Respiratory syncytial virus immune globulin (RSV-IGIV (RespiGamTM) contains a sixfold higher concentration of RSV neutralizing antibodies than does standard immunoglobulin preparations. It was developed to provide passive immunity against RSV in infants who were born preterm, before the third trimester when maternal IgG antibodies are typically passed from the mother to the fetus.
In studies, RSV-IGIV was found to be effective, safe, and well tolerated, though it also has various limitations. For example, it is not effective in children with congenital heart disease or cyanotic heart disease because of blood hyperviscosity, which can be worsened by the immunoglobulin. RSV-IVIG, in clinical studies, was responsible for more hypercyanotic events than albumin. In addition, administration of RSV-IGIV is time-consuming and inconvenient, involving 3to 4-h-long monthly intravenous infusions of large fluid volumes and protein loads. This can lead to fluid overload in some children and is of special concern in children, particularly infants, with chronic cardiopulmonary conditions.
Monoclonal Antibodies
Monoclonal antibodies were investigated in an effort to avoid the difficulties associated with RSV-IGIV. The first monoclonal preparations could be administered intranasally, thereby protecting the portal of entry and precluding the difficulties associated with parenteral therapy.
In a study using rhesus monkeys, a mouse monoclonal IgA antibody against RSV F glycoprotein was administered as nose drops. The monkeys developed high titers of RSV neutralizing antibodies, but this result was not repeated in human phase III clinical trials, and efficacy could not be proved. Regardless, because the half-life of IgA is short, dosing schedules would require repeated applications, reducing the likelihood of compliance.
Likewise, a clinical trial with the intramuscular IgG humanized monoclonal antibody SB 209763 also failed to produce favorable results.
The development of a humanized monoclonal antibody produced by recombinant DNA technology – palivizumab – was a major advance in protection against RSV. Palivizumab (Synagis) is a humanized monoclonal antibody (IgG1) directed to an epitope on the A domain of the F glycoprotein on the surface of the respiratory syncytial virus. Its mechanism of action is to neutralize and inhibit the fusion activity of both types A and B clinical RSV isolates on respiratory epithelial cells. Unlike RSV-IGIV, palivizumab is not derived from human blood and does not require intravenous administration. Its greater safety and convenience of use are clear advantages to previous methods of passive immunoprophylaxis. It is administered seasonally to high-risk individuals by monthly intramuscular (IM) injections. Studies showed that overall hospitalization rates for RSV infection were reduced in children that received palivizumab compared with rates in children that received placebo. Hospitalization rates were reduced in children with bronchopulmonary disease. In premature infants who had received palivizumab, there was a reduction in subsequent wheezing and asthma 2–4 years later. Palivizumab was safe in children with hemodynamically significant congenital heart disease.
So far, the search for a safe and effective vaccine against RSV has not succeeded, and clinical outcomes in studies of children treated symptomatically for RSV with bronchodilators, steroids, and antiviral agents (ribavirin) have not been improved. Until such a vaccine is discovered and proven, palivizumab remains the only safe, effective, and convenient treatment to prevent RSV disease in young children at risk.
Prognosis
Mortality
The mortality of children admitted to hospital with RSV-ALRI is low in developed countries, and even in developing countries with a generally higher hospital mortality, only approximately 1–3% of hospital admissions die, mostly those with an underlying illness, such as congenital heart disease or bronchopulmonary dysplasia. However, where oxygen is not routinely available, or where inpatients are not routinely monitored to detect complications or the inability to feed, mortality may be considerably higher. The impact of RSV on mortality in the community is unknown.
Further Wheezing
There is debate about whether RSV triggers further episodes of wheezing. Data from The Gambia indicate that children with severe RSV infection are at higher risk to be admitted again with respiratory problems over the next few years, but appear to have no higher risk of asthma later. A recent study from Europe and Canada shows that by preventing RSV lower respiratory tract infection (LRTI) in infancy (using palivizumab) there was a 50% reduction of subsequent physician-diagnosed recurrent wheezing in the next 3–4 years. Long-term follow-up of these future subjects is under way.
Bibliography:
- Smyth RL and Openshaw PJ (2006) Bronchiolitis. Lancet 368: 312–322.
- White LJ, Waris M, Cane PA, Nokes DJ, and Medley GF (2005) The transmission dynamics of groups A and B human respiratory syncytial virus (hRSV) in England & Wales and Finland: seasonality and cross-protection. Epidemiology and Infection 133: 279–289.