Researchers solve failed vaccine mystery

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Researchers solve failed vaccine mystery

Published: Monday, 15-Dec-2008

Medical Research News

Research led by s 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 Polack, M.D., 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

of s Hopkins; Herng-Yu Chang and Wayne Mitzner, of the s

Hopkins Bloomberg School of Public Health; Florencia Delgado, Silvina

Coviello, A. Clara Monsalvo, Batalle, Leandro of the INFANT

Foundation, Buenos Aires, Argentina; Alfonsina Trento and Melero, of

Instituto de Salud III, Madrid, Spain; Ravetch, of

Rockefeller University, New York; Pablo Irusta of town University

School of Medicine. The research was funded by an NIH grant and money from

the and Carol McCann Innovative Research Fund for Asthma and

Respiratory Diseases.

http://www.jhmi.edu