A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins.

Guntur Fibriansah,James E Crowe,Aravinda M De Silva,Ruklanthi De Alwis,Scott A Smith,Petra Kukkaro,Shee-Mei Lok,Joanne L Tan,Ramesh S Jadi,Victor A Kostyuchenko,Thiam-Seng Ng

doi:10.1038/ncomms7341

Abstract

Dengue virus (DENV) infects ~400 million people annually. There is no licensed vaccine or therapeutic drug. Only a small fraction of the total DENV-specific antibodies in a naturally occurring dengue infection consists of highly neutralizing antibodies. Here we show that the DENV-specific human monoclonal antibody 5J7 is exceptionally potent, neutralizing 50% of virus at nanogram-range antibody concentration. The 9 Å resolution cryo-electron microscopy structure of the Fab 5J7–DENV complex shows that a single Fab molecule binds across three envelope proteins and engages three functionally important domains, each from a different envelope protein. These domains are critical for receptor binding and fusion to the endosomal membrane. The ability to bind to multiple domains allows the antibody to fully coat the virus surface with only 60 copies of Fab, that is, half the amount compared with other potent antibodies. Our study reveals a highly efficient and unusual mechanism of molecular recognition by an antibody.

Highlights

Dengue virus (DENV) infects B400 million people annually
To provide further support to the type 3-specific binding pattern and the potency of human MAbs (HMAbs) 5J7, we repeated the binding assays here with intact particles or recombinant E proteins, and the neutralization assays as an independent laboratory
Comparison of the DENV3 amino acid sequence (Fig. 3a) and surface electrostatic potential (Fig. 4) of the regions corresponding to the epitope with the other serotypes showed that some residues on DENV1, 2 and 4 have opposite charges

Summary

Introduction

Dengue virus (DENV) infects B400 million people annually. There is no licensed vaccine or therapeutic drug. In a secondary infection by a different DENV serotype, the formation of non-neutralizing complex of DENV with cross-reactive antibodies from the previous infection may enhance viral infection through a mechanism known as antibody-dependent enhancement[8]. This may lead to an increased risk of developing the severe dengue haemorrhagic fever. This suggests that a safe and effective vaccine would have to include only neutralizing epitopes from all four DENV serotypes. Neutralizing antibodies principally target the E protein[18]

Methods

Results

Conclusion