Escape mutant of respiratory syncytial virus resists palivizumab prophylaxis
Objective Palivizumab (PZ), a humanized monoclonal antibody against RSV fusion protein, is prophylactically given in certain high risk children. Expanding use in children and in individuals with ineffective cell mediated viral clearing will provide opportunities for the emergence of antibody resistant viruses. The ability of PZ resistant virus to evade PZ prophylaxis was evaluated in cotton rats. Methods A2 RSV was passed in culture in increasing PZ concentrations (0.4 to 40 μg/ml) and the resulting virus was characterized from a single plaque (MP4). Antigenecity, resistance to PZ in vitro and in vivo were assessed by use of Western blot, microneutralization assay and prophylactic experiment in cotton rats, respectively. Results MP4 was 100 fold less susceptible to PZ neutralization as compared to A2. The F protein gene of MP4 had a nucleotide substitution (base 828 A to T) that resulted in a coding change (amino acid 272 Lys to Met). Cotton rats were given prophylactic PZ and challenged with virus intranasally. The MP4 challenged rats had no reduction in lung viral titers as compared to rats that did not receive PZ. The A2 challenged rats revealed the expected PZ protection against RSV replication. Conclusion A virus resistant to PZ in culture was also resistant to the prophylactic effect of PZ in cotton rats. Whether PZ resistant viruses will occur in humans and result in clinical consequences is unknown.