[Press kit]

A Brief History of AmFARfunded Research Related to
Vaccine Development
Murray B. Gardner, M.D., University of California, Davis: Analysis of AIDS Retrovirus Envelope Gene (1986). A virus cannot infect a cell
unless it can attach to specific docking sites or
receptors on the membrane of its target, then enter
the cell. HIV accomplishes this primarily by linkage of its outer envelope coat, known as gp120,
to the CD4 protein found on T cells, monocytes,
and several other cells of the immune and nervous systems. (The ability of the virus to enter
the cell also requires binding of gp120 to a then
unidentified "fusion factor" on the target cell.
This factor, now known as a "chemokine receptor," was discovered during the course of a
recent AmFAR award to Dr. Nathaniel Landau
of the Aaron Diamond AIDS Research Center).
Dr. Gardner recognized early on that it was important to understand whether all patient isolates
of HIV shared similar abilities to bind to the CD4
receptor. Indeed, much time and effort was
being directed at developing a potential therapeutic based solely on this hope. It was thought that
genetically engineered CD4 proteins, injected into
HIV+ patients, would act as decoys and protect
uninfected cells from HIV, permitting new immune cells to grow. Dr. Gardner's research helped
to show that this was unlikely to be a successful
strategy because of the great variation in the
ability of viruses found in patients, rather than
artificially-propagated in the laboratory, to bind
to such receptors. This type of work helped
deflect much wasted effort in further trials of such
strategy. In addition, Dr. Gardner suggested that
certain patients might have antibodies in their
blood with high affinity for binding to and
neutralizing the AIDS virus. If these antibodies
could be captured by chemical methods, they
might prove useful as therapeutics for patients
lacking such defenses. This has been the basis for
a strategy know as "passive immunization."
Nancy T. Chang, Ph.D., Baylor College of Medicine, Houston: The Construction of a "Packaging
Defective" HTLV-III and Its Use as a Vaccine
(1986). Dr. Chang and her colleagues at Baylor
constructed, using molecular techniques, a
mutant version of HIV that is only the outer shell
or covering of the virus and which does not contain the genetic material that makes HIV lethal.
These defective mutants would hopefully induce
both humoral and cellular immune responses
while not being able to grow and cause disease.
Francis R. Carbone, Ph.D., Monash University
Victoria, Australia: Cytotoxic T Lymphocyte
Recognition of HIV Proteins (1990). One problem characteristic of all early HIV candidate
vaccines was that antibody production was their
primary objective. Killer T cells, however, not
antibodies, appear to be much more important in
controlling the spread of the virus in the body.
Dr. Carbone developed a method by which killer
T cells can be primed to recognize protein struc
tures on the surface of HIV, as well as internal
structures of the virus.
J. Donald Capra, M.D., University of Texas
Southwestern Medical Center, Dallas: Genetic
Engineering of Human Antibodies (1992, renewed
in 1993 as a Concerned Parents for AIDS Research
Grant). Dr. Capra genetically engineered antibodies to bind especially securely to HIV. Production of large quantities of "improved"
antibodies, the next step in this research, could
enable patients to be infused with very tightlybinding anti-HIV antibodies. High enough
concentrations of virus-neutralizing antibody in
the blood could deter infection or delay disease
progression. Antibodies improved by the genetic
engineering techniques employed by Dr. Capra
were to provide the immune system with a boost
that would either help prevent a new HIV infection from taking root, or increase the body's
defenses against an existing infection.
Stephen A. Johnston, Ph.D., University of Texas
Southwestern Medical Center, Dallas: Genetic
Immunization: A New Approach to an HIV
Vaccine (1992, a Gift for Life Research Grant).
Immunization with the genes of a disease-causing organism, or "genetic immunization," is a
simple, extremely promising approach to making safe vaccines. Such vaccines are popularly
known as "DNA vaccines" (they can consist of
either RNA or DNA, but DNA appears to be best),
and the method often referred to as the "naked
DNA" approach. When injected into a person's
body, the viral DNA enters cells; the cells then
manufacture viral proteins, which the immune
system learns to attack. Dr. Johnston and his
colleagues have designed a method that should
enable the construction of effective DNA vaccines
for any infectious disease. Dr. Johnston also finds
it more efficient to "shoot" DNA-coated gold
microparticles into the skin using a "gene gun" as
opposed to a syringe. His AmFAR grant enabled
him to test the gene gun and build better versions.
(Continued top of page 3)

