Historical discourse on the development of the live attenuated tetravalent dengue vaccine candidate TV003/TV005

Abstract

Dengue is the most important arboviral disease world-wide with an estimated 400 million annual infections. Dengvaxia™ is a live attenuated tetravalent vaccine recently licensed for dengue seropositive individuals aged 9-45 years. There is great need for a dengue vaccine that could be given to dengue-naïve individuals and very young children. To that end, the U.S. NIH developed a live attenuated tetravalent dengue vaccine using an iterative approach evaluating the safety, infectivity, and immunogenicity of different candidates. This approach identified poor candidates who were then discarded from further evaluation. Each of the components of the tetravalent vaccine formulation is able to replicate to very low titer, inducing a homotypic immune response to each. The immune response elicited by the tetravalent vaccine is balanced, without immunodominance of one component. The vaccine was licensed by several manufacturers for development, including the Instituto Butantan which initiated a Phase 3 efficacy trial.

Figure 1:

The neutralizing antibody titers induced by TV003 in CIR287 as measured in Vero cells (Blue) and Vero cells expressing CD32a (Vero-CD32a, Red). Neutralizing antibody titers were measured at study days 0, 28, 56, 90 post-vaccination and challenge. The study day 180 titer is the day of challenge. Seroconversion was defined as 1:10 post-vaccination or ≥ 4-fold rise in titer post-challenge. All subjects were flavivirus-naïve prior to challenge (PRNT₅₀ < 5).