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Genetic mutations led to palivizumab-resistant RSV infection in infancy
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Two mutations in the drug-binding region of the respiratory syncytial virus gene RSV-VI-1447 caused palivizumab-resistant infection in an infant who had already received prophylactic treatment with the medication, according to a recently published case report.
Researchers from the Institute of Virology and University Children’s Hospital at Heinrich-Heine University in Düsseldorf, Germany, described a case in which a male preterm infant born at 25 weeks’ gestation received palivizumab (Synagis, MedImmune) to prevent respiratory syncytial virus (RSV) infection. The drug was administered as a 13.8 mg/kg-dose on day 69 and was followed by a 19.1 mg/kg-dose 36 days later. A third 10.6-mg/kg-dose was then given 34 days after the second.
Despite prophylaxis, the infant developed recurrent episodes of apnea, poor feeding, respiratory distress and other unspecific signs of infection. His oxygen saturation was also low, the researchers noted, and blood gas analysis revealed a carbon dioxide retention with partial pressure of carbon dioxide of 48 mm Hg. RSV RNA was eventually discovered at 463,000,000 K/mL.
The researchers utilized a one-step multiplex real-time polymerase chain reaction (PCR) to detect the RSV RNA, and they sequenced the virus isolates using reverse transcription PCR. Sequencing data were taken from amplification with two RSV F gene-specific primers encompassing almost the entire F gene. They also conducted nucleotide alignment with group A and B sequences. To determine resistance to the drug, several passages of the virus cultures with and without the addition of palivizumab were also obtained using samples of the infant’s pharyngeal aspirate.
Microneutralization assay with palivizumab showed a reduction in virus growth up to a concentration of 142 mcg/mL. Data for the laboratory strain RSV-Long, however, indicated that the median infective dose (ID50) with palivizumab was 9 ng/mL (95% CI, 3.7-22.0). After analysis of the second passage with addition of the palivizumab, results showed complete resistance to the medication and a 20-fold increase in resistance (ID50, 199.4 ng/mL; 95% CI, 81-490) when compared with the second passage of RSV-Long without palivizumab.
Sequence alignment demonstrated clustering of the RSV F gene RSV-VI-1447 to human RSV group A. Sequence analysis of the F gene and more passages showed that a stable nucleotide exchange at position 827 from A to G led to an amino acid change from asparagine to serine (N276S). The researchers noted that this change did not react to the addition of palivizumab. Further tests revealed that this particular mutation only existed in RSV-VI-1447.
A second mutation was also discovered at nucleotide position 814 from A to G and led to an amino acid exchange at position 272 from lysine to glutamic acid (K272E). However, the researchers only found this mutation in passages with the addition of palivizumab.
“That RSV-VI-1447 lost its resistance to palivizumab as soon as the selection pressure was no longer present has impact for the clinical and epidemiologic role of such mutants,” wrote the researchers. “The occurrence of specific resistance mutations seems to be an individual phenomenon during prophylaxis with palivizumab with implications for the distribution of resistant mutants in the population. This also includes the possibility that under certain circumstances, such as in a clinic or office, nosocomial infections of palivizumab-resistant [human RSV] strains could occur.”
As a result of their findings, the researchers advocated future surveillance studies on the development of resistant viruses in infants receiving palivizumab.
Adams O. Clin Infect Dis. 2010; 51:185-188.