Dengue virus (DENV) is a mosquito-borne flavivirus that infects up to 400 million people each year, leading to 100 million cases of dengue fever and 21,000 deaths (1). Thus far, there are no approved therapeutics or vaccine available. Current treatment of the disease is mainly supportive, e.g., bed rest and electrolyte replacement for relief of symptoms. DENV consists of four serotypes; DENV1 to DENV4. Infection with one serotype confers lifelong protection against the homologous serotype. However, the antibodies generated against this virus serotype may cause the development of a more severe disease, dengue hemorrhagic fever, if the host is infected with another serotype (2). This, in part, is due to the binding of weakly neutralizing serotype cross-reactive antibodies to the new DENV serotype. The antibody is unable to neutralize the virus; instead, it helps to concentrate the virus on the host macrophage cell surface by the binding of antibody to the macrophage Fc receptors, thereby causing enhanced infection. This complicates the development of a vaccine as it would need to stimulate strong neutralizing antibody response against all serotypes. Therefore, for the last few decades, there is a quest in identifying neutralizing epitopes for all serotypes. With the recent availability of technologies to generate dengue virus infectious clones and human monoclonal antibodies (HMAb), the identification of immuno-dominant neutralizing epitopes recognized by humans is made possible. In PNAS, Messer et al. (3) identify a major epitope commonly recognized by most neutralizing human antibodies.The mature DENV particle consists of multiple copies of three proteins: the envelope (E), the membrane (M), and the capsid proteins (4). The positive sense genomic RNA complexed with capsid proteins forms the inside of the virus particle. It is surrounded by a bilayer lipid membrane. Anchored on the outside of the membrane are the M and E proteins. The M protein is a small protein that is hidden under the E protein. The major protein that stimulates antibody response is the E protein (Fig. 1A). Each E protein monomer has three domains: DI, DII, and DIII (5, 6). DIII is thought to be involved in receptor binding. DII contains the fusion loop, which interacts with the endosomal membrane to facilitate fusion of the virus with the endosomal membrane during virus entry into the cell (7). The hinge that connects DI to DII is very flexible and is used to flex DII in the low pH environment of the endosome, leading to the exposure of its fusion loop (5). Cryo-electron microscopy (cryoEM) reconstruction of the DENV particle showed that there are 180 copies of E proteins on the surface of the virion (Fig. 1A) forming an icosahedral symmetry shell (4,8). The E proteins exist as dimers; three of these dimers lie parallel to each other forming a raft. There are 30 rafts on the surface of the virus, and they are arranged in a herringbone pattern.In the past, only mouse monoclonal antibodies were available; therefore, epitope mapping work was don...