title: Analysis of respiratory syncytial virus preclinical and clinical variants resistant to neutralization by monoclonal antibodies palivizumab and/or motavizumab.
abstract: 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.
authors.affiliation: Department of Infectious Disease-Vaccines, MedImmune, Gaithersburg, Maryland, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Josie M
authors.initials: JM
authors.lastname: McAuliffe
authors.forename: Nita K
authors.initials: NK
authors.lastname: Patel
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Palmer-Hill
authors.forename: Chin-fen
authors.initials: CF
authors.lastname: Yang
authors.forename: Brandon
authors.initials: B
authors.lastname: Liang
authors.forename: Lan
authors.initials: L
authors.lastname: Su
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Leslie
authors.initials: L
authors.lastname: Wachter
authors.forename: Susan
authors.initials: S
authors.lastname: Wilson
authors.forename: Randall S
authors.initials: RS
authors.lastname: MacGill
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Krishnan
authors.forename: Michael P
authors.initials: MP
authors.lastname: McCarthy
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Losonsky
authors.forename: JoAnn A
authors.initials: JA
authors.lastname: Suzich
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral; D000998:Antiviral Agents / Q000276:immunology*; D024882:Drug Resistance, Viral / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D009154:Mutation; D009297:Nasal Mucosa / Q000821:virology; D000069455:Palivizumab; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000914:Antibodies, Viral; D000998:Antiviral Agents; C506968:motavizumab; D000069455:Palivizumab