[Frontiers in Bioscience 1, e55-64, August 1,1996]
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IMMUNOGLOBULIN THERAPY IN KAWASAKI SYNDROME AND RSV PROPHYLAXIS

H. Cody Meissner, M.D.1, and Donald Y.M. Leung, M.D., Ph.D.2

1 Department of Pediatrics, Floating Hospital for Children at New England Medical Center; Tufts University School of Medicine, Boston, MA 02111;

2 Department of Pediatrics; The National Jewish Center for Immunology and Respiratory Medicine; Denver, CO 80262

4. RSV prophylaxis and the role of passive immunity

Respiratory syncytial virus (RSV) was first isolated in 1956 (45). The significance of this virus as a cause of clinical disease was first reported by Chanock in 1961 (46). By the early 1970s, RSV was recognized to be an important cause of nosocomial disease among children. It is now recognized that RSV is the single most important respiratory pathogen in infancy and early childhood (47). Predictable yearly outbreaks of RSV disease begin in late fall or early winter and continue into the spring months. Nearly 30% of primary RSV infections result in lower respiratory tract disease consisting of bronchiolitis and pneumonia. Serologic surveys indicate that most children are infected by RSV before 2 years of age. Despite such widespread immunity, reinfection by RSV is common in both children and adults. Forty to 50% of children hospitalized with bronchiolitis and 25% of pediatric hospitalizations due to pneumonia are caused by RSV (47). Children with certain underlying conditions are particularly at risk of severe disease and hospital-ization. This includes low birth weight infants, children with chronic lung disease such as bronchopulmonary dysplasia, children with congenital heart disease and children with immunodeficiencies (48-51).

Epidemiologic studies have found that term neonates tend to experience less severe RSV disease in the first few weeks of life when maternal neutralizing antibodies are highest (51, 52). Studies in both term and premature infants have demonstrated an inverse relationship between severity of RSV illness and the level of maternal neutralizing antibody. Severe RSV-mediated lower respiratory tract disease in infants tends to occur when the concentration of antibodies fall to low levels. These observations suggest that serum neutralizing antibodies to RSV play a beneficial role in preventing the lower respiratory tract disease caused by RSV.

Active immunization against RSV has proceeded cautiously because of concern that augmentation of the immune response may result in worsening pulmonary complications in RSV infected infants (53). In the 1960s, using a formalin inactivated RSV vaccine, the incidence of severe acquired RSV disease proved to be greater in vaccinated infants than in control children (54-56). Serologic studies subsequently demonstrated that although the complement fixation antibody response in the vaccinees was satisfactory, the neutralizing antibody response to RSV was poor. After natural RSV infection, the vaccinees experienced an appropriate neutralizing antibody response, suggesting an incomplete immune response following use of the formalin inactivated vaccine. Since that experience, attempts to develop a safe and immunogenic RSV vaccine have met only with a limited success.

As an alternative to active immunization, the role of passive immunization in the prevention of serious RSV illness has been examined in both animals and humans (57). RSV contains at least 10 viral polypeptides, 2 of which are surface glycoproteins. The G glycoprotein is involved in attachment of the virus to a susceptible host cell. The smaller of the two molecules, the fusion glycoprotein (F), appears to be responsible for viral penetration of the host cell and for fusion of infected cells resulting in cell to cell spread. Neutralizing epitopes have been identified on both glycoproteins. In adults, there is an inverse correlation between antibody levels to F and G glycoproteins and susceptibility to reinfection. In infants, one study found no significant difference between the concentration of antibodies to F and G between infants who became infected and those who did not (58).

Based on animal studies, immunity to RSV is felt to depend largely on antibodies to F and G. Newborn cotton rats experience RSV replication in the upper and lower respiratory tract following intranasal inoculation, although they do not develop illness. In the cotton rat, a high titer of intraperitoneally administered, neutralizing antibody to RSV is protective against disease (59). The titer of virus that can be recovered in the lungs varies inversely with the concentration of neutralizing antibody in the serum. In the animal model, a neutralizing titer of >1:350 is associated with protection of the lower airway tracts (60). Serologic studies in newborn infants has shown that neutralizing titers between 1:300 and 1:400 results in similar protection from disease.

