Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape From Antibody MEDI8897. (30th March 2018)

• Record Type: Journal Article
• Authors: Zhu, Qing; Lu, Bin; McTamney, Patrick; Palaszynski, Susan; Diallo, Seme; Ren, Kuishu; Ulbrandt, Nancy D; Kallewaard, Nicole; Wang, Weijia; Fernandes, Fiona; Wong, Steve; Svabek, Catherine; Moldt, Brian; Esser, Mark T; Jing, Hong; Suzich, JoAnn A
• Is Part Of: Journal of infectious diseases. Volume 218:Number 4(2018)
• Page Start: 572
• Page End: 580
• Publication Date: 2018-03-30
• Subjects: MEDI8897 -- monoclonal antibody -- neutralization escape -- respiratory syncytial virus; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiy189
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract : In vitro-selected MEDI8897 monoclonal antibody resistant mutants of RSV encoded mutations in the antibody binding site and reduced susceptibility to the antibody correlated with reduced binding to RSV F protein. The frequency of clinical RSV exhibiting MEDI8897 resistance is low. Abstract: Background: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children. To date, no vaccine is approved for the broad population of healthy infants. MEDI8897, a potent anti-RSV fusion antibody with extended serum half-life, is currently under clinical investigation as a potential passive RSV vaccine for all infants. As a ribonucleic acid virus, RSV is prone to mutation, and the possibility of viral escape from MEDI8897 neutralization is a potential concern. Methods: We generated RSV monoclonal antibody (mAb)-resistant mutants (MARMs) in vitro and studied the effect of the amino acid substitutions identified on binding and viral neutralization susceptibility to MEDI8897. The impact of resistance-associated mutations on in vitro growth kinetics and the prevalence of these mutations in currently circulating strains of RSV in the United States was assessed. Results: Critical residues identified in MARMs for MEDI8897 neutralization were located in the MEDI8897 binding site defined by crystallographic analysis. Substitutions in these residues affected the binding of mAb to virus, without significant impact on viral replication in vitro. The frequency of natural resistance-associated polymorphisms was low. Conclusions: Results from this study provide insights into the mechanism of MEDI8897 escape and the complexity of monitoring for emergence of resistance.