Large Trial Finds AIDSVAX Vaccine Fails to Stop
Infection
By Andrew Pollack
and Lawrence Altman
The New York Times
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.
GMHC Criticizes VaxGen for Obfuscation of Trial Results of Its AIDS Vaccine
Gay Men's Health Crisis (GMHC), the nation's
oldest AIDS service organization, today criticized VaxGen, the maker of the AIDS vaccine
candidate, AIDSVAX, for obfuscation of its trial results. Despite showing no effect
overall in protecting against infection with HIV, the company highlighted a subset of
results which seemed to show efficacy in African-Americans and Asians.
GMHC looks forward to the day when HIV will be
a preventable disease and is a strong supporter of AIDS vaccine research, including
VaxGen's research efforts. However, the conduct of vaccine research must be held to the
highest standards of ethics and accuracy, as millions of lives depend on the results of
these scientific studies.
"Subset analyses are problematic in the
best of cases. With small numbers of African-Americans and Asians in the trial and wide
confidence intervals associated with the results, making any statements about efficacy in
this subpopulation is grossly premature," said Gregg Gonsalves, Director of Treatment
and Prevention Advocacy at GMHC. VaxGen's assertions of its vaccine's efficacy among
blacks are based on 13 infections in this population in a trial of more than 5000
participants. The assertions about efficacy among Asians are based on only 4 HIV
infections in the study.
GMHC is particularly worried that the
"spin" of these results will sow confusion in communities particularly at risk
in the United States, specifically African-Americans. "VaxGen has not proven that
this vaccine is effective among African-Americans or Asians, yet preliminary press reports
are claiming that this may be the case," said Ana Oliveira, GMHC's Executive
Director. GMHC is asking the company to clarify its statements on the subset analysis of
African-Americans and Asians, particularly its claims of efficacy for this population, and
is calling on the media to look more closely at the data before drawing any conclusions.
GMHC also has concerns that VaxGen's
interpretation of its results will also provide false hopes in Africa and Asia, where the
rates of HIV infection are highest in the world, and which will be the major market for
AIDS vaccines. It is important to note that the vaccine in this study did not use strains
of HIV prevalent in Africa and Asia.
GMHC fears that claims of partial protection for African-Americans and Asians, by
extension, could imply that Africans and Asians living outside of the United States could
see some protection from this vaccine. GMHC is urging the company not to overstate the
promise of its product based on scant and inconclusive data.
02/25/03
Sources
- A Pollack and L Altman. Large Trial Finds AIDS Vaccine Fails to Stop Infection. The
New York Times. February 24, 2003.
- Gay Men's Health Crisis. GMHC Criticizes VaxGen for Obfuscation of Trial Results of Its
AIDS. Press Release. February 24, 2003.
http://www.hivandhepatitis.com/vaccines/022503a.html
VaxGen's AidsVax: midnight release of trial
data catches critics napping
The failure of AidsVax to prevent infection
with HIV - in clinical trial results published in 2003 - triggered an intense debate about
the controversial product and its manufacturer, VaxGen Inc of Brisbane, California. Mail
to this website, maintained by Brian Deer, shows that existing material on a VaxGen-AidsVax index is read by
significant numbers. This page seeks to further inform the discussion
After a well-trailed pledge
to release results of the first phase III clinical trial of a candidate vaccine against
HIV-1 at 6am ET Monday July 24 2003, VaxGen Inc of Brisbane, CA, published headline
information in a press release six hours early (midnight
ET, 6am GMT), catching the majority of specialist reporters and scientists capable of
interpreting the results, well, asleep.
So guess who wrote the headlines? Reuters and AP wire services, utilized heavily by news
organizations worldwide, lead on curious VaxGen claims, mined from intense analysis of
statistically questionable subgroups, that although AidsVax hadn't protected trial
volunteers as a whole it had shown extraordinary efficacy among selected ethnic groups.
Here's how the Reuters agency snapped the story at 12.33 am ET:
VaxGen's AIDSVAX protects blacks,
Asians
WASHINGTON, Feb 24 (Reuters) - VaxGen's AIDSVAX vaccine does not appear to protect the
general population against the AIDS virus but may protect blacks and Asians, the company
said on Monday.
And AP at 4.06 am ET:
Experimental AIDS Vaccine May Help
Some
By PAUL ELIAS
AP Biotechnology Writer
SAN FRANCISCO -- An experimental AIDS vaccine being developed by VaxGen Inc. does not
appear to protect most people from the disease, but does show promise in protecting blacks
and Asians, the company said.
USA Today was given advance
information on the results and, perhaps in gratitude, published a shallow puff for the
company. It drew extensively on quotes from Jose Esparza at UNAIDS, who had worked closely
with VaxGen vice-president Dr William Heyward, later prosecuted by the US
government for channeling millions of dollars to the company while in public service at
the Centers for Disease Control. Significantly, Esparza reveals that UNAIDS had for some
time enjoyed priviledged access to confidential market-sensitive data.
Vaccine for AIDS appears to work
By Steve Sternberg, USA TODAY
Nearly two decades after the discovery of the AIDS virus, researchers Monday report for
the first time that an AIDS vaccine can prevent infection, but with sharply different
success rates depending on race.
The first full-scale human trial of the vaccine, AIDSVAX, indicates that, although the
vaccine failed to protect whites and Hispanics, it appears to be effective in Asians and
blacks. Blacks account for half of all new infections in the USA, federal statistics show.
"The results are fascinating and surprising," says Donald Francis, CEO of
VaxGen, the Brisbane, Calif., firm that has spent 10 years and about $200 million to
develop the vaccine. "We think they're scientifically and socially important. It's at
least a beginning."