As a result of these observations, an initial study was begun, in 1988, to examine the safety of a standard, commercial immune globulin. This immune globulin had an RSV neutralizing antibody titer of 1:1100 (61). A controlled trial was conducted between 1989 and 1990 using an IVIG from the same manufacturer (Gamimune N, Cutter Biological, Miles, Inc., Berkeley, CA) to evaluate protection against RSV-induced disease (62). During 2 RSV seasons, a total of 49 children with severe congenital heart disease or bronchopulmonary dysplasia were randomized to receive monthly infusions of IVIG at a dose of 500 mg/kg or to be followed as controls. There were six RSV infections in the prophylaxis group and six RSV infections in the control group. There was a trend toward less severe RSV disease in the IVIG recipients as determined by the length of hospitalization. In contrast to 51 hospital days among 4 RSV infected controls, four of 6 IVIG recipients were hospitalized for a total of 35 days due to RSV illness. The average peak serum RSV neutralizing titer was 1:124 with trough titers of 1:57. Although a significant difference between groups could not be demonstrated, there was a trend toward fewer hospital days in the IVIG recipients. Failure to demonstrate a significant difference between groups was most likely due to an inability to attain a sufficient titer of RSV neutralizing antibody.

These results suggested that an IVIG preparation with a higher titer of RSV neutralizing antibody would be necessary to provide more effective prophylaxis against RSV disease. An RSV hyperimmune globulin was prepared at the Massachusetts Public Health Biologic Laboratories from human plasma selected because of a high titer of neutralizing antibodies to RSV. The RSV neutralizing antibody titer ranged from 1:2400 to 1:8073. Using this product, a randomized, blinded, multi-institutional trial was conducted over three respiratory virus seasons to evaluate efficacy and safety in three groups of high risk children: congenital heart disease, bronchopulmonary dysplasia and prematurity (63). Two hundred and forty nine infants and young children received monthly infusions between November and April during three consecutive respiratory virus seasons. Participants were randomized to receive RSVIG at 750 mg/kg, 150 mg/kg or no immune globulin. Infants were seen when symptoms developed and respiratory status was assessed in a blinded fashion. In the high dose group there were fewer RSV lower respiratory tract infections (P=0.01), fewer hospitalizations (P=0.02) and fewer hospital days (P=0.02) than in the control group. In the low dose group, statistical significance was not obtained in any of these parameters. The trough serum titers in the high dose group generally exceeded 1:200. Thus, this trial demonstrated that a hyperimmune RSV globulin which is able to maintain neutralizing serum titers greater than 1:200 reduces both the incidence and severity of RSV illness.

In January 1996, RSVIG was approved by the FDA for immunoprophylaxis of two groups of children known to be at high risk of severe RSV disease. In addition to the study by Groothuis et al. (64), supporting data came from 3 additional trials indicating that polyclonal, hyperimmune RSVIG has a role in prevention of disease in carefully selected infants with prematurity who either have or do not have bronchopulmonary dysplasia. The largest trial included 510 infants who were randomized to either placebo infusions or to 750 mg/kg RSVIG on a monthly basis during the respiratory virus season. Perhaps, the most striking data from that trial indicated that the total days of hospitalization due to any respiratory illness was reduced from 317 days/100 control children to 170 days/100 children who received prophylaxis. This observation suggests that the polyclonal product was useful both in reducing disease severity of RSV as well those due to other respiratory viruses.

This polyclonal immunoglobulin represents a first generation product that is likely to be replaced by alternative approaches to immunoprophylaxis. The disadvantage of hyperimmune RSVIG is that it must be administered intravenously and that a dose must be given every 4 to 5 weeks in order to sustain a sufficiently high titer of neutralizing antibodies to reduce the risk of the disease. Two alternative therapies under investigation include monoclonal IgG and monoclonal IgA antibodies directed against the F protein. The potential advantage of this approach is that a monoclonal antibody can be administered less frequently than once a month and still maintain a protective titer. It is likely that the antibody can be administered by an intramuscular route rather than intravenously and still produce a protective titer. An alternative approach is the use of a IgA monoclonal antibody which could be administered topically to the mucous membranes of the upper respiratory tract. While it is still early to discern the practicality of monoclonal antibody therapy in preventing RSV disease, such therapy presents a promising next step in the control of RSV infections, the most common respiratory pathogen in children.

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