination coverage against certain flaviviruses, the likelihood of being exposed to multiple flaviviruses in a lifetime has increased. Although many Asian countries have routine vaccination campaigns against Japanese encephalitis virus (JEV), the effect of JEV immunity on dengue disease severity is largely unknown. Here, we aimed to understand the effect of preexisting immunity against JEV on subsequent dengue disease outcomes in a prospective human cohort in Nepal, which has a high prevalence of JEV immunity and rapidly rising dengue virus (DENV) infections. A cohort consisting of 546 participants was studied over three dengue seasons and 5 years. Chymase, a serum biomarker of severe dengue across multiple patient cohorts, was assessed alongside clinical outcomes to determine whether there were associations between JEV immunity and dengue severity. We observed that midrange neutralizing antibody titers, approximately a 1:160 serum dilution capable of inhibiting JEV, were associated with heightened biomarkers of dengue disease severity and warning signs of severe disease in this cohort of patients who were mostly experiencing primary dengue infections. These results suggest that waning immunity to JEV could enhance the severity of dengue disease. This highlights the potential of maintaining strong immunity to JEV through vaccine boosters, not only to maintain protection against JEV in endemic regions but also to limit the potential of antibody-mediated enhancement of dengue disease.