Pioneering DNA Vaccine Research

n the years to come, we can look forward to the intro
duction of many new antiviral treatments, and we will
learn how to use them in various combinations to slow
or even halt disease progression in people with HIV But we
will not win our battle against HIV and AIDS without a preventive vaccine on our side.
No viral disease has ever been eradicated without the
help of a vaccine. HIV and AIDS are rampant in many parts
of Africa and Asia', where current treatments are too costly
for widespread use. Thus, despite their promise, the new
antivirals cannot be used where the disease is most prevalent. A vaccine would be the easiest and most economical
means of controlling the spread of HIV, not only on those
two continents but throughout the world.
Why is there no vaccine to protect people from HIV/
AIDS? Great effort has certainly been expended in the attempt to create one. However, neither the applicationi of
traditional technology nor that of newer technologies, such
as recombinant DNA technology, have resulted in candidate
vaccines capable of eliciting protective immune responses.
The answer lies in the differences between the nature of HIV
and the nature of those viruses against which vaccines have
been made successfully.
Very few viral vaccines prevent infection; rather, they
assist the immune systems of vaccinated people in recognizing and eliminating infected cells at an early stage. Traditional "subunit" vaccines (those that contain part of a viral
surface protein) trigger an antibody response, but do not
effectively stimulate the cellular immune response specifically needed to fight a virus like HIV In fact, HIV infects the
very immune cells needed to mount this cellular response.
Vaccines made from attenuated viruses trigger a cellular
immune response in animals, but an attenuated HIV vaccine
is considered too dangerous for use in humans. Furthermore,
HIV is able to mutate quickly to escape the immune system,
a capability similar to that of the influenza virus, which must
be fought with a new vaccine each year. (Unfortunately, HIV
can mutate much faster than influenza.) Traditional vaccine
approaches cannot counter these nor other challenges posed
by HIV
Recently, however, an exciting new strategy with great
promise-one that shows signs of clearing the obstacles presented by HIV-has emerged. Pioneered with the help of an
AmFAR "seed grant," this approach is known as genetic
immunization, or DNA vaccination; it uses the genes of a
disease-causing organism, such as HIV, as a vaccine. The
Economist of June 8, 1996 noted, "If this approach works,
it could be a simple way to make cheap, safe, and effective
vaccines. So far, the data have been astoundingly good."
Five years ago, little interest and little funding were
being directed toward the development of DNA vaccines for
HIM. AmFAR, however, recognized that new approaches to
vaccine development were required and, in 1992, awarded
a basic research grant to Dr. Stephen A. Johnston of the University of Texas Southwestern Medical Center, Dallas. That
grant enabled Dr. Johnston to test HIV DNA vaccines in

animal models, using the "gene gun" to shoot DNA vaccinecoated particles into the skin. Dr. Johnston's study showed
that DNA vaccines stimulate a strong cellular immune
response and that delivery of the vaccine by the gene gun is
vastly more efficient than delivery by intramuscular injection. He also developed a general method for making DNA
vaccines that could be used for immunization against any
disease-causing organism.
AmFAR's early funding of Dr. Johnston's critical work
on DNA vaccines was acknowledged in the journal Nature
(377: 632-635), where his findings were published in October 1995. The editors of Nature wrote that Dr. Johnston's
approach may offer "a simple route to identifying candidate
vaccines against a variety of human pathogens." The article
in The Economist described it as "tantalizing stuff."
How does the DNA strategy differ from more traditional
approaches? Once in the body, the DNA enters cells. There,

its information is
read, just as the
genes of a live virus
would be read during a true infection.
The resulting processes resemble
infection, but because only part of
the virus' DNA is
present, the same
dangers are not
posed. DNA vaccines lend themselves to manipulations. For example,
the components of a
DNA vaccine are
easily modified to
make a vaccine that Stephen A. Johnston, M.D.,
targets different, University of Texas Southwestern
even multiple, Medical Center, a pioneer in the field
strains of a virus or of DNA vaccine research and an
AmFAR Gift for Life basic science
diffe.reoventp rgrantee. Dr. Johnston says in regard
virus. Moreover, to his research, which began in 1992,
since DNA vaccines "AmFAR was the only one that
are heat-stable (i.e., would fund DNA vaccination at
they don't need re- the time. AmFAR was therefrom
frige ration) and the very beginning."
inexpensive to produce, they have the
potential for distribution at a reasonable cost throughout
the world. No wonder DNA vaccines are generating so much
excitement among researchers, public health officials, and
drug companies worldwide!
Today, several companies are developing HIV DNA vaccines, and a number of these vaccines are now being tested
in clinical trials. Looking back, Dr. Johnston, whose early
grant applications were rejected by other agencies, has said,
"AmFAR was the only one that would fund DNA vaccination at the time. AmFAR was there from the very beginning."
This article is reprinted from the 1996 Annual Report.

Targeted
Initiatives
(Continued from page 1)
AmFAR always seeks to encourage
and promote research of the highest
quality. Therefore, all the grant applications received are peer-reviewed by
AmFAR's Scientific Advisory Committee, a voluntary body whose members
include experts in the various fields of

AIDS research supported by AmFAR.
The Committee evaluates the scientific
merit of each proposal; its relevance to
the control of the epidemic or its potential benefit to patients with AIDS and
related conditions; the qualifications,
experience and productivity of the
investigator(s), and the facilities available to them. The Scientific Advisory
Committee makes its recommendations
to AmFAR's Board of Directors, which
makes all awards.