The Potent and Broadly Neutralizing Human Dengue Virus-Specific Monoclonal Antibody 1C19 Reveals a Unique Cross-Reactive Epitope on the bc Loop of Domain II of the Envelope Protein

Abstract

Following natural dengue virus (DENV) infection, humans produce some antibodies that recognize only the serotype of infection (type specific) and others that cross-react with all four serotypes (cross-reactive). Recent studies with human antibodies indicate that type-specific antibodies at high concentrations are often strongly neutralizing in vitro and protective in animal models. In general, cross-reactive antibodies are poorly neutralizing and can enhance the ability of DENV to infect Fc receptor-bearing cells under some conditions. Type-specific antibodies at low concentrations also may enhance infection. There is an urgent need to determine whether there are conserved antigenic sites that can be recognized by cross-reactive potently neutralizing antibodies. Here, we describe the isolation of a large panel of naturally occurring human monoclonal antibodies (MAbs) directed to the DENV domain II fusion loop (FL) envelope protein region from subjects following vaccination or natural infection. Most of the FL-specific antibodies exhibited a conventional phenotype, characterized by low-potency neutralizing function and antibody-dependent enhancing activity. One clone, however, recognized the bc loop of domain II adjacent to the FL and exhibited a unique phenotype of ultrahigh potency, neutralizing all four serotypes better than any other previously described MAb recognizing this region. This antibody not only neutralized DENV effectively but also competed for binding against the more prevalent poor-quality antibodies whose binding was focused on the FL. The 1C19 human antibody could be a promising component of a preventative or therapeutic intervention. Furthermore, the unique epitope revealed by 1C19 suggests a focus for rational vaccine design based on novel immunogens presenting cross-reactive neutralizing determinants.

Inhibition of dengue virus replication by diisopropyl chrysin-7-yl phosphate

“…Several neutralizing antibodies have been characterized and showed potent neutralizing activity against DENV Fibriansah et al, 2015;Rouvinski et al, 2015;Smith et al, 2013). DENV subunit vaccines are being developed, too (Coller et al, 2011).…”

Deconstructing the Antiviral Neutralizing-Antibody Response: Implications for Vaccine Development and Immunity

“…Considerable insight into how antibodies protect against viral infection, via direct neutralization of infection or antibody effector function, has come from studies of MAbs (60,137,160,167,170,171,177,207,221,222). However, how antibodies function in concert as part of a polyclonal response is not well understood, nor is the breadth of the functionally significant components.…”

Dengue Virus prM-Specific Human Monoclonal Antibodies with Virus Replication-Enhancing Properties Recognize a Single Immunodominant Antigenic Site

“…In other words, the binding of any one antibody in the panel blocked the binding of any other. As a control reagent we used the human MAb 3D18 that recognizes the DENV E protein fusion loop (28) when determining whether any of the MAbs in the panel could bind exclusively to the portion of the E protein around the fusion loop, which is in the area underlying prM in immature particles (28). For several of the MAbs in the panel, we generated Fab fragments to determine whether competition for binding could be reduced or eliminated if the steric footprint was smaller.…”