Journal Article

Analysis of Respiratory Syncytial Virus Preclinical and Clinical Variants Resistant to Neutralization by Monoclonal Antibodies Palivizumab and/or Motavizumab

Wachter, Leslie, McCarthy, Michael P., Su, Lan, McAuliffe, Josie M., Patel, Nita K., Krishnan, Subramaniam, MacGill, Randall S., Zhu, Qing, Palmer-Hill, Frances J., Yang, Chin-fen, Wilson, Susan, Zhu, Wei, Losonsky, Genevieve A., Liang, Brandon, Suzich, JoAnn A.

2011

Overview

Background. Palivizumab is a US Food and Drug Administration—approved monoclonal antibody for the prevention of respiratory syncytial virus (RSV) lower respiratory disease in high-risk infants. Motavizumab, derived from palivizumab with enhanced antiviral activity, has recently been tested in humans. Although palivizumab escape mutants have been generated in the laboratory, the development of resistant RSV in patients receiving palivizumab has not been reported previously. Methods. We generated palivizumab and motavizumab escape mutants in vitro and examined the development of resistant mutants in RSV-breakthrough patients receiving immunoprophylaxis. The effect of these mutations on neutralization by palivizumab and motavizumab and in vitro fitness was studied. Results. Antibody-resistant RSV variants selected in vitro had mutations at position 272 of the fusion protein, from lysine to asparagine, methionine, threonine, glutamine, or glutamate. Variants containing mutations at positions 272 and 275 were detected in breakthrough patients. All these variants were resistant to palivizumab, but only the glutamate variant at position 272 demonstrated resistance to motavizumab. Mixtures of wild-type and variant RSV soon lost the resistant phenotype in the absence of selection. Conclusions. Resistant RSV variants were detected in a small subset (∼5%) of RSV breakthrough cases. The fitness of these variants was impaired, compared to wild-type RSV.

• Publisher: Oxford University Press
• Subject: Amino acids / Antibodies / Antibodies, Monoclonal - genetics / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal, Humanized / Antibodies, Viral / Antiviral Agents - immunology / Biological and medical sciences / Cultured cells / Drug Resistance, Viral - genetics / Drug Resistance, Viral - immunology / Fundamental and applied biological sciences. Psychology / Genetic mutation / Human respiratory syncytial virus / Humans / Infant / Infectious diseases / Major and Brief Reports / Medical sciences / Microbiology / Molecular Sequence Data / Monoclonal antibodies / Mutation / Nasal Mucosa - virology / Palivizumab / Respiratory syncytial virus / Respiratory syncytial virus infections / Respiratory Syncytial Virus Infections - prevention & control / Respiratory syncytial viruses / Respiratory Syncytial Viruses - drug effects / Respiratory Syncytial Viruses - genetics / Respiratory Syncytial Viruses - immunology / Reverse Transcriptase Polymerase Chain Reaction / Vero cells / Viruses