Johns Hopkins Gazette | January 5, 2009
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The newspaper of The Johns Hopkins University January 5, 2009 | Vol. 38 No. 16
Johns Hopkins-led Team Solves Mystery of Failed Kids Vaccine

By Katerina Pesheva
Johns Hopkins Medicine

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 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," said senior investigator Fernando Polack, an infectious disease specialist at Johns Hopkins.

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, which helps the immune system recognize a virus and mount a defense against it. Toll-like receptor activation is the first in a 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, with a weakened form of the RSV virus and 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 create 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 than 1 year, and is 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 from Johns Hopkins were Guillermina Melendi and Johanna Zea Hernandez, both of the School of Medicine; and Herng-Yu Chang and Wayne Mitzner, both of the Bloomberg School of Public Health. Other researchers were from the INFANT Foundation, Buenos Aires, Argentina; Instituto de Salud Carlos III, Madrid, Spain; Rockefeller University, New York; and the 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.


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