Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets.

OBJECTIVE: Palivizumab reduces respiratory syncytial virus (RSV) hospitalization in children at high risk by ∼50% compared with placebo. We compared the efficacy and safety of motavizumab, an investigational monoclonal antibody with enhanced anti-RSV activity in preclinical studies, with palivizumab. METHODS: This randomized, double-blind, multinational, phase 3, noninferiority trial assessed safety and RSV hospitalization in 6635 preterm infants aged ≤6 months at enrollment or children aged ≤24 months with chronic lung disease of prematurity who received 15 mg/kg palivizumab or motavizumab monthly. Secondary end points included outpatient medically attended lower respiratory tract infections (MALRIs), RSV-specific LRIs, otitis media, antibiotic use, development of antimotavizumab antibodies, and motavizumab serum concentrations. RESULTS: Motavizumab recipients had a 26% relative reduction in RSV hospitalization compared with palivizumab recipients, achieving noninferiority. Motavizumab was superior to palivizumab for reduction of RSV-specific outpatient MALRIs (50% relative reduction). Overall, adverse events (AEs) were not significantly different between groups. Cutaneous events were reported in 2 percentage points more motavizumab recipients (7.2% vs 5.1%); most were mild, but 0.3% resulted in dosing discontinuation. Antidrug antibodies (ADA) were detected in 1.8% of motavizumab recipients. Patients with anti-drug antibody reported 6 RSV events and 17 cutaneous events. CONCLUSIONS: Children receiving prophylaxis with motavizumab or palivizumab had low rates of RSV hospitalization; motavizumab recipients experienced 50% fewer RSV MALRIs than palivizumab recipients. AEs were similar in both groups, although cutaneous AEs were higher for motavizumab recipients. Motavizumab may offer an improved alternative in prophylaxis for serious RSV disease in infants and children at high risk.

https://espace.library.uq.edu.au/view/UQ:211576/Motavizumab_study_group.pdf

Motavizumab for Prophylaxis of Respiratory Syncytial Virus in High-Risk Children: A Noninferiority Trial

Respiratory syncytial virus (RSV) is the leading cause of serious respiratory infections in children as well as a serious cause of disease in elderly and immunosuppressed populations. There are no licensed vaccines available to prevent RSV disease. We have developed a virus-like particle (VLP) vaccine candidate for protection from RSV. The VLP is composed of the NP and M proteins of Newcastle disease virus (NDV) and a chimeric protein containing the cytoplasmic and transmembrane domains of the NDV HN protein and the ectodomain of the human RSV G protein (H/G). Immunization of mice with 10 or 40 μg total VLP-H/G protein by intraperitoneal or intramuscular inoculation stimulated antibody responses to G protein which were as good as or better than those stimulated by comparable amounts of UV-inactivated RSV. Immunization of mice with two doses or even a single dose of these particles resulted in the complete protection of mice from RSV replication in the lungs. Immunization with these particles induced neutralizing antibodies with modest titers. Upon RSV challenge of VLP-H/G-immunized mice, no enhanced pathology in the lungs was observed, although lungs of mice immunized in parallel with formalin-inactivated RSV (FI-RSV) showed the significant pathology that has previously been documented after immunization with FI-RSV. Thus, the VLP-H/G candidate vaccine was immunogenic in BALB/c mice and prevented replication of RSV in murine lungs, with no evidence of immunopathology. These data support further development of virus-like particle vaccine candidates for protection against RSV.

https://jvi.asm.org/content/jvi/84/2/1110.full.pdf

Newcastle disease virus-like particles containing respiratory syncytial virus G protein induced protection in BALB/c mice, with no evidence of immunopathology.

The Palivizumab Outcomes Registry contains data on infants and young children who received palivizumab for the prevention of respiratory syncytial virus (RSV) that causes serious lower respiratory tract illness. Prospective observational registry enrolling those who received ⩾1 dose of palivizumab during any RSV season (2000 to 2004) at participating US sites. Of 19 548 subjects enrolled, 40% were born before 32 weeks’, 48% between 32 and 35 weeks’ and 12% after 35 weeks’ gestation. Risk factors included child-care attendance, prematurity, chronic lung disease (CLD) and congenital heart disease (CHD). The RSV hospitalization rate of palivizumab recipients was 1.3%. Gender, gestational age 2 children in household were associated with significantly higher rates. Home-care prophylaxis with palivizumab was associated with reduced hospitalization rates. Data on the use of palivizumab prophylaxis in primarily high-risk infants confirm low RSV hospitalization rates.

