Rotavirus
A new vaccine to prevent rotavirus will save
children's lives around the world
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A Timeline History of the Rotavirus Vaccine
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1963
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Rotavirus identified in animals. |
1973
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Human rotavirus identified. |
1981
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Richard Ward, PhD, begins studying
rotavirus. |
1983
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David Bernstein, MD, begins to collaborate with
Dr. Ward. |
1988
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After evaluating a vaccine that is a failure,
they develop a concept for a candidate
vaccine. |
1989
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They collect a sample from one child and grow
the virus over and over in the lab to produce a
weakened strain. |
1994
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First trials (Phase I) in adults to test
vaccine safety. |
1995
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Cincinnati Children's licenses vaccine to AVANT
Immunotherapeutics. |
1995
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First trials in infants. |
1996
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Larger trials (Phase II) begin, testing
effectiveness in infants at four centers across the
US. |
1997
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AVANT sublicenses vaccine to GlaxoSmithKline
(GSK). |
1999
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GSK begins Phase I and Phase II studies in
Europe, Asia and Latin America. |
2003
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Phase III trials begin; 60,000 children in 12
Latin American countries to be involved in the
trials. |
2003
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Vaccine submitted for licensure in Mexico. |
2004
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Rotarix" approved for licensure in Mexico. |
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Niaryah had a bad stomach infection last winter. Bad enough to
put the 1-year-old in the hospital for three days.
"She started throwing up and having diarrhea. We flew through
diapers," her mother, Kanisha Pryor, recalls. "She couldn't keep
anything down."
When the symptoms did not get better after a few days, Kanisha
took Niaryah to the doctor. Her pediatrician sent her to the
Emergency
Department at Cincinnati Children's Hospital Medical Center,
where Niaryah received intravenous (IV) fluids for dehydration. She
went home that day, but the bug was still working on her. Two days
later, she was back in the Emergency Department for more fluids,
and this time she was admitted to the hospital.
"She had no energy. She wouldn't play. She wouldn't eat," her
mother says. "She had bag after bag of IV medicine. It scared me. I
just hated to see her like that."
The bug that caused so much vomiting and diarrhea was rotavirus
— the most common cause of gastroenteritis in infants and
young children. There's no treatment for rotavirus infection other
than to give rehydration fluids to replace the water and
electrolytes the children lose.
A Worldwide Problem
It may seem like an exaggeration, but almost every child in the
world gets infected with rotavirus at least once, usually by age 5.
The most severe illness occurs after the child's first infection,
which typically is before age 2. The virus infects children in
urban, suburban and rural settings alike, in rich industrialized
countries and poor, underdeveloped countries. It's universal, but
the outcome is not the same everywhere.
In the United States, rotavirus causes approximately three
million cases of gastroenteritis a year, resulting in 500,000
visits to the doctor. Usually the diarrhea and vomiting last a
short time and can be cared for at home, but many children, like
Niaryah, require more aggressive care. In the US, there are an
estimated 50,000 hospitalizations a year for rotavirus, and —
sadly — 20 to 40 deaths from the resulting dehydration.
But in third-world countries, the toll is devastating. Every
year 500,000 children die of rotavirus infection because medical
care is not available.
Imagine if we could change the outcome by immunizing children
against rotavirus.
That is the dream of researchers at Cincinnati Children's.
Richard Ward, PhD, and David Bernstein, MD, have developed a
rotavirus vaccine that may soon be commercially available around
the world. In July 2004, Mexico became the first country to approve
the vaccine, which will be sold under the name Rotarix". Successful
launching in Mexico is expected to pave the way for rapid approval
elsewhere, beginning with Latin American countries.
Commercial use of this vaccine is the spectacular culmination of
20 years of research that took it from the laboratory to worldwide
clinical trials in the United States, Europe, Latin America, Africa
and Asia.
The Story Begins in the Lab
Dr. Ward began doing research on rotavirus infections in 1981,
soon after he joined the J.N. Gamble Institute for Medical
Research, now part of the Cincinnati Children's Division of
Infectious Diseases.
The Gamble program is one of only a few centers in the United
States that carries out all aspects of vaccine research, from basic
laboratory studies to vaccine evaluation and development through
vaccine trials in adults and children.
