By Thomas M. Burton
The Ebola virus outbreak in West Africa created a rare
opportunity: New vaccines could be tested, and if they worked,
serve as a firewall in future epidemics.
It now appears this chance is slipping away amid public health
officials' squabbles over the right way to test vaccines. As a
consequence, there may never be a definitive answer about the
vaccines' effectiveness.
The study generally regarded as the most scientifically solid,
which is run by the U.S. National Institutes of Health, began in
Liberia but is struggling as new Ebola cases have subsided. The
other studies, in Guinea and Sierra Leone, fall short of the
scientific gold standard--a randomized, placebo-controlled
study--partly because some medical officials have opposed giving a
placebo to anyone at risk for the deadly disease. As a result, this
outbreak could end without the vaccines' being rigorously
tested.
"I don't see how it's going to happen unless our trial gets
expanded," said Dr. H. Clifford Lane, deputy director of the NIH's
National Institute of Allergy and Infectious Diseases (NIAID), who
is helping to lead the trial in Liberia. He said expanding the
study to Guinea, or perhaps Sierra Leone, "is the right thing to
do."
Just this week, following inquiries by The Wall Street Journal,
the World Health Organization said it and the government of Guinea
will allow the NIH study to expand there. However, a senior Guinean
health official said in an interview that no such decision has been
made. Some other doctors in the Guinea trial oppose NIH study
expansion into Guinea because it might harm their own research.
Randomized, placebo-controlled trials are overwhelmingly
regarded as the best scientific way to evaluate medical products.
People are randomly assigned to get the product or a placebo--in
this case, a placebo vaccine. Ideally, such a study is
"double-blind," meaning that neither patients nor doctors know who
gets the real thing.
At NIH, NIAID Director Anthony S. Fauci and Dr. Lane say a
placebo-controlled study is both essential and ethical because
otherwise no one would know if the vaccines actually are working.
Early results of the NIH trial show it is safe, but testing hasn't
determined whether the experimental vaccines can actually protect
against Ebola.
The NIH research in Liberia was set to enroll about 27,000
health-care workers. They were to be given a vaccine developed by
NIH and GlaxoSmithKline PLC, another vaccine from the Public Health
Agency of Canada, Merck & Co. and NewLink Genetics Corp., or a
placebo.
But Ebola rates have plummeted since last year. The WHO reports
that as of the week ended April 5, there were 21 new cases in
Guinea, nine in Sierra Leone and none in Liberia.
In Guinea, the WHO is conducting a study along with Doctors
Without Borders and other groups. They are using a design called
"ring vaccination." When a new Ebola case appears, people in
contact with that person get vaccinated with the Merck/NewLink
vaccine, establishing a "ring" around that first case. The next
test group is formed when a person in, say, another village gets
Ebola; people in that person's ring get vaccinated 21 days later.
The next ring is vaccinated immediately, the next 21 days later,
and so on.
The researchers say the decision about giving an immediate
vaccination or waiting 21 days--the end of the estimated incubation
period for Ebola--produces a randomized study that could find a
difference in the rate of susceptibility to Ebola from ring to
ring. But Dr. Lane sees a big flaw: After 21 days, all of the test
subjects have received a vaccine, making it difficult to tell
differences between those who were inoculated and those who
weren't.
Dr. John-Arne Rottingen of the Norwegian Institute of Public
Health, a leading figure in the Guinea study, said researchers in
Guinea stayed away from using a placebo because they feared "that
the outbreak would really continue into an epidemic." He said the
Guinean study nevertheless could produce definitive results about
the vaccine by late summer, and argues against allowing NIH to
expand its research into Guinea. He and others say people in Guinea
might not be willing to be in a placebo-controlled study.
"I don't think it's feasible to do the NIH study at the same
time as the ring vaccination study," he said, partly because there
may not be enough patients for both.
Study participants said they shied away from using a placebo
because Guinean doctors didn't want it. Neither did Doctors Without
Borders.
"When there is a placebo, one person might get an effective
vaccine, and another person might not get the vaccine," said Annick
Antierens, the international group's deputy medical director. She
said the humanitarian group "is reluctant to be engaged in a
randomized, controlled trial in an Ebola context." Still, Dr.
Antierens and colleagues say their study is scientifically
rigorous.
"The tragedy to me is that the protocol designs are not
equivalent," said the NIH's Dr. Lane. The Guinea study, he said,
"has the look of a drug distribution system in the guise of
research. We don't know that any of this stuff works, and they're
pumping it into people."
Mandy Kader Konde, chairman of the Ebola Research Commission in
Guinea, said some doctors in his country also have had concerns
about giving some patients a placebo. Dr. Konde said it is "under
discussion" to possibly allow the NIH to expand its research into
Guinea but that, "We have to see a research protocol" first.
In Sierra Leone, the U.S. Centers for Disease Control and
Prevention is helping run a study in which about 6,000 health-care
workers get vaccinated with the Merck/NewLink vaccine, either right
away or up to six months later. But all participants will know if
they were vaccinated or not.
The main problems with this method are that vaccinated people
could engage in riskier behavior, or that their bosses might order
them into riskier situations, biasing the results. Also, those who
weren't might be more careful.
"We are aware that there are biases, and possible differences in
behavior," said Dr. Anne Schuchat, the CDC official heading its
Sierra Leone effort.
"There is no doubt that the quickest, most definitive way to
determine whether an Ebola vaccine is truly effective" and not
harmful, said the NIH's Dr. Fauci, "is to perform a double-blind,
randomized, placebo-controlled trial."
Write to Thomas M. Burton at tom.burton@wsj.com
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