Prevention of hospitalization due to respiratory syncytial virus: results from the Palivizumab Outcomes Registry.

Although it has been on the market for over a decade, confusion remains regarding the pharmacokinetics (PK) and optimal dosing of palivizumab, a humanized IgG1κ monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. The objectives of this analysis were to characterize the population PK of palivizumab in adults and children using nonlinear mixed-effect modeling, quantify the effects of individual covariates on variability in palivizumab disposition, and compare palivizumab exposures for various dosing scenarios. Palivizumab PK data from 22 clinical studies were used for model development. The model was developed using a two-stage approach: (i) a 2-compartment model with first-order absorption after intramuscular administration was fitted to adult data, and (ii) the same structural model was fitted to the sparse pediatric data using the NONMEM $PRIOR subroutine, with informative priors obtained from the adult analysis. Body weight and an age descriptor that combines gestational age and postnatal age (PAGE) using an asymptotic-exponential model best described palivizumab clearance in pediatric patients. Palivizumab clearance increased slightly from 10.2 ml/day to 11.9 ml/day as a function of PAGE ranging from 7 to 18 months. Covariate analysis indicated a 20% higher clearance in children with chronic lung disease and in children with antidrug antibody titer values of ≥80. These covariates did not substantially explain interindividual variability. In the label-indicated pediatric population, body weight was the primary demographic factor affecting palivizumab PK. Body weight-based dosing of 15 mg/kg yields similar palivizumab concentrations in children of different gestational and postnatal ages. Simulations demonstrated that there was little difference in palivizumab PK between healthy term and premature infants. Simulations also demonstrated that the 5 monthly palivizumab doses of 15 mg/kg, consistent with the label and studied in two randomized, clinical trials, provided greater and more prolonged palivizumab exposure than did an abbreviated dosing regimen of 3 monthly doses.

Population Pharmacokinetics of Palivizumab, a Humanized Anti-Respiratory Syncytial Virus Monoclonal Antibody, in Adults and Children

The objective of the Registry was to characterize the population of infants receiving prophylaxis for respiratory syncytial virus (RSV) disease by describing the patterns and scope of usage of palivizumab in a cross section of US infants. RSV hospitalization outcomes were also described. The Palivizumab (Synagis, MedImmune, Inc., 25 West Watkins Mill Road, Gaithersburg, MD 20878) Outcomes Registry was a prospective multicenter survey conducted at 63 sites. Demographics, injection history, and RSV hospitalization outcomes were collected on 2,116 infants receiving palivizumab. Infants were enrolled in the Registry between September 1, 2000-March 1, 2001, at the time of their first injection. Infants born at less than 32 weeks of gestation accounted for 47% of infants enrolled, and those between 32-35 weeks accounted for 45%; approximately 8% were greater than 35 weeks of gestation. Lower RSV hospitalization rates were observed in infants who had greater adherence to regularly scheduled injections. Nearly one-half of all hospitalizations occurred within the first and second injection intervals, suggesting the importance of early RSV protection. The confirmed RSV hospitalization rate of all infants in the Registry was 2.9%; the rate was 5.8% in infants with chronic lung disease of infancy, and 2.1% in premature infants without chronic lung disease. In conclusion, these data support the continued effectiveness of palivizumab prophylaxis for severe RSV lower respiratory tract disease in a large cohort of high-risk infants from geographically diverse pediatric offices and clinics. The Palivizumab Outcomes Registry provides an opportunity to assess palivizumab utilization and clinical effectiveness in the US.

Zinno

Papers

Palivizumab prophylaxis of respiratory syncytial virus disease in 2000-2001: results from The Palivizumab Outcomes Registry.