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

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 (similar to 5%) of RSV breakthrough cases. The fitness of these variants was impaired, compared to wild-type RSV.