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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