Jose Esparza, director of AIDS vaccine research for the Joint United Nations Programme on
HIV/AIDS (UNAIDS), called the finding "probably the most important accomplishment in
vaccine research in 15 years. This is the first time anyone has shown protection (against
HIV) in humans, not monkeys. The results tell us that a vaccine can protect humans against
HIV."
He says the vaccine's "remarkable" effectiveness in non-whites, especially
blacks, "obviously has worldwide ramifications." Last year alone, 3.5 million
people were infected with HIV in Sub-Saharan Africa and roughly a million in Asia. VaxGen
also is conducting a study in Thailand that is expected to be done by the end of the year.
Experts say the vaccine will have to be reformulated, though, to protect against the HIV
strains circulating in Africa.
Phillip Berman, VaxGen's vice president for research and development and the vaccine's
inventor, says researchers don't fully understand why the vaccine protected blacks and
Asians but not the others in the study. Preliminary evidence from the study, Berman says,
suggests that blacks and Asians mount a better antibody response than whites and
Hispanics.
VaxGen researchers are studying volunteers' serum, he says, to figure out what protects
blacks and Asians so they can use that information to boost the vaccine's potency.
The vaccine study involved 5,108 gay men and 309 high-risk women. The volunteers got seven
injections over three years. Two volunteers received vaccine for every one who got a
placebo. Although the vaccine failed to provide protection overall, it was 78.3% effective
in blacks and 68% effective in Asians.
Esparza says VaxGen turned a substantial amount of data over to UNAIDS for independent
statistical analysis that "confirmed the results found by VaxGen." But he added:
"We have a number of unknowns here that have to be answered by more research."
The Food and Drug Administration has said it would consider approving a vaccine that was
30% effective, but the agency won't comment on products before they're approved. Neither
Francis nor any other experts would predict how the agency would respond in this
unprecedented situation, but they said it was unlikely the vaccine would be approved soon.
"We've discussed the findings with FDA," Francis says. "We will work with
them to see what needs to be done to lead to licensure."
A more accurate picture for
those who knew where to look, however, came from the New York-based International Aids
Vaccine Initiative:
NEW YORK, 24 February 2003—VaxGen Inc. announced today that its investigational AIDS
vaccine, AIDSVAX, although safe, did not prove effective in human trials in North America
and Europe.
AIDSVAX was designed to prevent people who are uninfected with HIV from contracting the
virus or developing AIDS. AIDSVAX is the first AIDS vaccine ever fully tested in humans.
In the trial, 3330 volunteers received AIDSVAX, and 1679 received a placebo (an inactive
substance). The percentage of volunteers who received AIDSVAX and became infected with HIV
is statistically equal to the percentage of volunteers who received the placebo and became
infected with HIV. This means that the vaccine is not protective.
In response, Seth Berkley, MD, President and CEO of the International AIDS Vaccine
Initiative (IAVI), released this statement:
"The news on VaxGen's AIDSVAX is disappointing, but we are not discouraged. The
search for an AIDS vaccine will—and must—go on. A vaccine is the world's best
hope to end the spread of a virus that infects nearly 15,000 men, women and children daily
and threatens the survival of whole communities.
"Scientists remain confident that an AIDS vaccine is possible. Alternative AIDS
vaccines, employing different design strategies, are now in development, and some have
already entered human trials. These must move forward through further study, without
delay. (More information on why an AIDS vaccine is possible and what approaches are in
development.)
"The results on AIDSVAX must be further analyzed, and independently reviewed. For
example, VaxGen's preliminary analysis of the small number of nonwhite volunteers suggests
that there were fewer infections among black volunteers who received AIDSVAX than blacks
who received the placebo. However, it is difficult to draw conclusions about what this
means, given that the number of blacks in the study was so small (VaxGen's analysis is
based on just 13 infections among black volunteers, 4 in the vaccine group and 9 in the
placebo group). [Continues]
A similar line was taken by
the Aids Vaccine Advocacy Coalition:
Vaccine Fails to Show Efficacy
Data from subgroup analysis is intriguing
But drawing conclusions would raise false hopes
NEW YORK — The AIDS Vaccine Advocacy
Coalition (AVAC) today expressed disappointment that the first efficacy trial of an AIDS
vaccine failed to show protection in the study population. The trial was
of the vaccine candidate AIDSVAX that is made by VaxGen.
"Of course it's unfortunate that AIDSVAX did not demonstrate efficacy in the study
population of over 5000 men who have sex with men and over 300 women at risk of HIV
infection," said Chris Collins, Executive Director of AVAC. "But this trial
should not be characterized as a failed effort. More human trials of better candidates in
several countries will likely be necessary to identify an AIDS vaccine."
"The AIDSVAX results did provide surprising data in the sub-population of African
American trial participants," Collins said. "But the trial simply was not
designed to demonstrate efficacy in this subgroup and the numbers of participants in this
group are too small to draw any conclusions about the vaccine's effects in this
subpopulation."
"The African American community has been devastated by AIDS, and finding a vaccine
that could protect African Americans would be truly outstanding," Collins said.
"But given the overall finding, at this stage in the data analysis, it would be
hazardous to jump to conclusions about what the AIDSVAX data mean for this subgroup. Such
premature conclusions run the risk of raising false hopes in a world desperate for an AIDS
vaccine.
Further examination, and perhaps further trials, are necessary before conclusions can be
drawn."
There are over 20 other AIDS vaccine candidates in or nearing clinical trials and several
are considered more promising than AIDSVAX. These candidate vaccines use multiple
different approaches to protect from HIV.
"AIDS vaccine research is a long term effort," Collins said. "The North
American AIDSVAX trial has been one important step in that effort."
http://briandeer.com/vaxgen/aidsvax-results.htm
