Hopkins-Led Team Solves Failed Vaccine Mystery

Research led by Johns Hopkins Children's Center scientists has figured out why a respiratory syncytial virus vaccine used in 1966 to inoculate children against the infection instead caused severe respiratory disease and effectively stopped efforts to make a better one. The findings, published online on Dec. 14 in Nature Medicine, could restart work on effective killed-virus vaccines not only for RSV but other respiratory viruses, researchers say. The new findings also debunk a popular theory that the 1966 vaccine was ineffective because the formalin used to inactivate the virus disrupted critical antigens, the substances that stimulate the production of protective antibodies.

Instead, researchers said, the problem occurred when the antibodies created by the vaccine failed to successfully bind to the real virus after exposure to it, thereby incapacitating it. Like vaccines against influenza and polio, the 1966 formalin-inactivated RSV vaccine produced antibodies, but these turned out to be defective ones with poor virus-binding ability.

"We have found the root cause of the problem, and in doing so we have uncovered clues that will help us design even safer and more effective vaccines in the future," says senior investigator Fernando Polack, MD, an infectious disease specialist at Hopkins Children's.

More specifically, in a series of experiments, the research team discovered that the old RSV vaccine failed to trigger a "signaling" mechanism — called toll-like receptor activation — that helps the immune system recognize a virus and mount a defense against it. Toll-like receptor activation is the first in cascade of immune system responses that occur after infection, firing off signals to other immune cells telling them to produce and release antibodies.

First, the team compared immune system response in three groups of mice: those vaccinated with a placebo, those with a weakened form of the RSV virus, and those with inactivated or killed-virus vaccines. Researchers found that in the last group, the toll-like receptor activation was weak and led to the production of defective antibodies.

Next, they infused the vaccine with a substance that stimulates toll-like receptor activation to see if it would created antibodies better equipped to bind to and neutralize the virus. Indeed, mice vaccinated with the toll-like receptor stimulating form of the inactivated vaccine produced antibodies with better binding and virus-neutralizing ability. Mice immunized with this form of the vaccine had milder symptoms and less inflammation in the bronchi and the lungs when infected with the real RSV.

RSV is the most common culprit of serious viral infections in newborns and infants younger than1 year, and the leading cause of hospitalization in this age group. Half of all infants contract RSV during their first year of life, and hospitalizations for children with RSV have more than doubled in recent decades, researchers say. To date, there is no vaccine against RSV.

Other investigators in the study: Guillermina Melendi and Johanna Zea Hernandez of Johns Hopkins; Herng-Yu Chang and Wayne Mitzner, of the Johns Hopkins Bloomberg School of Public Health; Maria Florencia Delgado, Silvina Coviello, A. Clara Monsalvo, Juan Batalle, Leandro Diaz of the INFANT Foundation, Buenos Aires, Argentina; Alfonsina Trento and Jose Melero, of Instituto de Salud Carlos III, Madrid, Spain; Jeffrey Ravetch, of Rockefeller University, New York; Pablo Irusta of Georgetown University School of Medicine. The research was funded by an NIH grant and money from the Thomas and Carol McCann Innovative Research Fund for Asthma and Respiratory Diseases.