While in the vast majority of scenarios explored vaccination reduced the risk of unvaccinated individuals by 50–80% (due to indirect effects), direct effects of vaccination (i.e. reductions in the number of cases in vaccinated individuals as compared to unvaccinated PCI-32765 datasheet individuals) were smaller ( Fig. 4). Interestingly, in scenarios that included high heterogeneity in the transmission intensity and very low vaccine efficacy against DENV-2, direct effects of vaccination were negative. However, even under these scenarios, there was an absolute reduction in the cumulative incidence among vaccinated individuals, as compared to themselves had no vaccination

program been implemented (counterfactual effect). This reduction reflects the cumulative effects of both direct and indirect protection that vaccinees experience. We assessed the impact of vaccination on the yearly incidence of clinically apparent dengue, across all serotypes, for 50 years after vaccine introduction (Fig. 5). While significant decreases were observed in all scenarios (relative to the average incidence prior to vaccination), several short-term increases over pre-vaccine levels occur within thirty years of vaccine introduction. These increases result from the build up of susceptible individuals in certain

age groups and, as expected, are less B-Raf mutation frequent in scenarios with higher efficacy against DENV-2. Despite these periodic increases, the expected cumulative incidence of clinically apparent dengue was significantly lower than the cumulative Oxygenase incidence without vaccine for the great majority of scenarios explored (Fig. 5, right panel). We also explored the impact of vaccination on the mean-age of clinical cases (Fig. 6). While vaccination with high efficacy across all serotypes led to an increase in the mean age of cases, in certain instances of low vaccine efficacy against DENV-2 we observed decreases

in the mean-age. The largest decreases were observed in scenarios that included heterogeneity in transmission intensity (Fig. 6B), and result mostly from breakthrough infections by DENV-2 in vaccinated children. Sudden increases in the mean-age of cases were also observed at varying times after vaccine introduction and result from susceptibility accumulating in certain age-classes. The impact of any particular vaccine formulation depends on at least four separate effects: (1) direct protection of vaccinees against infection and/or disease, (2) indirect protection of all members of vaccinated communities, (3) an impact on serotype distribution, and (4) the immunopathogenic effects of partial vaccine-induced immunity. Our results from a four-serotype, age-specific compartmental dengue transmission model suggest that partially effective vaccines can have a significant positive impact, on average, in reducing dengue transmission and disease.