Editorial

Indian Pediatrics 2000;17: 243-247

Immunoprophylaxis of Respiratory Syncytial Virus Infection

It has been estimated that 3.76 million deaths occur from acute respiratory tract infections in under fives annually, about 3 million of which are due to acute lower respiratory tract infection (ALRI)(1). Most of these occur in children in developing countries with the commonest pathogens being Streptococcus pneumoniae, Haemophilus influenzae and respiratory syncytial virus. Respiratory syncytial virus is so named because it causes syncytia in epithelial cells of the respiratory tract. A pneumovirus, RSV is a single stranded RNA virus, with a lipid bilayer envelope from which several surface proteins project(2). Among these is a transmembrane protein, F, that is responsible for facilitating viral entry into host cells and stimulating cell-to-cell fusion to form syncytia. It is particularly well conserved between the two major strains of RSV, A and B, making Protein F a target to prevent RSV infection, either through active or passive immunization.

In developed countries, recognized risk factors for development of severe RSV infection requiring hospitalization or resulting in death are prematurity(3), chronic lung disease(4), con-genital heart disease(5), immune compro-mise(6), and age <6 weeks(7) in normal children. During the first year of life 50-70% of infants will develop an RSV infection, and virtually all will by the third year of life. Unfortunately, children and adults alike remain susceptible, year after year, to re-infection. Immunity is not durable and will not prevent re-infection from year to year, or sometimes even within the same season. While the role of RSV has been established as a major cause of infectious respiratory hospitalizations in children under five in developed nations, and its role as a major pathogen in ALRI in developing countries is undisputed, its role as a cause of death in developing countries has been underestimated. In order to clarify the role of RSV in morbidity and to describe children at high risk for developing severe disease, the WHO has funded ongoing community based studies in Indonesia, Mozambique, South Africa, Ethiopia, Guinea-Bissau and Nigeria to help clarify this situation. It has been estimated that about 600,000 infants and young children die from RSV annually, and if bacterial co-infections are included, this number may approach 1,000,000 deaths anually(8). Thus in developing countries, where RSV is the main cause of LRI in the community it's prevention may result in significant reductions in RSV related morbidity and mortality.

Prevention of RSV may result in significant cost saving in antibiotic over usage (for treatment of suspected bacterial pneumonia) and possibly in the reduction of the rate of development of antibiotic resistant strains of bacteria. The creation of a vaccine for RSV has proven extremely difficult. In the late 1960's there were four clinical trials in children of an inactivated, formalin-treated RSV vaccine which was administered intramuscularly(9). The recipients did mount an immune response, but when subsequently exposed to RSV, they experienced much more severe LRI than the study controls. The risk of hospitalization was five fold greater in the vaccinated group younger than one year of age, and there were also several deaths. This lack of success with early vaccine trials, coupled with only supportive treatment options and an ever-editorial increasing population of high risk children, lead to a shift in research toward providing passive immunity against this disease.

Early clinical studies using gamma globulin to prevent severe infection with RSV were unsuccessful at significantly diminishing the incidence of lower respiratory tract infection (LRI), when compared with children who did not receive it, due to a low titer of specific RSV-neutralizing antibodies(10). In the early to mid-1990's three randomized, controlled clinical trials evaluated the efficacy and safety of a high titred RSV immuneglobulin (RSV-IGIV) in preventing severe RSV-related lower respiratory tract infection.

The first of these the National Institute of Allergy and Infectious Disease (NIAID) trial(11), included three high risk populations of children_those with prematurity, chronic lung disease (CLD), or congenital heart disease, evaluated the use of monthly infusions of RSV-IGIV, given during the RSV season, in 249 high risk infants and children. Three groups were studied_a control group receiving no infusions, a low dose group (150 mg/kg) and a high dose group (750 mg/kg). In the high dose group (750 mg/kg/dose) there was 62% reduction in the incidence of lower respiratory tract disease caused by RSV (p = 0.01), in the number of hospitalizations from RSV (63%; p = 0.02) and the days in the hospital for this group (63%; p = 0.02), and in the number of days spent in the intensive care unit, (43 vs 128, p = 0.05) as compared to the control group. Most of this effect appeared to be in premature infants but not in those with cardiac disease. In addition to these outcomes there was a 6-fold reduction in the number of cases of acute otitis media in the high dose infused children in a subset of the patients from Denver and Buffalo(12).

Adverse reactions were uncommon. The most frequent of these were fluid overload in children with CLD that was responsive to a slower rate of infusion, fever, and mild, transient decrease in oxygen saturation. There were six deaths in this study, 3 occurring in the low dose intervention, and 3 in the high dose group. Five of these six deaths occurred in children with underlying congenital heart disease (CHD), primarily in relation to cardiac surgery. Though not statistically significant, this observation raised a concern for the safety of RSV-IGIV in this subset of high risk children.

