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The tetravalent dengue vaccine CYD-TDV (Dengvaxia) is the first licensed vaccine against dengue, but recent findings indicate an elevated risk of severe disease among vaccinees without prior dengue virus (DENV) exposure. The World Health Organization currently recommends CYD-TDV only for individuals with serological confirmation of past DENV exposure. Our objective was to evaluate the potential health impact and cost-effectiveness of vaccination following serological screening. To do so, we used an agent-based model to simulate DENV transmission with and without vaccination over a 10-year timeframe. Across a range of values for the proportion of vaccinees with prior DENV exposure, we projected the proportion of symptomatic and hospitalized cases averted as a function of the sensitivity and specificity of serological screening. Scenarios about the cost-effectiveness of screening and vaccination were chosen to be representative of Brazil and the Philippines. We found that public health impact depended primarily on sensitivity in high-transmission settings and on specificity in low-transmission settings. Cost-effectiveness could be achievable from the perspective of a public payer provided that sensitivity and the value of a disability-adjusted life-year were both high, but only in high-transmission settings. Requirements for reducing relative risk and achieving cost-effectiveness from an individual perspective were more restricted, due to the fact that those who test negative pay for screening but receive no benefit. Our results predict that cost-effectiveness could be achieved only in high-transmission areas of dengue-endemic countries with a relatively high per capita GDP, such as Panamá (13,680 USD), Brazil (8,649 USD), México (8,201 USD), or Thailand (5,807 USD). In conclusion, vaccination with CYD-TDV following serological screening could have a positive impact in some high-transmission settings, provided that screening is highly specific (to minimize individual harm), at least moderately sensitive (to maximize population benefit), and sufficiently inexpensive (depending on the setting)., Author summary Among several viral diseases transmitted by Aedes aegypti mosquitoes, dengue imposes the greatest and most persistent burden on global health. Efforts to curb its spread would benefit greatly from the availability of an effective vaccine. Currently, the only licensed dengue vaccine, known as CYD-TDV or by the brand name Dengvaxia, is only recommended for use in people who are known to have been exposed to dengue virus in the past. Because symptoms of dengue can range from severe to mild to imperceptible, using clinical history alone to assess whether a person was previously exposed is unreliable. Instead, serological assays, which measure a person’s immune response to dengue virus, are necessary to confirm whether a person was previously exposed. Because serological assays can be subject to substantial error, we used a simulation model to assess how impactful CYD-TDV vaccination would be under different scenarios about the accuracy of a serological assay and the intensity of transmission in a given area. We found that the health impact and cost-effectiveness of CYD-TDV vaccination depended on the accuracy of the serological assay, its cost, and the setting in which it is deployed.