Engineered mRNA-expressed antibodies prevent respiratory syncytial virus infection

Nat Commun. 2018 Oct 1;9(1):3999. doi: 10.1038/s41467-018-06508-3.

Abstract

The lung is a critical prophylaxis target for clinically important infectious agents, including human respiratory syncytial virus (RSV) and influenza. Here, we develop a modular, synthetic mRNA-based approach to express neutralizing antibodies directly in the lung via aerosol, to prevent RSV infections. First, we express palivizumab, which reduces RSV F copies by 90.8%. Second, we express engineered, membrane-anchored palivizumab, which prevents detectable infection in transfected cells, reducing in vitro titer and in vivo RSV F copies by 99.7% and 89.6%, respectively. Finally, we express an anchored or secreted high-affinity, anti-RSV F, camelid antibody (RSV aVHH and sVHH). We demonstrate that RSV aVHH, but not RSV sVHH, significantly inhibits RSV 7 days post transfection, and we show that RSV aVHH is present in the lung for at least 28 days. Overall, our data suggests that expressing membrane-anchored broadly neutralizing antibodies in the lungs could potentially be a promising pulmonary prophylaxis approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / genetics
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Neutralizing / metabolism
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / immunology
  • Cell Line
  • Cell Membrane / metabolism
  • Female
  • Humans
  • Lung / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Palivizumab / genetics
  • Palivizumab / immunology*
  • Palivizumab / metabolism
  • Pre-Exposure Prophylaxis
  • RNA, Messenger / administration & dosage*
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology
  • Respiratory Syncytial Virus Infections / immunology
  • Respiratory Syncytial Virus Infections / prevention & control*
  • Respiratory Syncytial Virus Infections / virology
  • Respiratory Syncytial Virus, Human / immunology*
  • Viral Fusion Proteins / immunology

Substances

  • Antibodies, Neutralizing
  • Antiviral Agents
  • F protein, human respiratory syncytial virus
  • RNA, Messenger
  • Viral Fusion Proteins
  • Palivizumab