Money, media and a 10-year-or-bust mandate made the cause
sexy. But with the first tests on deck, the risks are bigger than
In 1984, when scientists finally nabbed
HIV, it instantly raised prospects that a vaccine would follow. Even
to hope that the new disease might soon join the list of deadly
epidemics stopped cold by a vaccine was an awesome leap; if anything
in medicine seems like a magic bullet, it's these tried-and-true
weapons. But in the heady flush of success over identifying HIV,
Margaret Heckler, then secretary of the Health and Human Services
Department, blithely served up a science-fiction scenario of a quick
fix when she said that a candidate would be ready to test within two
years. After all, in the real world even a decade is turbo speed for
a new vaccine.
Fourteen years later, a vaccine is nowhere in sight; in fact,
even the fantasy has faded. During these years, while AIDS activists
-- desperate to save lives -- pushed the National Institutes of
Health (NIH) toward a massive research effort on treatments, there
was no one fighting with such passion for a vaccine. In fact, many
in the AIDS community cast a cold eye on the vaccine cause, fearful
that research into, let alone development of, a shot that protected
against HIV would dash the hopes of the already infected. Moreover,
some scientists even grew skeptical that a vaccine was possible. And
most drug companies steered clear, anticipating a long, difficult
scientific path fraught with uncertain profits and a political and
Now, with some big successes in anti-HIV therapy but the virus
still spreading like wildfire worldwide, vaccines are starting to
make a comeback -- although so far there's still more talk than
action. Take, for example, President Clinton's 1997 call for an HIV
vaccine within the decade, which invoked "can do" images of a
man-on-the-moon-type effort. Yet he offered no Apollo-esque
strategies to support it, nor has NIH come up with a concrete plan
for trying to meet the deadline.
Is "10 years till a vaccine" remotely realistic? NIH top brass
are wary. "I'll be happy if we can get a good candidate to the point
of large-scale clinical trials in that time," says Dr. Carole
Heilman, deputy director of the agency's Division of AIDS. Others
are eager to go for it, but say that far more energy and focus are
necessary. "The whole mentality of how we're looking has to change,"
says Dr. Margaret Johnston, scientific director of the International
AIDS Vaccine Initiative (IAVI), a new nonprofit group dedicated to
pushing vaccines forward. "We have to be much more aggressive.
People haven't woken up yet to what making a vaccine really means."
Re-invigorating the national vaccine effort has been a rocky road
since 1996, when a blue-ribbon panel of AIDS researchers diagnosed
the federal program as "in crisis": It was deemed too small, of low
priority and poorly funded, and too narrowly focused on basic
science while neglecting targeted research. Added to this is not
only the huge cost but the very slow and long development pipeline
that leads promising vaccine candidates out of academic labs, into
manufacture for human use, through early clinical tests for safety
and ability to stimulate immune responses, and then finally into a
Phase 3 efficacy trial, which tests if the candidate works.
Yet many scientists view the biggest obstacle as the formidable
scientific challenge of HIV itself. A major mystery is that people
usually show strong immune responses to HIV but still eventually get
sick, so no one knows for sure which type of immunity a vaccine
should stimulate to protect against disease. One emerging view
suggests that a vaccine should aim at several arms of the immune
system: The cells producing antibodies that destroy free virus in
the blood, the cytotoxic T lymphocytes (CTL) that target
already-infected cells, and also perhaps the dimly understood immune
responses in the body's mucosal membranes, including those lining
the vagina and rectum -- ports of entry for sexually transmitted HIV
-- and the gut, likely a key destination of HIV soon after
infection. Another high hurdle: Since no animal immune system
perfectly mirrors that of humans infected with the virus, there's no
way to know if a vaccine works without testing it in people.
Although daunting, none of this is new to vaccinologists, who
rarely know all they'd like to about their prey. So they rely
instead on educated trial and error, where experimental vaccines are
tested in people and their designs improved based on the results.
Another way they've sidestepped ignorance is to stick with the
strategy that produced the very first vaccines and is still hard to
beat: Take the whole virus, weaken or kill it so it can't make
people sick, and then count on the body's own immune response to do
the rest. But there's a tradeoff because weakened whole-virus
vaccines still carry a tiny risk of causing disease. For example, in
the United States, there are about eight cases a year of
With HIV, fears about potential risks have steered researchers
away from this traditional strategy and toward genetically
engineered "designer" vaccines that are harmless because they use
only parts of the virus. Again, there's a price -- these vaccines,
even if they work, may give weaker or less long-lasting immunity.
