An analysis performed by scientists studying the world's first marketed dengue virus vaccine (Dengvaxia) has identified the need for a better understanding of how it should be deployed on a global scale, perhaps in conjunction with a diagnostic tool to identify individuals most at risk of negative effects. The results, which delineate vaccine use scenarios that would maximize benefit as well as those that could create greater risk, will provide policymakers in dengue-affected countries with critical insights as they evaluate which populations should receive this vaccine. Dengvaxia's path to approval was two decades in the making, primarily because of the complex interactions between the four dengue serotypes and the immune system, which can lead to a more severe form of the disease for individuals who had a prior infection with one serotype, followed by subsequent infection with another. Phase III clinical trials of the vaccine administered to children in South East Asia and Latin America revealed mixed efficacy - results that pose challenges for those considering how best to use the vaccine on a global scale. In an effort to help policymakers evaluate the vaccine in a real-world setting, Neil Ferguson et al. applied mathematical modeling to assess the impact of its use in different dengue backgrounds. Results corroborated existing clinical study data to date - confirming that the vaccination either boosted host immunity in individuals who had been previously exposed to dengue (seropositive), or enhanced the risk of illness upon infection in those who were naïve to specific virus serotypes (seronegative). Seropositive recipients gained a substantial benefit from the immunization and were 90% less likely to be hospitalized after contracting dengue, compared to seronegative recipients, the researchers found. As a solution to help inform vaccination recommendations, they propose screening potential vaccine recipients with serological testing - an approach previously used to immunize pregnant women against rubella and hepatitis B. According to the authors, this strategy could result in up to 30% fewer incidences of hospital visits. The researchers emphasize that although characterizing real-world differences in exposure is challenging, this should be a key priority for developing future candidate dengue vaccines.