Date: Wed, 06 Jan 1999 19:24:24 -0500
Subject: Re: Happy New Year!
From: LGNY@nycnet.com (LGNY)

I hope everyone will read this article I'm sending you here and consider: 
AIDS as a chronic, manageable illness is not enough:  activism that is
POST-INFECTION oriented is no longer what is needed to end this worldwide
epidemic that has affected more than 33,000,000 people.  We need 
desperately focus our efforts and develop a PRE-INFECTION orientation.

This is the great, undeveloped frontier of AIDS activism. 

ANY PUBLICATION CAN REPRINT THIS ARTICLE BY EMAILING US FOR PERMISSION TO
DO SO.

Troy Masters

GETTING SERIOUS ABOUT A VACCINE TO PREVENT HIV INFECTION

By Paul Schindler
It has been nearly 18 years since AIDS was first identified as a medical
crisis among gay men in New York and San Francisco, but only in the past
six months has a prevention vaccine moved into the third, or final, phase
of human trials designed to measure its effectiveness.
In June, AIDSVAX, a genetically engineered protein identical to one found
on the outer coat of the HIV virus, began human trials, launched amidst
considerable controversy, that will eventually include up to 5,000
Americans and an additional 2,500 in Thailand. Troy Masters, an
HIV-negative, sexually active gay man who publishes LGNY, is among the
first New Yorkers to volunteer for the trials.
The AIDSVAX trials, sponsored by VaxGen, a small biotech company in South
San Francisco, represent only the latest indication " coming from
government and AIDS activists as well as from private enterprise " that we
are starting to get serious about finding a vaccine to end the scourge of
HIV.
The first clear signal came in 1997, when President Bill Clinton borrowed
a page from John F. Kennedy's bold lunar landing pledge and promised to
find a vaccine within a decade. Many experts were skeptical, but since
then, spending on vaccine development has become the fastest growing
segment of the federal government's AIDS budget.
VaxGen will not disclose how much it is spending on the efficacy trials,
but informed estimates routinely put the figure at $25 million plus. Since
1997, the International AIDS Vaccine Initiative (IAVI), a non-profit
agency founded in New York to remove barriers to private sector
development of an effective and universally-available vaccine, has raised
close to $20 million from sources ranging from the Rockefeller, William H.
Gates, and Elton John AIDS Foundations to Levi Strauss International. Late
last year, IAVI announced grants of $4.5 million to each of two vaccine
research enterprises in North Carolina and Oxford, England.
Activists who have put the bulk of their efforts into AIDS treatment and
services agree that the push for a vaccine is vital. Derek Link, director
of federal affairs at Gay Men's Health Crisis (GMHC), termed the search
for a vaccine `the highest and most important goal' of AIDS activism.
Gregg Gonsalves, policy director at the Treatment Action Group (TAG) in
New York, is currently at work on a major study of vaccine development.
Although Gonsalves is highly critical of the specific approach being taken
by VaxGen, he does not waver in his support for the ultimate goal: `I want
a vaccine. If there had been one four years ago, I wouldn't be infected.'
The growing interest in a vaccine, which depends in part on a
corresponding faith that one can be found, is a response to the staggering
growth in HIV infections worldwide and the practical limitations of
available treatments, even under the most optimistic scenarios. 
As of 1998, there were an estimated 34 million people living with HIV
around the globe, with new infections growing at 16,000 each day. More
than 90% of those infections are occurring in developing areas of the
world where the costs of new drugs " a year's supply of one protease
inhibitor can exceed $5,000 " have made treatment prohibitive. For these
parts of the world, stretching from Africa through India into Southeast
Asia and also including portions of Latin America, AIDS remains a sure and
usually quick killer.
Even in the industrialized world, the need for a vaccine is clear. The
reported effectiveness of the new therapies has been no better than 50%,
and side effects and difficulties adhering to drug regimens have become
apparent. Most alarming is the continued rate of new infections " for
example, among young gay and bisexual men " at a time when evidence has
emerged that multi-drug resistant strains of HIV can be sexually
transmitted. These factors pose the greatest threat in areas where the
baseline level of infections is relatively high, such as the United
