Prophylaxis with Monoclonal Antibody for RSV Infections in High-Risk Infants
By Hal B. Jenson, MD, FAAP
A randomized, double-blind, placebo controlled trial was conducted at 139 centers in the United States, Canada, and the United Kingdom. During the 1996-1997 respiratory syncytial virus (RSV) season, 1502 children with prematurity (< 35 weeks) or bronchopulmonary dysplasia (BPD) were randomized to receive five injections every 30 days of either Palivizumab, a "humanized" monoclonal antibody against RSV, or placebo.1 The children were followed for 150 days. Children who were hospitalized for RSV infections were evaluated for total hospital days, total days with severe or moderate lower respiratory illness, and total days of intensive care and mechanical ventilation.
Palivizumab prophylaxis resulted in a 55% reduction in hospitalizations for RSV; children with prematurity but no BPD had a 78% reduction; children with BPD had a 39% reduction. The treatment group had fewer hospital days, fewer RSV hospital days with increased oxygen, fewer RSV hospital days with a moderate or severe lower respiratory tract illness, and a lower incidence of ICU admissions. Palivizumab was safe and well tolerated.
RSV is the most important cause of lower respiratory tract infections in infants and young children, accounting for 90,000 pediatric hospitalizations and 4500 deaths annually during yearly outbreaks in winter and spring. Approximately half of all children become infected with RSV each winter season. The frequency and severity of repeat RSV infections diminish with advancing age. In the first 3-4 years of life, RSV infections are an important cause of significant mortality and morbidity in children who are born prematurely, especially those prematures who have suffered from bronchopulmonary dysplasia.
Aerosolized ribaviran treatment for RSV infection has been controversial. The most recent study found that ribavirin was not effective in reducing severity of RSV and could have prolonged illness compared to placebo treated control patients.2 The financial costs, logistical problems with the aerosol route of administration, concern for potential toxicity in exposed personnel (especially pregnant women), and uncertain clinical efficacy have diminished its use.3
RSV-IGIV (RespiGam) intravenous immune globulin prepared from individuals with high titers of anti-HSV antibodies was licensed in January 1996. It is administered as a series of five monthly injections of RSV-IGIV given during the RSV season and reduces the incidence of RSV infections by 41%, hospital days with moderate or severe RSV by 54%, and total RSV-associated hospital days by 53%. RSV-IGIV also reduces hospitalization for respiratory illness from any cause by 38% and also the incidence of otitis media.4
In a March 1997 comment on RSV-IGIV, I indicated that monoclonal antibody preparations against HSV were under development.5 A "humanized" monoclonal antibody that is highly active against RSV has been prepared by inserting the antibody determining region of a murine monoclonal antibody directed to the RSV F protein into a human I.G. framework. The resulting humanized monoclonal antibody named palivizumab and marketed as Synagis, is composed of 95% human and 5% murine sequences. Since it is not prepared from human blood, there is no potential transmission of blood-borne pathogens. Palivizumab is 50-100 times more potent against RSV than an equivalent amount of RSV-IGIV. It is reconstituted with sterile water and is administered in monthly intramuscular doses of l5 mg/kg with up to 1 mL per injection site.
The IMpact-RSV Study Group showed a 55% reduction in RSV-associated hospitalizations (10.6 for placebo vs 4.8 for psalivizumab), which compares favorably to the 41% reduction reported earlier with the use of RSV-IGIV. The primary advantage of palivizumab is the ease of intramuscular administration compared to the intravenous administration of RSV-IVIG that requires intravenous access, sometimes difficult in these patients, and it may take 4-6 hours for the infusion. Another advantage is that there is no interaction that necessitates delay of live virus vaccination, such as the nine months that measles vaccine must be deferred after RSV-IVIG. One advantage of RSV-IVIG is the reduced incidence of respiratory infections other than RSV, including a reduced incidence of otitis media. Palivizumab and RSV-IVIG are only indicated for prophylaxis and not treatment of RSV disease.
Palivizumab will supplement most of the use of RSV-IVIG. The cost, using average wholesale pricing, which is higher than the actual cost for many hospitals of a five- month treatment of a 5 kg infant with RSV-IVIG is approximately $7600 compared to $4500 for Palivizumab. One cost consideration is that reconstituted Palivizumab must be used within six hours, so that the actual cost may be higher due to wastage. This can be minimized by seeing all patients receiving Palivizumab at the same time. Despite the high costs, savings from reduced hospitalizations and ICU care are cost effective for both Palivizumab and RSV-IVIG.
I have one final comment about this latest study. The use of a placebo control design for a serious disease that has an accepted and recommended, effective alternative available therapy is a little troubling.
1. The IMpact-RSV Study Group. Palivizumab, a human respiratory syncytial virus monoclonal antibody (RSV), reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102:531-537.
2. Randalph AG, Wanf EE. Ribaviran in respiratory syncytial virus lower respiratory infection: A systemic overview. Arch Pediatr Adolesc Med 1996;150:942-947.
3. American Academy of Pediatrics Committee on Infectious Diseases. Reassessment of indications for ribavirin therapy. Pediatrics 1996;97:137-140.
4. The Prevent Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997;99:93-99.
5. Jenson HB. Prevention of RSV infections with RSV-IVIG. Pediatr Adolesc Med Rep 1997;2:9-10.