Previously Dr. Ward had done environmental research for the
Environmental Protection
Agency. Now, as part of a clinical research program, he asked,
"What could I do that would be of value? It seemed obvious to me
that I should work on rotavirus." He started doing molecular
studies to understand immune response. In 1983, Dr. Bernstein
joined the Gamble Institute. He was interested in testing vaccines,
and the two men began their collaboration.
"When we started, the odds were over 100 to one against us," Dr.
Bernstein says. Very few vaccines even make it to the first phase
of human testing.
The rotavirus vaccine is being tested in 12 Latin
American countries. Above and with her mother is the
first child in Nicaragua to be vaccinated.
Drs. Bernstein and Ward know
that their research could not have been successful
without the cooperation of families in Cincinnati who
took part in the earliest stage of testing.
"I want to thank the parents
in Cincinnati who participated in the trials," says Dr.
Bernstein. "Someone had to be the first child to take it.
The involvement of hundreds of kids in Cincinnati may
prevent 500,000 deaths a year in kids around the
world."
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Learning Step by Step
Their first study in humans was to give rotavirus to adult
volunteers. They wanted to know what was the smallest dose that
would cause infection and better understand what protected people
from this infection.
In 1988, they began a study evaluating a vaccine being developed
at another center. They recruited families for a vaccine trial and
gave the vaccine to 220 children in Cincinnati. "It was an absolute
failure," Dr. Bernstein recalls. "But we learned a lot." They
learned how the body responds and which proteins of the virus are
important. They did a follow-up study and found that children who
were infected in 1988 didn't seem to get infections the next
year.
Gradually they were coming to conclusions about rotavirus and
thought they had a promising idea for
a vaccine.
Their plan was to develop a vaccine candidate based on a live
but weakened strain of the human rotavirus that seemed to have
protected children during the 1988-89 study. They took the virus
from a child who became infected with rotavirus in 1989. That
specimen became the basis of their vaccine.
To weaken the virus, they grew it over and over in the lab,
selecting for mutations that made it grow well in cell culture but
not well in children. The goal was to develop a strain that would
produce an immune response without causing illness.
The work moved forward steadily. With support from the National Institutes of Health, Phase I testing in
adults began in 1994. (Phase I trials test a new medication in a
small group of people to evaluate its safety.) Results were good.
The weakened form of the virus did not cause diarrhea and vomiting,
and it induced an immune response.
Next came a small trial in children. Families recruited through
several Cincinnati pediatricians' offices volunteered to
participate. Again the results were good.
As the work progressed, it became clear that the researchers
needed a commercial partner that could sponsor larger, Phase II
clinical trials. (Phase II trials test a new medication in a larger
group of people to evaluate its effectiveness.) In 1995,
Cincinnati Children's licensed the vaccine to AVANT
Immunotherapeutics, Inc., an international company that develops
vaccines.
The Phase II study tested the vaccine's effectiveness in infants
at four research centers in the United States. This study showed
that the vaccine protected children from getting rotavirus
disease.
At this point an even bigger partner was needed to conduct the
large-scale trials necessary to license a vaccine and eventually
market it. (Phase III clinical trials test a new medication in
large groups to confirm its effectiveness, monitor side effects and
collect information that will allow the drug to be used safely.)
AVANT sub-licensed the vaccine to one of the major vaccine
companies in the world, GlaxoSmithKline (GSK). GSK has been
conducting international clinical trials since 1997. The Phase III
trials involve 60,000 children; half get the vaccine and half get a
placebo.
Sometimes tests in large numbers of children turn up problems
not identified in earlier stages of testing. But studies of
Rotarix" continued to demonstrate that it was effective and safe.
By 2003, GSK had tested the vaccine in 5,000 children and announced
that it expected to begin filing applications for approval in 2004.
An additional 30,000 children in 12 Latin American countries have
now taken the vaccine. GSK has begun building a facility in Belgium
that will be used, in part, to produce Rotarix".
Drs. Bernstein and Ward know they have made a contribution to
the well-being of children, in the tradition of one of the greatest
scientists in the history of Cincinnati Children's — Albert
Sabin, MD, whose vaccine conquered polio. Asked how he feels at the
prospect of the rotavirus vaccine saving lives around the world,
Dr. Bernstein acknowledges, "I'll be very happy with my life if
this is all that I achieve."