States. Link at GMHC argues that `prevention has been very effective' and
that the available prevention tools would suffice in low-infection areas
such as Australia. In major American cities, however, he believes a
vaccine will be needed to finally turn back the epidemic.
Dr. Seth Berkley, president of IAVI, says that the greater success
achieved in the treatment area versus a vaccine could not have been
predicted when AIDS first emerged. At the time, he points out, there was
only one anti-viral drug in use. The early expectation, formalized when
Ronald Reagan's Health and Human Services Secretary Margaret Heckler
predicted a vaccine within a year or two, was that most effort would go in
that direction, rather than toward treatment.
Berkley says the progress that was instead made in the treatment area is a
testament to the tenacity of community activists who refused to accept
science's limited vision in the mid-1980's. That activism, he argues,
`drove science' and resulted in the therapeutic advances we have seen. The
unmistakable signs of treatment advances apparent since the 1996
International AIDS Conference in Vancouver for the first time provided the
breathing room to turn attention to the languishing efforts at finding a
vaccine.
But Berkley does not underestimate the barriers impeding vaccine
development efforts. In fact, IAVI's mission is to develop approaches that
surmount the remaining obstacles, particularly those inhibiting private
sector applied efforts needed to develop a working vaccine. From IAVI's
perspective the efficacy questions that must be addressed over a long time
frame by the science are compounded by significant questions about
financial risk, market size, and politics. 
In a typical drug development paradigm, financial risk is compensated by
the ability to enjoy high returns from marketing to the industrialized
world. But, Berkley argues that this model is `unacceptable' in the case
of an AIDS vaccine: Pharmaceutical interests are uncertain about the size
of demand from the industrialized world, where HIV continues to be viewed,
rightly or wrongly, as an affliction of gay men and drug users. The
developing world, where HIV is having a far more devastating impact,
provides a much surer source of vaccine demand, but offers little in the
way of paying for it. In mid-1998, IAVI spelled out a blueprint for
restructuring global incentives so that private enterprise would feel
comfortable moving forward on vaccine development, while at the same time
guaranteeing that any strides made would be available globally. The order,
of course, is a tall one.
The process begins with basic science research which, unlike drug
development, is typically funded by the government. Efforts in the U.S.
have not been without critics. Last May, the AIDS Vaccine Advocacy
Coalition, an activist group, leveled a broadside at the U.S. effort:
`Pretending to fill the leadership gap, marginally increasing public
funds, and improving part of the grant evaluation and awards process does
not add up to the full mobilization we need.' Whether or not this
criticism was just, it came amidst an unprecedented build-up of government
efforts.
Since 1994, spending by the National Institutes of Health (NIH) on AIDS
vaccine R&D increased from $89 million to estimated $200 for next year,
when it will represent more than 10% of the AIDS budget. Gonsalves from
TAG points out that this total does not factor in basic research spending
in immunology and virology that plays an important role. NIH's effort has
also been energized by the appointment of University of Pennsylvania
virologist Neal Nathanson to head the Office of AIDS Research. NIH is
moving forward with plans for a vaccine research facility that GMHC's Link
says will have a catalytic effect on attracting young scientists to the
effort.
NIH's effort has also been buffered by the return of Margaret Johnston to
head up the AIDS vaccine program at the National Institute of Allergy and
Infectious Diseases (NIAID). Johnston, who had earlier left NIAID to
become IAVI's scientific director, said, `I wouldn't go back unless I was
absolutely convinced that the NIH was taking AIDS vaccine development more
seriously.' Johnston indicated that important changes would be made to
NIH's peer review system so that empirical research appropriate to vaccine
development would not play second fiddle to more traditional basic science
efforts.
In discussing the federal government effort, Berkley at IAVI is careful to
sound an upbeat note. The resources directed to basic science are, in his
