Characterization of humoral and cellular immune responses in cynomolgus macaques upon primary and subsequent heterologous infections with dengue viruses.

Since studying the pathogenesis of dengue virus associated disease in humans has several limitations, an appropriate animal model is needed. Therefore, we investigated kinetics of viremia as well as humoral and cellular immune responses, after primary, secondary and tertiary heterologous dengue virus infections in cynomolgus macaques: these parameters were largely similar to those observed in natural human infection upon primary infection. Both antibody and T-cell responses measured were largely cross-reactive. Upon secondary infection with a heterologous virus serotype, T-cell responses specific for the primary infecting serotype were more pronounced, especially when the immune system was primed with dengue 1 virus. Measurement of transcription levels of pro- and anti-inflammatory cytokines in white blood cells upon primary and secondary infection generally showed a balanced response. In addition, a region of the NS2A protein of dengue viruses was identified that induces T-cell responses in macaques.

Efficacy of a live attenuated tetravalent candidate dengue vaccine in naïve and previously infected cynomolgus macaques.

The development of a safe and effective vaccine against dengue is a public health priority. Attempts to evaluate candidate vaccine formulations in human volunteers were largely unsuccessful, at least in part due to too high reactogenicity of some of the candidate vaccines tested. We evaluated a live attenuated tetravalent dengue vaccine candidate in flavivirus naïve and dengue virus type 3 immune non-human primates. Immune responses were measured both at the humoral and the cellular level and the efficacy of this vaccine candidate was evaluated by challenging the vaccinated animals with dengue virus type 4. Humoral and cellular immune responses upon vaccination were similar to those described after natural infection in humans. All animals were protected from developing viremia upon challenge infection. In addition, primary dengue virus type 3 infection of macaques neither influenced the immune response upon vaccination, nor interfered with vaccine-induced protection from dengue virus type 4 challenge infection. The data suggest that the live attenuated tetravalent vaccine candidate used is promising and warrant further safety and efficacy testing in clinical trials.