To gain a deeper understanding of the early DENV-specific immune response in humans, the four serotypes of DENV were sequentially screened with a non-immunized human Fab phage display library. Broadly cross-reactive prM-specific antibodies dominated the screen and the Fab with highest affinity, D29 Fab-IgG, was converted into full-length human IgG1 format for thorough characterization. This antibody (D29 Fab-IgG) was found to have high affinity for a conformational epitope on prM and, like other prM antibodies [11, 12] , was capable of restoring the infectivity of virtually non-infectious immature DENV (imDENV) in FccR-bearing K562 cells. The antibody also cross-reacted with E protein -fine mapping and site-directed mutagenesis studies localized the epitope to the DI/ DII junction of E, which would be inaccessible in a native virus particle. This suggests the possibility that immunization strategies employing E protein alone or subunits of E proteins may not be able to completely avoid generation of anti-prM antibodies that enhance DENV infection.