[Press kit]

A Review of HIV Vaccine
Approaches Currently in
Development by David Gold
he need for an effective HIV vaccine has never been greater. World
wide, more than 30 million people have been infected with HIV
and each day nearly 9,000 new infections occur, more than 90
percent of these in developing countries. In the United States, an estimated 40,000-80,000 new infections occur each year.
For most of the world's HIV-infected individuals, recent advances in
the treatment of HIV!AIDS will have little impact. The high cost of developing and producing new drugs and the lack of available funds for health
care in many countries, make it unlikely that the new therapies will ever
be widely available in the developing world.
Significant obstacles remain in the effort to develop an effective HIV
vaccine. Primary among these are: 1) a lack of understanding by researchers of what constitutes the so-called "correlates of immunity" that
protect against HIV infection or disease: 2) the highly variable nature of
HIV; and 3) the lack of an ideal animal model to test HIV vaccines.
Discussed below are some of the more promising vaccine approaches
that are currently in development.
Subunit vaccines (gp 120 vaccines), which are produced by genetic engineering, include a portion of HIV located on the outer surface of the virus (also known
as the envelope or glycoprotein). Two types of HIV subunit vaccines, gp160 and
gpl20, have been tested in a wide range of clinical studies. Both Chiron Corp.
and Genentech, Inc. (Genentech's HIV vaccine program has been spun off to a
newly created company, VaxGen) are developing gpl20 vaccines that have been
widely tested in Phase I and II studies.
In June, 1994, the NIH decided not to proceed with a large scale Phase III
study of the gp120 vaccines in the United States. Supporters of the decision noted
that the vaccines did not generate antibodies capable of neutralizing primary isolates, that is, samples of virus obtained from HIV-infected people, as opposed to
laboratory-grown virus. The vaccines also failed to generate a type of cellular
immune response that researchers have reason to believe important in preventing
HIV infection. Those opposed to the decision noted that the gpl20 vaccines had
protected a number of chimpanzees from HIV infection and that efficacy studies
were the only definitive way to determine whether the vaccines were effective.
Despite the NIH decision, Chiron's gpl20 vaccines continue to be studied in
Thailand and as part of a prime boost (see below) combination in the United
States. VaxGen is planning a Phase III efficacy study of its gpl120 vaccine in Thailand. The company also hopes to initiate a Phase III study in the U.S. as well.
For the subunit vaccines to be tested in Thailand, both VaxGen and Chiron
have incorporated new gpl20 components derived from freshly isolated HIV
VaxGen has also done so for the candidate vaccine that it plans to test in the U.S.
Recombinant vector vaccines utilize live virus or bacteria (known as a vector)
to transport an HIV gene into the body to create an immune response to the
product of that gene. The most promising live vector vaccine currently in clinical
trials is the "AkLVAC" class of vaccines. These vaccines, which consist of HIV
genes inserted into a live canarypox virus, are produced by the French pharma
ceutical company Pasteur-Merieux-Connaught (PMC). The ALVAC products are
being studied in combination with a booster shot of a gp120 vaccine. Another
recombinant vector that is being studied in human HIV vaccine trials is vaccinia
(used in the smallpox vaccine). Other vectors which are in the pre-clinical development stage include: polio virus, BCG (bacillus Calmette-Guerin, a strain of
mycobacterium used as a tuberculosis vaccine), Salmonella, Venezuelan equine
encephalitis virus, and adenovirus.
Prime boost regimens utilize a combination of vaccines to induce both cellular
and antibody responses. Generally, the prime will include a recombinant vector
vaccine which will, it is hoped, induce cellular immune responses. The boost
usually consists of multiple injections of a candidate vaccine (such as a subunit
vaccine) that stimulates antibody production and T-helper cells. Researchers hope
that the combination of the ALVAC prime plus Chiron's gp120 boost will generate strong cellular and antibody responses that can protect against HIV infection.
Preliminary data suggests that the combination of the ALVAC vaccine and a
gp120 boost is safe and can induce new cellular responses to HIV in 25 to 50
percent of participants. A Phase II study of this prime boost combination recently
began in the United States and the NIH and PMC are currently discussing plans
for a Phase III efficacy study.
DNA vaccines are being studied for a wide variety of diseases, including HIV,
influenza, tuberculosis and malaria. Also known as naked DNA vaccines or nucleic
acid vaccines, these vaccines utilize the direct injection of selected genes of the
pathogen directly into the body. These genes, when taken up by the cells, enable
the individual's own cells, in effect, to make selected HIV proteins. By doing so,
these vaccines attempt to induce an immune reaction akin to that induced by a
live vaccine without using a live virus.
In animal studies, DNA vaccines have demonstrated the ability to generate
significant cellular immune responses. Another advantage of DNA vaccines is
that they can be produced relatively inexpensively. Companies with HIV DNA
vaccine development programs include Merck, PMC, and Chiron, and smaller
biotechnology companies such as Apollon and Auragen. Of these companies, only
Apollon has initiated human studies. One of these studies examined the use of an
HIV DNA vaccine as an immune therapy in HIV-positive patients. According to
the company, the vaccine appears to be safe and immunogenic in these individuals. Apollon has also initiated Phase I studies of two different HIV DNA
candidate vaccines in HIV-negative volunteers, in conjunction with NIAID. Recently, Merck announced that it was expanding its HIV DNA vaccine program.

