Research shows why 1960s RSV shot sickened children

NEW YORK (Reuters Health) - Researchers from Johns Hopkins have solved the decades-old mystery of why a vaccine developed to prevent a common childhood viral infection wound up making kids sick.

The findings provide important clues to how to develop a safe, effective vaccine against respiratory syncytial virus (RSV), the main cause of wintertime hospital stays among babies and young children worldwide, Dr. Fernando P. Polack, the lead researcher on the study, told Reuters Health.

“A big concern for the scientists involved in RSV vaccine development is to make sure we do not repeat the same situation again,” said Polack, who is also affiliated with the INFANT Foundation in Buenos Aires.

In the late 1960s, children in Washington, DC received an RSV vaccine in which the virus was inactivated with formalin. Eighty percent of the children given the shot were hospitalized with severe respiratory disease, and two died. Many scientists had thought the formalin was responsible for the vaccine’s problems, but the chemical has been used safely in other vaccines.

For eight years, Polack and his team have been investigating why the vaccine caused the illness, known as enhanced respiratory disease, or ERD. They started by examining tissue from the lungs of the two patients who died, and comparing the effects of the vaccine to RSV itself in mice.

The problem, they report this month in the journal Nature Medicine, was that the children’s antibodies were not binding strongly enough to the inactivated virus to produce a protective immune response. Instead, the antibodies were dragging the dead virus with them, triggering a massive attack by other arms of the immune system.

The inactivated vaccine was only weakly stimulating molecules on the surfaces of cells that are responsible for recognizing infectious invaders and triggering an appropriate immune response, the researchers say. So an effective vaccine would need to do a better job of stimulating these molecules, known as Toll-like receptors, Polack explained.

Most likely, the researcher said, making an effective and safe RSV vaccine will require developing an attenuated form of the virus, meaning a strain that is too weak to cause infection but active enough to stimulate the Toll-like receptors adequately.

Such a vaccine is sorely needed, Polack said. Half of children develop RSV infections before their first birthdays, the researcher noted, while by age 2, 95 percent have been infected. About half the time, the infection only produces a cold, while in the other half of cases the infection enters the lungs and causes infection of the small airways, or bronchiolitis. A child will usually get better on his or her own, but in about one in 100 cases, the child will need to be hospitalized and be given oxygen. RSV kills a half million people worldwide every year.

SOURCE: Nature Medicine, online December 14, 2008.