view, `relatively enough.' His concern is moving the process from basic
research into applied private development efforts. Drawing on what he
acknowledges is an analogy with dubious political appeal, Berkley notes
that the Manhattan Project that developed U.S. atomic capability during
World War II went down four paths at the same time. IAVI hopes to see
anywhere from six to ten approaches moving toward the phase III trials
that so far only VaxGen has reached. Both Berkley and Link emphasize that
the lack of adequate animal correlates with which to study HIV makes human
trials all the more critical.
With this multi-pronged approach in mind, IAVI made two $4.5 million
grants this past November " one to AlphaVax, a Durham, NC biotech company
using a harmless form of the Venezuelan equine encephalitis virus as a
delivery vehicle, or `vector,' for a vaccine; and the other to an effort
out of Oxford University that combines two vaccines, one of which consists
of genetically engineered DNA for HIV core proteins and the other a
harmless virus used in smallpox vaccines modified to encode HIV core
proteins. 
Both IAVI efforts are distinguished by two characteristics. First, the two
research teams have agreed to use African strains of HIV in developing
their vaccines, in keeping with the goal of ensuring that products have
global applicability. Second, both vaccines produce cellular immune
responses, which are considered stronger than the antibody response that
vaccines have typically been designed to induce. Critics of the VaxGen
product have argued that its reliance on antibody response will prove
insufficient at preventing infection.
IAVI's early efforts have won high marks from a wide variety of sources,
including Link and Gonsalves. Anthony Fauci, NIAID's director, said that
`both of the IAVI vaccine initiatives hold promise.'
For IAVI, however, these two projects are just the start. Berkley
estimates that the overall cost of developing a successful vaccine for the
market, counting in all the costs of failed efforts, will amount to as
much as $500 million over the next nine years. But, much of that money
will flow from the private, for-profit sector once the proper structural
incentives have been created. The cost of providing those incentives, the
major task in IAVI's mission, could come as cheaply as $30 million,
Berkley argues. 
The cornerstone of that effort is something IAVI terms `social venture
capital,' a concept by which the group retains intellectual property
rights to products developed with its financial assistance. IAVI cuts a
very straightforward deal with its beneficiaries. In return for freedom to
price its vaccine at any desired level in the industrialized world, the
grantee must agree to make the same product available to public sector
buyers in the developing world at manufacturing cost plus 10%. 
IAVI is convinced that the deal is attractive enough to motivate vaccine
manufacturers to actually make product available universally.
Manufacturers would only have limited production runs if marketing
exclusively in industrialized countries; their production would grow
exponentially for a global market. The economies of scale in drug
production are such that the marginal cost of manufacture would be driven
down so that industrialized countries could provide a fat margin, and
sales at cost plus 10% elsewhere would remain attractive. By retaining
intellectual property rights, IAVI will be able to redirect production in
the event that shortages result.
There are, of course, political problems raised by the IAVI vision.
Industrialized nations will, in effect, be subsidizing production of
vaccine for the developing world, a fact not likely to be lost for long on
critics of wealth sharing in the U.S. Congress, for example. One approach
IAVI is exploring is ensuring that product is manufactured locally, but to
the same standards, so that the subsidy critique cannot take hold. Another
problem is that even at cost plus 10% much of the developing world could
be left out in the cold. IAVI is exploring `purchase fund' mechanisms with
the World Bank to address this problem.
Some AIDS activists express concern about any approach which might offer a
premature go-ahead for phase III trials, which are costly and `use up' the
available pool of volunteers. Gonsalves argues that the problem is at `the
beginning of the pipeline, not the end.' His concern is encouraging more
phase I trials, which address fundamental safety and immune response
issues. Gonsalves says that for many academic researchers with good new
ideas, making the step to phase I clinical testing is the most significant
