ONLINE COVER Long Distance Relationships. The cover image shows an Aedes aegypti mosquito, the vector for the four serotypes of dengue virus (DENV). Secondary infections with DENV can cause severe disease, which is thought to be a result of sub-neutralizing antibodies that actually enhance infection. Prior studies have demonstrated that the order of infections with the four DENV serotypes influences disease risk, but this work has generally considered each of the serotypes as a single entity. To look more closely at how within- and between-serotype antigenic variability influences disease risk, Wang et al. evaluated 21 years of DENV surveillance data, coupling information on viral antigenic variation with patient outcomes. The authors found that severe disease risk was maximized when the first and second infecting viruses had an intermediate antigenic distance. These data suggest that monitoring DENV antigenic variation could be used to predict when severe disease might arise in a population.