Most types will also be expensive, adding to the problem of making
an AIDS vaccine available to those most in need -- in developing
countries, where over 90 percent of the world's 31 million with HIV
But a more immediate worry in the vaccine field is how few
candidates have even made it out of the lab and into the pipeline.
And sadly, once in it, they don't flow through: Of the more than two
dozen products tested in Phase 1 safety trials, only three have made
it to the next step, and none to Phase 3, a record that prompted Dr.
William Heyward of the Centers for Disease Control and Prevention
(CDC), to write in The Journal of the International Association
of Physicians in AIDS Care (IAPAC), that the pipeline is more
like a pipette.
The reason for this paltry trickle is one of the most contentious
issues in the vaccine field. For many basic researchers, the bottom
line is that current candidates are simply not good enough. Even Dr.
David Baltimore, the retrovirologist and Nobel laureate who chairs
NIH's new AIDS Vaccine Research Committee, doubts that 14 years of
R&D have produced anything worth large-scale tests. To him and
others in the "theorist" camp, the key isn't "big trials now" but
more basic research and small trials aimed at understanding what's
needed for an effective vaccine. This is also the way to pull in
drug and biotech companies, Baltimore says. "We need to face
industry with real opportunities. Right now the pipeline isn't
exciting enough -- we're testing concepts that are clearly outdated.
Drug companies have made the reasonable judgment that the time isn't
But the "empiricists" -- mostly public health experts,
epidemiologists and vaccinologists favoring more applied research --
counter that it's too soon to write off current candidates, since
basic science can't predict which ones will pan out. "We don't know
what works, end of story," says Dr. Seth Berkley, president of IAVI.
"We have theories, but we don't know." Dr. Mary Lou Clements-Mann of
Johns Hopkins University, a vaccine researcher and member of the
FDA's vaccine advisory committee, agrees, saying, "I've seen
vaccines moved from small- to large-scale tests much more rapidly,
without answers as to why they might work." She adds, "After
licensing, often we still don't know." Some lab tests can even be
misleading, says Dr. Barry Bloom, an immunologist at the Albert
Einstein College of Medicine and chair of the UNAIDS vaccine
subcommittee. "If we went by animal models we wouldn't have the
newest whooping-cough vaccine," he says. "If we'd used the same
criteria as for HIV, it would never have gotten off the ground."
This long-simmering debate erupted last March when Dr. Jonathan
Mann, former head of the World Health Organization's Global Program
on AIDS, attacked the "theorists" in a passionate speech before
Clinton's AIDS advisory council. Mann criticized the failure to
mount efficacy trials as "unethical" and a "violation of human
rights," and called on the NIH leadership to involve more people who
have vaccine experience. And he accused the NIH of indifference to
the people now getting HIV in this country, most of whom come from
already-marginalized groups. "Very simply, if 40,000 college
students were becoming HIV infected each year, it's obvious that
field trials of AIDS vaccine candidates would have long been
underway," he said.
But as polarized and ideological as the debate sounds, in
practice there's a well-occupied middle ground, says José Esparza,
vaccine team leader at UNAIDS Geneva. And he points out that
opinions on efficacy trials reflect not only "theorist" vs.
"empiricist" arguments but practical issues as well -- such as
money. These tests take big bucks, and with limited funds it becomes
a matter of "competing priorities," he says. Funding, in turn,
reflects HIV vaccine research's low priority in the United States.
"The fact of the matter is that the country with the financial
resources and scientific know-how to develop the vaccine does not
feel the urgency of the epidemic," he says. "The only solution is to
increase funding for HIV vaccine research and proceed with parallel
development of several vaccine concepts, including several
large-scale efficacy trials."
Lurking in the shadows of this battle is the spectre of fallout
from a large trial that fails, a common occurrence with experimental
vaccines but much feared in the HIV field. Given the public
attention to AIDS, a bust would give HIV vaccine trials "a bad
name," says Baltimore. IAVI's Berkley disagrees. "Politically it's
considered too risky to have negative vaccine trials," he says. "But
why? With malaria, we've tested a lot of vaccines that didn't work.
We need a big shift in mind-set." And if a trial is well designed,
says vaccinologist Clements-Mann, a negative result can give crucial
information on how to make a better one.
That means a reality check on public expectations. "The public is
looking for an immediate, spectacular success," says immunologist
Bloom. "But you don't pull a vaccine out of a test tube and it
works. It takes constant modification. You're not going to get it
right the first time. A 99 percent effective vaccine? I don't see it
on the horizon. But even 50 percent effectiveness would be
Amid the clash of views, one vaccine is now inching its way
toward that historical milestone -- the first Phase 3 trial, likely
underway within a year or so. The figure behind the trial is Dr.
