RISBANE,
Calif., Feb. 23 — The first AIDS vaccine ever to be tested in a large number
of people has failed, over all, to protect them from infection with the
virus that causes the disease, the company that makes it,
VaxGen, said today.
The vaccine did, however, seem to significantly lower the infection rate
among African-Americans and other non-Hispanic minorities participating in
the trial, the company said.
Its researchers called this finding totally unexpected and said they were
at a loss to explain why there would be ethnic differences in response to
the vaccine. They conceded that the findings, though statistically
significant, might change if the vaccine were tested among more members of
minorities, who were only a small fraction of the people in the trial.
"We're skeptical about the small numbers," said Dr. Donald N. Forthal,
chief of infectious diseases at the University of California at Irvine and
one of the investigators in the trial. "On the other hand, this is a very
intriguing finding."
The findings suggest that the vaccine failed in its prime objective. The
vaccine showed virtually no effectiveness over all, making it extremely
unlikely that it could be approved for use without further trials. But the
data offer clues to possibly productive avenues of research.
Dr. José Esparza, the leading vaccine expert at the United Nations AIDS
agency in Geneva, said he was very encouraged by the results.
"This is the first demonstration of protection in humans, and one of the
most significant findings in H.I.V. vaccine research in many years," Dr.
Esparza said. Though the vaccine is "not the final product that we need for
public health use" and is not ready to be licensed for sale, he said, it
"should give encouragement to all vaccine developers."
Dr. Esparza said it was imperative to conduct more vaccine trials,
especially in Africa.
VaxGen, a small biotechnology company here, was formed to carry the
vaccine forward after the National Institutes of Health and the company that
invented the vaccine,
Genentech, decided it was not worthy of
clinical trials.
The fact that the vaccine advanced to such large trials was largely the
result of the doggedness of the company co-founder and president, Dr. Donald
P. Francis, an epidemiologist and virologist who formerly worked at the
Centers for Disease Control and Prevention, where he was one of the first
experts to see the dangers of AIDS when the disease became known more than
20 years ago.
The vaccine, known as Aidsvax, is made from a protein called gp120, the
same protein that protrudes from the surface of H.I.V. and helps the virus
dock with cells of the body's immune system. The protein in the vaccine is
made in genetically engineered hamster ovary cells. Since the vaccine
consists of only one protein and not the whole virus, it cannot give someone
AIDS. But it is designed to provoke the immune system into making antibodies
that will latch on to the gp120 protein in the real virus and the virus from
infecting immune cells.
Most mainstream AIDS researchers have said they do not believe the
approach will succeed. For one thing, HIV mutates rapidly and there are a
number of subtypes of of the virus, which themselves may have many different
strains. VaxGen's vaccine is designed to elicit antibodies to only two
strains of subtype B, the type most prevalent in North America and Europe.
Even VaxGen said it was hoping its vaccine would prevent 30 percent of
infections, which is far lower than for most vaccines, but could have been
enough for approval. But even that level was not attained.
Many scientists now say a more effective vaccine approach would be to
spur a second arm of the immune system, the so-called killer T cells, to
destroy cells infected by the AIDS virus.
These and other newer vaccines are under development, but they are all
several years behind Aidsvax. Because Aidsvax was the first to be tested in
a so-called Phase 3 clinical trial, usually the final testing stage for
marketing approval, interest in the results has been intense.
The trial took place at 59 sites, mostly in the continental United
States, with some in Canada, Puerto Rico and the Netherlands. It involved
5,400 volunteers, mostly men, none of whom were infected with H.I.V. at the
start of the trial.
About 5,100 of the participants were gay men who said they had had sex
with many other men. The other 300 were women who were considered at high
risk of infection through sexual contact.
Two-thirds of the participants were given a series of seven shots over
three years, while the other third were given the same number of placebo
injections. The goal was to see if the people who received the vaccine would
have a lower rate of infection. In the overall population of participants,
5.8 percent of those who received the placebo became infected, compared with
5.7 percent of those who received the vaccine. The difference was not
statistically significant.
But among black, Asian and other minorities the rate of infection was
only 3.7 percent in the vaccinated group, compared with 9.9 percent in the
placebo group.
That meant, after statistical adjustments, that the vaccine reduced the
infection rate in that group by 66.8 percent. The numbers were small, about
500 patients, but statistically significant. There was a less than 1 percent
chance that the findings were the result of chance.
All of the participants were counseled on safer sex and other ways to
protect themselves from infection with H.I.V. Some critics of vaccine trials
have said they feared that participants might abandon such protective
measures out of a false hope that they had received a vaccine that would
protect them. This study found no evidence for these fears.
Researchers have long wondered whether socioeconomic factors were enough
to explain the relatively high rates of infection among Africans and
African-Americans. VaxGen researchers said today that, in view of the new
findings, they would seek to do more research into possible genetic factors
that might affect susceptibility to the AIDS virus.
The VaxGen researchers also said they would study blood samples from
participants who received the vaccine, and would compare antibodies from
those who became infected with antibodies of those who remained free of the
virus. They hope to identify which antibodies actually protect against
infection, rather than simply signaling that infection has occurred. The
identification of such antibodies, known as correlates of immunity, might
greatly assist future vaccine development.
Aidsvax is by far VaxGen's most important product. It is unlikely now
that the data would be sufficient to get the vaccine approved for use as
early as the end of 2004, as the company had hoped. In interviews today,
though, VaxGen officials did not concede this, and said they would talk to
the Food and Drug Administration before deciding on their next move.
For Dr. Esparza of the United Nations, these results were important.
VaxGen sent the data on the vaccine trial to Dr. Esparza on Friday for
review by United Nations statisticians, who confirmed the VaxGen
calculations, Dr. Esparza said today.
Dr. Esparza said the United Nations AIDS program would soon convene a
number of experts to discuss what steps should be taken next. For one thing,
he said, it is important to learn whether the differences in response to the
vaccine were the result of ethnicity alone or differences in behavior
patterns in ethnic groups.
"We have to answer the questions," Dr. Esparza said. "Why only in blacks?
Is heterosexual transmission the explanation for what we are seeing? Would
this vaccine work in Africa? Would an equivalent vaccine based on strains
circulating in Africa have the same effect?"
Dr. Walter R. Dowdle, the chairman of the independent committee VaxGen
established to oversee the statistical analysis of study — a standard
practice in drug trials — said the company's "conduct of this trial lived up
to the highest standards of scientific integrity."
But he would not comment on the company's interpretation of its results
because he viewed his role as limited to studying the integrity of the data.
Dr. Dowdle, a former deputy director of the disease control centers, said
the committee was still reviewing data from a second part of the VaxGen
study, being conducted in Thailand.
Results of the Thai trial, which involves 2,500 injecting drug users, are
expected late this year.