Since the positive effect in the NIAID trial seemed to be in premature infants, and the safety issues were related to children with heart disease, two further trials were conducted_one in premature infants and children (the PREVENT Study)(13) and one in children with heart disease (the Cardiac trial)(14). The PREVENT trial enrolled 510 infants and children, their results corroborated those of the NIAID trial with a 41% reduction in RSV hospitalization (p = 0.047) and interestingly non RSV hospitalization (38%; p = 0.005). In the Cardiac study(14), in 416 infants and children less than four years old, with variable forms of congenital heart disease, there was no significant decrease in the overall hospitalization rate for RSV-related LRI. (31%; p = 0.16). However there was a 56% (p = 0.01) reduction in RSV hospitalization in infants under 6 months of age Unexpectedly, children with cyanotic heart lesions were at substantially higher risk of suffering an worsening of cyanosis. Although, the mechanism is unclear, it was postulated that RSV-IGIV increased a baseline hyperviscosity of serum, which cause the hyercyanotic events. These results reinforced concerns that RSV-IGIV may worsen the hemodynamic status in children with particular types of CHD, primarily cyanotic lesions. Indeed the use of any IGIV in children with cyanotic heart disease should be approached with caution.

The establishment of RSV-IGIV as a safe and effective mode of conferring passive immunity to high-risk children has been a tremendous step forward in the prevention of severe RSV disease, however the administration of RSV-IGIV is not without problems. Recurrent intravenous access is not easy to achieve, and RSV-IGIV administration requires a substantial time investment for providers, nursing staff, and parents, and it is an expensive and relatively inconvenient therapy. However, the combination of success with passive prophylaxis, and tremendous advances in technology, had paved the way for the development of a potentially more powerful therapeutic agent, an anti-RSV monoclonal antibody (palivizumab)(15).

A monoclonal antibody is a purified antibody, designed to recognize a single epitope of an antigen. A "humanized" anti-RSV monoclonal antibody (palivizumab) has been developed(16), that is 95% human and 5% mouse in composition. It is directed at an epitope on the F Protein, which is expressed on the surface of the virus envelope, as well as on the surface of infected cells. This monoclonal antibody is estimated to be 50-100 times more potent against RSV than the polyclonal RSV-IGIV, allowing the dose to be reduced 50 fold, and hence its use as an IM preparation.

In the winter season of 1996 a large, randomized, double-blind, placebo-controlled, multicenter trial(17) was conducted in 139 centers in North America and the UK, to test the efficacy of palivizumab when a 15 mg/kg dose was administered IM monthly for five months. One thousand five hundred and two subjects who were premature at birth with or without CLD, were enrolled in the study. There was a 55% reduction in hospitalization rate for RSV-related illness. This decrease was most pronounced (78% less, p <0.001) for infants with a history of prematurity without CLD. However, even among those with CLD, a significant reduction (38%, p <0.01) was seen. There was also a substantial decrease in the number of hospital days, the number of days that supplemental oxygen was required and in the number of admissions to the intensive care unit. There was no significant difference between the palivizumab and placebo groups for the number of children with otitis media or the number and duration of hospitalizations for non-RSV respiratory illnesses.

Overall, palivizumab was well tolerated by all study subjects and no serious side effects attributable to injection were noted. The most commonly reported events were local reaction at the injection site, fever, rash, `nervousness', and diarrhea in about 10% of patients and controls. Additionally, the children's sera were tested for the presence of anti-palivizumab antibodies to asses the immunogenicity of the drug itself. There were no significant responses on the part of the study patients against the monoclonal antibody. In June 1998 palivizumab was approved for use in a targeted, high-risk population. Both RSV-IGIV and palivizumab are likely to have a positive impact in the pediatric clinical setting for years to come in developed countries. However, they are not without their pitfalls. Both therapies are expensive. In comparing the cost of monthly treatment of a 3 kg infant, the cost for 5 infusions of RSV-IGIV is estimated to be from US$ 3621(18) to US$ 434(19), while palivi-zumab is US$ 2378(18). In developing coun-tries, where there is a burgeoning middle-class that can afford to pay for expensive medications, these two products may be considered for use in high-risk children. Thus for example, most middle-class Indians can afford to pay for HIB vaccines, but the vaccine itself is too expensive to be used in routine immunization in government-sponsored vaccination programs. For the majority of children in developing countries however, passive prophylaxis is not a viable option because of the cost of administration. Vaccinations with vaccines are urgently needed and may result in the prevention of significant numbers of ALRI deaths in under fives in developing countries.

- Eric A.F. Simoes, Associate Professor, Department of Pediatrics, Section of Infectious Diseases, The University of Colorado School of Medicine and The Children's Hospital, 1056 East 19th Avenue,  B070