Donald Francis, who, at the CDC in the early '80s, was one of the
first voices trying to awaken the world to the tragedy ahead. In
1993 he joined the HIV vaccine program at Genentech, a biotech
behemoth based in South San Francisco. Researchers there had adopted
the same strategy as nearly all early HIV vaccine makers -- focusing
on a genetically engineered version of the so-called gp120 protein,
which makes up the surface of HIV. These scientists had already
succeeded in making a vaccine that prevented HIV from infecting
chimpanzees. Early trials with small numbers of people found it to
be safe in humans and able to stimulate a strong antibody response.
The NIH's National Institutes for Allergy and Infectious Diseases
(NIAID) was prepared to pump $20 million into a Phase 3 trial.
And then NIAID wasn't. In a stunning reversal, the agency pulled
out. New data in early 1994 raised fears that differences among
gp120 proteins in HIV strains directly from people and those grown
in the lab -- used to make Francis' vaccine -- might doom the
vaccine to failure. Many voiced doubts about whether gp120s
stimulated the "right" kind of antibodies. And even the chimp data
didn't convince everyone, since HIV can infect chimps but doesn't
give them AIDS. As scientists feverishly debated the meaning of the
new findings, NIAID finally bailed out in June, saying that its
limited funds should be saved for better candidates. The decision
cast a pall over the whole field and led some companies to shrink or
shut down their HIV vaccine work (including Genentech, which spun
off Francis and the vaccine to a small new company, VaxGen).
Francis persisted, convinced that the vaccine's ability to
protect chimps meant more than the lab tests that gave NIAID cold
feet. Now he's ready once again, with his own funds -- $20 million
raised privately so far -- and modified vaccines. These newest
vaccines stimulate the type of antibodies NIAID wanted to see and,
along with gp120 from the lab strain, contains gp120s representative
of common strains at each of the two likely trial sites (Thailand
and the United States). And he expects to get the official go-aheads
soon. In the U.S., FDA approval for a Phase 3 trial is nearly
certain, he says, once data from the ongoing Phase 2 trial are in.
Meanwhile, in February an international group of scientists
recommended to Thai officials that the Phase 3 trial there go
forward. Together, the two trials would follow 7,500 high-risk
volunteers for three years.
These trials-to-be have triggered the full range of reactions.
Skeptics point to a growing belief that an HIV vaccine should induce
strong CTL responses, and Francis' doesn't. "Seriously wanting" is
how Dr. John Moore of the Aaron Diamond AIDS Research Center rates
the vaccine. "I'm absolutely certain that the vaccine's efficacy
would be immeasurably low," he says. "There is also a moral issue,"
he adds, arguing, "It's simply not appropriate to immunize human
volunteers with a protein that has no chance of protecting them from
HIV." Others are more supportive of Francis' trials. "I'm delighted
that VaxGen is moving ahead," says IAVI's Margaret Johnston. "It's
important to know if gp120 works at all based on data rather than on
what people see in a crystal ball. Any answer is worthwhile."
However the gp120 story ends, its cautionary moral -- don't put
all your eggs in one basket -- has already spurred those in the
vaccine field to pursue several other strategies. One is to put
selected HIV genes into harmless viruses that infect the cells of
vaccinated people and make them churn out HIV proteins, which should
stimulate immunity. Since these viral "vectors" often evoke good CTL
responses, some experimental strategies combine them with the
antibody-stimulating gp120 for a one-two immunizing punch. And high
hopes are pinned on the concept of vaccinating with HIV genes in the
form of "naked" DNA. Although at least a decade away, this
technology is a potentially revolutionary way to make vaccines
cheaply and simply, which would be ideal for the developing world.
Increasingly, these new approaches turn on the old-fashioned idea
of presenting the immune system with many different parts of HIV
(working "top down" from whole virus) rather than the "bottom up"
approach of selecting only one or two targets, as with gp120. This
would hopefully give the wily, changeable virus fewer chances to
evade immune attack. And that shift has sparked pockets of interest
in a strategy long viewed as unthinkable -- using live HIV.
