Carl Britto, Christina Dold, Arturo Reyes-Sandoval, Christine S. Rollier

The emergence of the Zika virus (ZIKV) in Latin America in 2015-2016 led to an expeditious search for vaccine candidates, with a DNA-based candidate having progressed to Phase II. However, several features of ZIKV infection and epidemiology are not understood, which may be key to maximizing efficacy and ensuring safety of ZIKV vaccines. Areas covered: Conceivable problems related to vaccine development and policy include: (1) paucity of diagnostics to satisfactorily discriminate between past ZIKV and dengue virus (DENV) exposure; (2) insufficient knowledge of the mechanisms of ZIKV neurovirulence, amongst other unknowns in the biology of this infection, is particularly relevant from a vaccine safety perspective; and (3) the potential for disease enhancement, as observed with DENV infection and vaccine. Expert opinion: Vaccine candidates that entered phase I/II trials have demonstrated protection in naïve animal models, while ZIKV epidemics occurred in populations that had encountered DENV before. The resulting cross-reactive antibodies pose problems for reliable serologic diagnostic assays, and for the potential of disease enhancement. The alleged neurological complications also warrant further exploration in order to reassure regulators of the safety profile of these vaccines in target populations. These research aspects should be an integral part of the efforts to develop a vaccine.