Whole-killed vaccines (also known as whole-inactivated vaccines) are used to
prevent a broad range of diseases, including polio, influenza, and a number of
bacterial infections. Whole-killed vaccines are produced by inactivating a virus or
bacteria. A number of different methods of inactivation can be used, including
inactivation by chemicals or irradiation.
To date, only one whole-inactivated HIV vaccine has reached human trials.
The vaccine, known as Immunogen (the anti-HIV "Salk vaccine") is produced by
the Immune Response Corp. and has been studied as an immunotherapy in HIVinfected individuals.
In early studies, whole-killed vaccines (using inactivated simian immunodeficiency virus) demonstrated promising results in macaque monkeys. However, later
studies indicated that the protection was based on both the vaccine and on the
challenge virus having been grown in human rather than monkey cell lines. In
studies in which both the vaccine and challenge virus were grown in monkey
cells, whole-inactivated SIV vaccines failed to provide consistent protection. Nevertheless, many researchers believe that whole-killed vaccines are still a potentially viable HIV vaccine approach.
Companies that are currently conducting pre-clinical studies of whole-killed
HIV and SIV vaccines include the Immune Response Corp., the Austrian pharmaceutical cojnpany Immuno AG, and an Italian pharmaceutical company,
Castevecchio, which is working with researchers at the London Hospital Medical
College. Other groups such as Acrogen, Inc. and the Salk Foundation are also
seeking to develop whole-killed HIV vaccine products.
Live-attenuated vaccines are used to protect against a broad range of diseases
including measles and polio. In monkeys, live-attenuated SIV vaccines have provided the most consistent and impressive protection against simian AIDS. Harvard
researcher Ron Desrosiers has tested a broad range of live-attenuated SIV vaccines with key genes deleted. Desrosiers demonstrated that monkeys injected
with the live attenuated vaccines usually become infected with very low levels of
SIV without developing disease for a long period of time, even when challenged
with massive doses of pathogenic SIV. Other laboratories in the U.S. and Europe
have replicated these results.
Despite these interesting results, human studies of live-attenuated AIDS vaccines appear unlikely at this time, primarily due to safety concerns. Researchers
are concerned that live attenuated HIV, when given to humans, may revert to
pathogenic virus at a later date. In fact, a few monkeys have recently developed
simian AIDS from the live attenuated SIV vaccine.
A U.S.-based group, the International Physicians for AIDS Care, recently
called for the initiation of a small and carefully monitored human study of a liveattenuated HIV vaccine. The group announced that 50 of its members would
volunteer for such a trial. However, many researchers are of the opinion that
given the evidence in monkeys, such a trial is premature at this time.
Virus-like particle vaccines (also known as VLP's) consist of non-infectious
HIV look-alike particles that contain one or more, but not all, HIV proteins. The
vaccines are produced by constructing a viral particle that is non-infectious, but
contains enough of the viral structural proteins to make it immunogenic.
One type of virus-like particle vaccine, or "pseudovirion" vaccine, is being
developed by Pasteur-Merieux-Connaught (PMC). The company is developing
an HIV pseudovirion vaccine that contains gpl60, gpl20, p55 and p24, but lacks
other essential HIV proteins. PMC hopes to initiate Phase I studies of their candidate vaccine in 1998.
Peptide vaccines consist of chemically synthesized pieces of HIV proteins
(peptides) known to stimulate HIV-specific immunity. To date, peptide-based

vaccines have shown less than impressive results in human studies, but some work
is continuing.
Overall, a broad range of HIV vaccine approaches are being studied and
slow, but steady, progress is being made in developing candidate vaccines. However, none of these products appear ready for large-scale
human trials at this time. Nevertheless, the growing realization that a
vaccine is the only way to stop the global AIDS epidemic may translate
into more substantial funding and greater future progress in the effort to
develop a safe and protective anti-HIV vaccine.
This article was reprinted from the Introduction of the most recent edition of the AIDS/HIV
Treatment Directory, with minor updates. AmFAR has a single goal in updating the Treatment
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* AmFAR is beginning to establish a place for itself in the HIV vaccine effort.: Despite a general increase in understanding and support for vaccine research
* and development, I believe AmFAR has two unique contributions to make. First,
at the intersection between treatment and prevention: AmFAR has consistently:
* been a visible, outspoken voice for the public good and a staunch defender of
* politically volatile positions, such as needle exchange. We need AmFAR's help
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* and experience in building a widespread national constituency for an AIDS
* vaccine. Secondly, AmFAR can fund new, risk-taking research that would oth* erwise have difficulty getting initial government funding, and can provide seed
* money for novel approaches to vaccine design and development. Such grants
* may not always lead to valuable results, but if even one innovative approach:
* does, it would be worth the dozens of safer, more easily-funded projects. This
is a niche no other private research organization has taken on. - Bill Snow,:
* ACT UP/Golden Gate and the AIDS Vaccine Advocacy Coalition (AVAC)
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