& Middle East Asia
& Central Asia
United Nations Programme on AIDS (UNAIDS)
From their backwater in the HIV field, live but weakened
("attenuated") AIDS vaccines made a sudden, dramatic appearance in
the headlines last September when IAPAC announced an initiative to
push for a Phase 1 human trial by the year 2000. But that wasn't
all. Recognizing the potential risk -- and the public fears -- of a
live HIV vaccine, several IAPAC members volunteered to be the first
guinea pigs, following the tradition of Louis Pasteur, Walter Reed
and other vaccine pioneers. It was a vivid, startling gesture
showing that the need for a vaccine was so great worldwide that
people were willing to accept the risk of getting AIDS (although
IAPAC considers this low). And since IAPAC's announcement, more than
270 people have volunteered to join them in rolling up their sleeves
(a first trial would probably involve 10 or less).
IAPAC's attempt to put live vaccines on the agenda isn't a stab
in the dark: There's already powerful evidence that they may work.
In 1992, Ronald Desrosiers of the Harvard Medical School injected
monkeys with a weakened version of SIV, a simian virus related to
HIV, made by clipping out several genes. When the same animals were
infected later with the intact, nasty SIV, they were fully protected
from disease -- just as a good vaccine should do. No other vaccine
candidate has come close to matching this stellar performance.
Yet most AIDS researchers reacted to IAPAC's announcement with
alarm, aware of then-emerging data that some attenuated SIV strains
cause full-blown simian AIDS in baby monkeys and in a small
proportion of adults. And even though IAPAC proposed using a more
weakened strain, critics say that too little is known about HIV
genetics to ensure that the virus can be made meek enough to not
Whether a U.S. trial kicks off by the year 2000 or later depends
on the FDA, whose primary concern is public safety, not necessarily
the shortest road to an effective vaccine. Vaccinologist
Clements-Mann ticks off some of the concerns: Could vaccinated
people get sick from the attenuated virus years later? What happens
when their immune systems weaken from age or illness? Is attenuated
HIV transmissible, even at a low frequency? None of these questions
can be tackled in short human trials.
IAPAC's deputy director, José Zuniga, acknowledges these fears.
"I don't envy the FDA's position. We're not asking them to throw
caution to the wind, to say we don't need more data. But we need to
move from animals and ask what the vaccine does in humans." And he
cites an accidental experiment in humans that suggests that a safe
attenuated HIV is possible. Eight people, including seven in
Australia, were found to be infected with weakened forms of HIV
since the early '80s, without any apparent ill effects.
Yet for the FDA to even consider trials, and to ensure that
potential volunteers are fully aware of the possible consequences,
more animal data will be needed. Enter IAVI. Although the
organization sees a trial in healthy volunteers as premature, it
also believes strongly that the live-attenuated approach should be
pursued, and have funded a pilot project to design a large safety
study involving hundreds of monkeys. Similar studies were done for
other live vaccines, such as polio. "I would consider enrolling in a
trial if there was more data," says IAVI's scientific director,
Margaret Johnston. "I'm not willing to make the leap of faith now."
In the meantime, Dr. John Sullivan of the University of
Massachusetts has proposed an alternative plan for the first human
trial, one that may be more acceptable to the FDA. Rather than
vaccinating healthy volunteers, Sullivan suggests recruiting
terminally ill cancer patients with still-intact immune systems.
This plan, dubbed "a very reasonable first step" by IAVI's Johnston,
could throw light on key issues, such as whether the chosen
attenuated HIV strain replicates in humans, what types of immune
responses it stimulates, and how its behavior in people compares to
that of attenuated SIV in monkeys.
Researchers in Australia are also pursuing plans to test a
live-attenuated vaccine within the next few years. Dr. John Mills,
director of the Macfarlane Burnet Centre for Medical Research, is
modeling his candidate on the naturally weakened HIV strain found in
the seven Australians (who got it through blood from a single
donor), with this speculative twist: He hopes to vaccinate with DNA
only, not with whole virus. If that works, it would make vaccine
preparation vastly simpler, safer and cheaper. With funding from
IAVI, he's now working on safety studies in monkeys.
In the United States, despite both outside criticism and
Clinton's 10-year call, the NIH is sticking with its present
strategy, beefed up with some extra funds and the involvement of big
gun David Baltimore. Several new mechanisms are also in place to
help researchers negotiate the arduous vaccine development pipeline.
But there's no specific 10-year plan, and a proposed NIH Vaccine
Center, meant as a cornerstone of NIH's born-again vaccine effort,
has yet to get on its feet.
IAVI will likely shake things up when it presents its "scientific
blueprint" for an HIV vaccine in 10 years at the World AIDS
Conference in Geneva. Based on a 1994 brainstorming meeting of big
vaccine players worldwide, the plan is "a very different approach
from the basic science one," says IAVI president Berkley. Its
central elements: "Work on different things in parallel. Work top
down. And go fast into humans -- don't sit around and argue about