Abstract

Dengue virus (DENV) infects an estimated 390 million people each year, and of the 96 million individuals who develop an acute systemic illness, approximately 500,000 experience potentially life-threatening complications, including hemorrhage and shock. The four genetic DENV types have long been thought to exist as four serotypes, and the antigenic differences between the serotypes are believed to have a key role in clinical severity, epidemic magnitude, viral evolution, and the design of effective vaccines. However, investigations that rely on the classification of DENV as serotypes do not fully explain clinical and epidemiological phenomena. Despite this, antigenic properties are still thought to play a critical role in the biology of DENV infections. One hypothesis is that antigenic differences are critical, but that categorization by serotype is too coarse a measure. For example, differences in epidemic magnitude might reflect antigenic differences between the particular infecting viruses that populations experience during sequential epidemics, but not the serotype of those viruses. Antigenic variation within and among the DENV types may explain why previously successful lineages of a given DENV type become extinct and are replaced, why genetically similar viruses can cause both severe and mild epidemics, and why a vaccine could protect against one DENV type in one country but not protect against that type in another. We have used antigenic cartography to test the antigenic relationships among panels of diverse DENV isolates to revisit the notion that DENV exists as discrete serotypes. Our antigenic analyses using one-month, five-month, and published data from non-human primate and human antisera show that while DENV isolates are usually located closer to other viruses of the same type, some viruses, both modern and historical, have greater antigenic resemblance to viruses of a different type than to some viruses of the same type. This finding is a shift in our understanding of the antigenic properties of DENV .