The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome

Antimicrob Agents Chemother. 2016 Mar 25;60(4):2118-31. doi: 10.1128/AAC.02457-15. Print 2016 Apr.

Abstract

Most cases of severe influenza are associated with pulmonary complications, such as acute respiratory distress syndrome (ARDS), and no antiviral drugs of proven value for treating such complications are currently available. The use of monoclonal antibodies targeting the stem of the influenza virus surface hemagglutinin (HA) is a rapidly developing strategy for the control of viruses of multiple HA subtypes. However, the mechanisms of action of these antibodies are not fully understood, and their ability to mitigate severe complications of influenza has been poorly studied. We evaluated the effect of treatment with VIS410, a human monoclonal antibody targeting the HA stem region, on the development of ARDS in BALB/c mice after infection with influenza A(H7N9) viruses. Prophylactic administration of VIS410 resulted in the complete protection of mice against lethal A(H7N9) virus challenge. A single therapeutic dose of VIS410 given 24 h after virus inoculation resulted in dose-dependent protection of up to 100% of mice inoculated with neuraminidase inhibitor-susceptible or -resistant A(H7N9) viruses. Compared to the outcomes in mock-treated controls, a single administration of VIS410 improved viral clearance from the lungs, reduced virus spread in lungs in a dose-dependent manner, resulting in a lower lung injury score, reduced the extent of the alteration in lung vascular permeability and protein accumulation in bronchoalveolar lavage fluid, and improved lung physiologic function. Thus, antibodies targeting the HA stem can reduce the severity of ARDS and show promise as agents for controlling pulmonary complications in influenza.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Bronchoalveolar Lavage Fluid / virology
  • Capillary Permeability / drug effects
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Immunologic
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology
  • Humans
  • Influenza A Virus, H7N9 Subtype / drug effects*
  • Influenza A Virus, H7N9 Subtype / growth & development
  • Lung / drug effects*
  • Lung / virology
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred BALB C
  • Neutralization Tests
  • Orthomyxoviridae Infections / complications
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / mortality
  • Orthomyxoviridae Infections / virology
  • Respiratory Distress Syndrome, Adult / etiology
  • Respiratory Distress Syndrome, Adult / mortality
  • Respiratory Distress Syndrome, Adult / prevention & control*
  • Respiratory Distress Syndrome, Adult / virology
  • Survival Analysis
  • Viral Load / drug effects

Substances

  • Antibodies, Monoclonal
  • Hemagglutinin Glycoproteins, Influenza Virus
  • hemagglutinin, human influenza A virus