Development of Sanofi Pasteur tetravalent dengue vaccine.

The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of 4 recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the TV dengue vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFV 17D and does not infect mosquitoes by the oral route. In vitro and in vivo preclinical studies also showed that the TV dengue vaccine induced controlled stimulation in human dendritic cells and significant immune responses in monkeys. TV dengue vaccine reactogenicity, viraemia induction and antibody responses were investigated in three Phase I trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. Results showed that the majority of adverse events were mild to moderate and transient in nature. Viraemia was transient and low, and was not increased after initial dengue TV administration, even in the case of incomplete responses. ϕSeropositivity [≥10 in a PRNT 50 assay] was 100% for all four serotypes in flavivirus-naive adults injected with 3 doses of TV dengue vaccine in the USA. Similarly, seropositivity was 88-100% following three administrations in flavivirus-naive Mexican children aged 2-5 years. Furthermore, the proportion of seropositive subjects increased with each dengue TV injection in the Philippines where baseline flavivirus immunity was high. Responses were also monitored at the cellular level in humans, and their level and nature were in good agreement with the observed safety and the immunogenicity of the vaccine. Finally, the challenges inherent to the development of such TV dengue vaccines will also be discussed in the last part of this review. In conclusion, preclinical and clinical results support the favorable immunogenicity and short-term safety of the dengue TV vaccine. An extensive clinical development program for dengue TV is underway including completion of the enrollment of 4,000 4-11 years old children in an efficacy trial in Thailand, in an area of high dengue incidence. Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.