hurdle. `If the approach has promise, phase III will come,' he says.
`Phase III for the sake of phase III is counterintuitive.'
This perspective is at the heart of Gonsalves' critique of the VaxGen
effort. `Bottom line, I think it's a waste of time and money,' he says,
even while acknowledging that the money is private funds. Gonsalves voices
a concern echoed by many " he argues most " in basic science research,
that by aiming only at antibody response, without conquering the more
difficult task of inducing cellular immune response, the VaxGen effort is
doomed to fall short of the goal of preventing infection.
In a May 1998 letter to Science Magazine, a blue-ribbon group of AIDS
experts, including Dr. David Ho of New York's Aaron Diamond AIDS Research
Center, outlined their concerns regarding the inadequacy of the VaxGen
approach. Signers of the letter included both Gonsalves and Link. 
Stephen Wolinski, a virologist at Northwestern University, also signed
onto the letter. Wolinski did a study of 18 `breakthrough' volunteers from
VaxGen phase II trials, who became infected despite taking the vaccine.
Wolinski's main point was not that some of those inoculated became
infected, but rather that careful study of them indicated that the vaccine
had `neither beneficial nor adverse effects.' Wolinski said that the
findings, while not proving the vaccine ineffective, were `very
disappointing.' Fauci said the results `fortifies the decision I made
three years ago' when NIH declined to move toward with phase III trials on
the approach VaxGen is using.
VaxGen was quick to respond with its own study of breakthrough volunteers.
That study, led by immunologist Phillip Berman, VaxGen's head of research,
found that infections among the breakthroughs were caused by HIV
structurally different from that used to develop the vaccine. VaxGen has
modified its product to incorporate protein structure from at least two
HIV strains, in a `bivalent' approach tailored to the natural viruses at
specific trials venues.
Despite the public criticisms lodged at VaxGen, there are increasing signs
of accommodation to the reality that trials have begun. Largely at the
behest of Neal Nathanson, NIH, which earlier spurned funding of phase III
trials, has agreed to participate in evaluating VaxGen results. Nobel
Laureate David Baltimore, who described the prospects of VaxGen success as
`extremely unlikely,' nonetheless said that `potentially valuable science
will be captured' in NIH's review of the trials. After meeting with Thai
officials to discuss VaxGen trials in Asia, Baltimore described their
thinking as `all very reasonable.'
Other questions about the VaxGen effort relate to ethics matters. Some
activists argued that VaxGen should have included information on the NIH
decision not to fund phase III trials in its informed consent form given
to volunteers. The company instead included it as background information
for prospective volunteers. The company may also face criticism down the
road in its decision not to provide treatment to Thai volunteers who
become infected with HIV. A company spokesperson, Nicole Lynch, explained
that given the lack of treatment resources available in Thailand, the
promise of such treatment would pose an unethical inducement for
volunteers, and possibly encourage them to participate in unsafe behavior
before the study ends and provision of treatment is withdrawn.
Despite a variety of concerns about the VaxGen effort, many in the AIDS
community welcome the fact that phase III trials have finally begun. Link
says from GMHC's perspective, `these trials are great.' But, he also
articulates the conundrum faced in deciding on when to move forward, on
the debate between basic scientists and `trial and errorists.' 
`The reality is that that's how most vaccines have been developed,' Link
explains. `When Edward Jenner developed the smallpox vaccine, he didn't do
a lot of preliminary immunological research. But, then again, he didn't
have the tools. Today, we have tools that are very sophisticated.' 
Link doesn't offer any easy answers for making the judgment call, but says
that volunteers need to be mindful of one key fact: `Trials are a gift to
community . No one should in with the view that the vaccine will give
protection.'
Mary Clements-Mann, a Johns Hopkins virologist who died in an air crash
last year along with her AIDS researcher husband Jonathan Mann, was quoted
in Science expressing the scientific dilemma more bluntly: `If we don't
move forward to phase III, we will never have a vaccine.'

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