Development of a dengue vaccine in humans: So near, yet so far

Due to a combination of favourable factors promoting the population growth and geographical spread of the Aedes mosquito vector of dengue, the incidence of this rapidly emerging tropical infectious disease has increased over 30-fold in less than half a century. Today, there are around 100 million reported clinical cases each year. Co-circulation of multiple serotypes of the dengue virus causes a variety of manifestations ranging from mild symptoms, via debilitating morbidity, to a severe form that, although relatively rare, has a high mortality rate. As current dengue control programs are severely strained, an efficacious vaccine to prevent infection is an urgent global public health priority. However, production of a dengue vaccine is compromised by an incomplete understanding of compounding factors including the existence of five now known serotypes, duration of protection provided by vaccination, dosing regimen and period, cost of production, and determination of the immune status of vaccine recipients. All these issues need to be considered in successful vaccine design. Encouragingly, prior success with immunization strategies against the closely related viruses Japanese encephalitis and yellow fever provides a precedent to deliver a safe, effective and affordable dengue vaccine. At least seven candidates are presently in clinical trials. These preparations are based on: DNA; protein subunit; purified inactivated virus; classic live attenuated virus; live attenuated heterologous virus chimera; live attenuated homologous dengue chimera; live attenuated deletion mutation. Of these, CYD-TDV, the three-dose live recombinant tetravalent chimeric vaccine based on a backbone of the yellow fever 17D vaccine strain, has advanced furthest and it is hoped to soon be granted a commercial license.