Adaptive Immunity to Dengue Virus: Slippery Slope or Solid Ground for Rational Vaccine Design?

The four serotypes of dengue virus are the most widespread causes of arboviral disease, currently placing half of the human population at risk of infection. Pre-existing immunity to one dengue virus serotype can predispose to severe disease following secondary infection with a different serotype. The phenomenon of immune enhancement has complicated vaccine development and likely explains the poor long-term safety profile of a recently licenced dengue vaccine. Therefore, alternative vaccine strategies should be considered. This review summarises studies dissecting the adaptive immune responses to dengue virus infection and (experimental) vaccination. In particular, we discuss the roles of (i) neutralising antibodies, (ii) antibodies to non-structural protein 1, and (iii) T cells in protection and pathogenesis. We also address how these findings could translate into next-generation vaccine approaches that mitigate the risk of enhanced dengue disease. Finally, we argue that the development of a safe and efficacious dengue vaccine is an attainable goal.