Neutralization of antibody-enhanced dengue infection by VIS513, a pan serotype reactive monoclonal antibody targeting domain III of the dengue E protein

PLoS Negl Trop Dis. 2018 Feb 9;12(2):e0006209. doi: 10.1371/journal.pntd.0006209. eCollection 2018 Feb.

Abstract

Dengue virus (DENV) infection imposes enormous health and economic burden worldwide with no approved treatment. Several small molecules, including lovastatin, celgosivir, balapiravir and chloroquine have been tested for potential anti-dengue activity in clinical trials; none of these have demonstrated a protective effect. Recently, based on identification and characterization of cross-serotype neutralizing antibodies, there is increasing attention on the potential for dengue immunotherapy. Here, we tested the ability of VIS513, an engineered cross-neutralizing humanized antibody targeting the DENV E protein domain III, to overcome antibody-enhanced infection and high but brief viremia, which are commonly encountered in dengue patients, in various in vitro and in vivo models. We observed that VIS513 efficiently neutralizes DENV at clinically relevant viral loads or in the presence of enhancing levels of DENV immune sera. Single therapeutic administration of VIS513 in mouse models of primary infection or lethal secondary antibody-enhanced infection, reduces DENV titers and protects from lethal infection. Finally, VIS513 administration does not readily lead to resistance, either in cell culture systems or in animal models of dengue infection. The findings suggest that rapid viral reduction during acute DENV infection with a monoclonal antibody is feasible.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Neutralizing / blood
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / administration & dosage
  • Antibodies, Viral / blood
  • Antibodies, Viral / genetics
  • Antibodies, Viral / immunology*
  • Antigens, Viral / chemistry
  • Antigens, Viral / genetics
  • Cell Line
  • Chlorocebus aethiops
  • Cross Reactions / immunology
  • Dengue / immunology*
  • Dengue Virus / genetics
  • Dengue Virus / immunology*
  • Dengue Virus / pathogenicity
  • Disease Models, Animal
  • Epitopes
  • Female
  • Humans
  • Immune Sera
  • Immunotherapy
  • In Vitro Techniques
  • Mice
  • Models, Structural
  • Mutation
  • Neutralization Tests
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Serogroup
  • THP-1 Cells
  • Vero Cells
  • Viral Envelope Proteins / chemistry
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / immunology*
  • Viral Plaque Assay

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigens, Viral
  • Epitopes
  • Immune Sera
  • Recombinant Proteins
  • Viral Envelope Proteins

Grant support

This study was funded by the National Healthcare Innovation Centre grant (NHIC-I2D-1409009) from the Ministry of Health, Singapore to E.E.O. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.