Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape From Antibody MEDI8897
| Autor: | Nicole L. Kallewaard, Susan R. Palaszynski, Steve Wong, Fiona Fernandes, Weijia Wang, Seme Diallo, Nancy Ulbrandt, Mark T. Esser, Bin Lu, Catherine Svabek, Patrick M. Mctamney, Kuishu Ren, Qing Zhu, Hong Jing, JoAnn Suzich, Brian Moldt |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Protein Conformation medicine.drug_class viruses 030106 microbiology Population Virus Attachment Respiratory Syncytial Virus Infections Antibodies Viral Crystallography X-Ray Virus Replication medicine.disease_cause Monoclonal antibody Neutralization Virus 03 medical and health sciences Gene Frequency Neutralization Tests Drug Resistance Viral Prevalence medicine Humans Immunologic Factors Immunology and Allergy education Immune Evasion Biological Products Mutation education.field_of_study Binding Sites biology Antibodies Neutralizing Virology Fusion protein United States 030104 developmental biology Infectious Diseases Amino Acid Substitution Viral replication Respiratory Syncytial Virus Human biology.protein Mutant Proteins Antibody Viral Fusion Proteins |
| Zdroj: | The Journal of Infectious Diseases. 218:572-580 |
| ISSN: | 1537-6613 0022-1899 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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