Engineered mRNA-expressed antibodies prevent respiratory syncytial virus infection

• Type of Material: Article
• Authors: Pooja Munnilal Tiwari, Georgia Institute of Technology; Daryll Vanover, Georgia Institute of Technology; Kevin E. Lindsay, Georgia Institute of Technology; Swapnil Subhash Bawage, Georgia Institute of Technology; Jonathan L. Kirschman, Georgia Institute of Technology; Sushma Bhosle, Georgia Institute of Technology; Aaron W. Lifland, Georgia Institute of Technology; Chiara Zurla, Georgia Institute of Technology; Philip J. Santangelo, Emory University
• Language: English
• Date: 2018-12-01
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-06508-3
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 3999
• End Page: 3999
• Grant/Funding Information: This work was also funded through contributions from Children’s Healthcare of Atlanta.; This work was funded by DARPA grant W911NF-15–0609.
• Keywords: influenza; antibodies; immunology; respiratory syncytial virus; mRNA-expressed antibodies; synthetic mRNA; infectious agent
• Research Categories: Engineering, Biomedical; Health Sciences, Immunology

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.