Still long road ahead in development of prophylaxis for RSV

BOSTON — The future of prophylaxis for respiratory syncytial virus (RSV) may lie in nasal vaccines and expanded use of palivizumab (Synagis, MedImmune).

The first attempt to gauge the efficacy of RSV vaccination occurred in 1964. Children in the initial study who received the vaccine had a worse outcome than control children who received no vaccine or a parainfluenzae virus vaccine. “The children who received the RSV vaccine had a higher mortality and hospitalization rate in subsequent seasons when they became infected with RSV,” said H. Cody Meissner, MD, chief of the department of pediatric infectious disease at Tufts-New England Medical Center. “This early failure set back the development of RSV vaccines. Even today, we continue to feel the impact.”

Will we get one?

It may still be several years before physicians see a safe and effective vaccine that prevents RSV infection in children. One reason is the necessity of immunizing infants in the first month after birth. “Hospitalization due to RSV generally occurs in the first six months of life,” Meissner said here at the Annual Meeting of the American Academy of Pediatrics. “So the vaccine must be administered early in life.”

There are several other stumbling blocks to vaccine development. Maternal antibodies neutralize killed vaccines, to some extent, and may have the same effect on live attenuated vaccines. Additionally, the immune response to certain glycoproteins in the first few months of may be limited.

“We know that immunity to RSV is complex and that there are at least two strains of RSV based on the G glycoprotein,” he said. “There are also numerous subtypes of RSV that the vaccine would have to be active against. And there are safety concerns, as well. So there are a lot of problems in developing an effective RSV vaccine.”

Nasal vaccines and ribavirin

The FDA is reviewing a cold-adapted influenza vaccine that is administered as an intranasal spray. The vaccine replicates at 32° C to 34° C, the temperature of the nasal turbinates. The virus will replicate on the nasal mucosa, stimulate an immune response that mimics a natural infection and protect the individual from influenza when the virus is encountered in the community.

“This is important because there are trials underway looking at a similar approach for RSV vaccine,” he said. “The problem so far has been that even the attenuated RSV vaccines cause symptoms in very young children. So it is necessary to further attenuate those temperature-sensitive mutant strains. The problem is that if the virus is attenuated too much immunogenicity can be lost.”

Ribavirin is an option for RSV treatment. Most institutions, however, do not use ribavirin due to its cost. “It has not been shown to reduce the length of hospitalization,” he said. “It may slightly improve oxygenation in the blood, but whether or not it reaches a clinically significant benefit in oxygenation remains controversial.”

Other alternatives

RSV immune globulin IV (Respigam, MedImmune) was the first agent proven to be efficacious against RSV and is still available. It is seldom used today, however, because it must be administered intravenously and due to other problems associated with its use. “For a while, people suggested that [Respigam] not only protected against RSV, but parainfluenzae virus, adenovirus and other respiratory viruses as well,” he said. “But the concern is that Respigam is not selected for antibodies to any virus other than RSV. So the lot of Respigam that is being administered may not have a sufficient titer of antibodies to protect against other respiratory viruses.”

RSV immune globulin IV has been largely replaced by palivizumab (Synagis, MedImmune). The RSV impact trial in 1998 demonstrated that palivizumab is effective in reducing RSV hospitalization. Among all infants in the trial there was a 55% reduction in hospitalization.

“The control group in this trial was hospitalized at a rate of 10.6%, and the palivizumab group was hospitalized at a rate of 4.8%,” Meissner explained. “In subsequent phase-4 trials, the hospital rate was similar or even lower. While these post marketing studies are not controlled, the results suggest that the efficacy rate is at least as good as it was in the clinical trial.”

Studies have also shown that premature children without lung disease or broncopulmonary dysplasia have an 80% reduction in hospitalization with palivizumab. “Based on this and other data, it is safe to say that palivizumab reduces the hospitalization rate due to RSV even in high-risk children,” he said.

Buck stops here

One of the key issues surrounding palivizumab use is cost. Palivizumab does not reduce RSV upper respiratory tract infection. It reduces lower respiratory tract disease due to RSV. Palivizumab works to keep the infection confined to the upper airways. Much higher doses of circulating antibody are necessary to prevent upper airway infection.

“There are going to be breakthrough infections,” he said. “Children still will be hospitalized due to RSV. Among children who experience breakthrough RSV infections despite palivizumab, there is no apparent difference in the severity of infection, according to days in the intensive care unit, days of supplemental oxygen, and length of stay.”

It will be difficult to prove that palivizumab is cost effective. “However, these many interventions that are not cost effective and yet have a significant role in minimizing disease severity,” he said. “The issue becomes one of deciding where to draw the line. The Committee on Infectious Disease is in the process of rethinking the recommendations for the use of palivizumab and the selection of children who are most likely to derive benefit.”

For more information:

• Meissner HC. Management of RSV: From steroids to albuterol and synagis. Presented at the 2002 Annual Meeting of the American Academy of Pediatrics. Oct. 18-23, 2002. Boston.

• Dr. Meissner has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.