HIV/AIDS Vaccines - National Institute of Health
by The NIH
HIV/AIDS Vaccines
NATIONAL INSTITUTES OF HEALTH
Despite education and treatment advances, experts project a
worsening of the human immunodeficiency virus (HIV) crisis
through the year 2000. HIV infection and AIDS death rates will
continue to mount worldwide. In the United States, the tally of
AIDS cases will escalate, particularly among women and
minorities. If present trends continue, numbers of new
infections will remain relatively stable in Europe and North
America but will increase in parts of Latin America, Africa and,
most markedly, in Asia.
Developing safe and effective vaccines to curb the human and
economic costs of the HIV/AIDS pandemic has become an
international health priority. To help accomplish this goal, the
National Institute of Allergy and Infectious Diseases (NIAID),
which spearheads federal funding for biomedical research on
HIV/AIDS for the National Institutes of Health (NIH), has
intensified its HIV vaccine research program.
NIAID'S HIV VACCINE PROGRAM - A BALANCED STRATEGY
The Institute's Division of AIDS (DAIDS) directs the HIV
vaccine research program. Institute staff meet regularly with
scientific, public health and community advisors to review the
priorities and operation of the program.
To accelerate research progress, the program has two main
thrusts: 1) foster basic research on the structure and function
of HIV, vaccine formulations, vaccine delivery systems and
laboratory studies of vaccine performance; 2) promptly evaluate
promising candidate vaccines in animal models and, if warranted,
in humans.
NIAID grantees and contractors around the country work
closely with DAIDS staff to attain these goals. The Institute
funds several collaborative ventures to enhance coordination of
HIV vaccine research. These include the following:
þ National Cooperative Vaccine Development Groups for AIDS:
Teams of scientists from academia, government and industry
generating novel approaches to HIV vaccine design and evaluate
these concepts in the laboratory and in animal models.
þ AIDS Cooperative Adjuvant Groups: Multidisciplinary
groups of scientists developing new adjuvants, substances that
can be combined with a vaccine to increase the type, strength or
duration of immune responses elicited.
þ AIDS Vaccine Clinical Trials Network: Clinical
researchers conducting Phase I and II human trials of
experimental HIV vaccines. The network includes a
specimen bank, immunology laboratories and data analysis center
that support this research.
þ Primate research laboratories: Scientists investigating
HIV-vaccine-related questions by testing HIV and HIV-like
vaccines in chimpanzees and monkeys.
þ HIV Variation Project: Researchers examining the rates
and magnitudes of genetic and immunologic changes in HIV and
related retroviruses and their consequences for vaccine design.
In addition, NIAID's nationwide university- and community-
based clinical trials programs are conducting trials of candidate
therapeutic HIV vaccines.
Planning for Efficacy Trials
Inevitably, promising HIV candidate vaccines suitable for
large-scale testing of their effectiveness will be identified.
The Institute has begun laying the groundwork for such Phase III
trials in the United States and abroad to ensure that no delay in
starting these trials occurs.
Field data on virus strains being transmitted, rates of new
infections and the prevalence of sexually transmitted disease and
other potential co-factors of HIV transmission are being
collected from various populations at high risk for HIV
infection.
Institute staff assist public health and government
officials, community members, scientists and others affiliated
with potential trial sites to resolve numerous legal, practical
and ethical issues that attend planning for efficacy trials.
These concerns include vaccine cost, delivery and liability,
training of medical personnel and conduct of the trial at
potential overseas sites.
CHALLENGES IN DESIGNING HIV VACCINES
The ideal HIV vaccine would be inexpensive, easy to store
and to administer, and elicit strong, appropriate immune
responses that confer long-lasting protection against both
bloodborne and mucosal (sexual) exposure to multiple HIV
subtypes. What follows describes some reasons this ideal has not
been easy to achieve.
What Constitutes Immune Protection?
Researchers face unprecedented scientific obstacles in
trying to develop effective vaccines for HIV. First, exactly how
the body can protect itself against HIV remains a mystery.
Unlike most other viral diseases for which successful vaccines
have been made, recovery from HIV infection has not been
documented. HIV researchers have no human model of protection to
guide them when constructing candidate vaccines.
Now that the pandemic has matured, however, long-term HIV
survivors and others provide ample evidence that some people
appear better able than others to resist HIV infection or the
development of AIDS. Much of this information has come from
protracted studies of people at high-risk for HIV. The
"resisters" can be grouped as follows: 1) those who maintain
healthy levels of CD4+ T cells, a crucial immune cell and HIV's
main target, for seven to ten years or more after becoming
infected; 2) individuals with HIV infection who lose a
significant proportion of CD4+ T cells but seem to remain healthy
in spite of this loss; and 3) people who appear to escape
infection despite repeated exposure to the virus.
To determine if genetic or biologic factors affect the
body's response to HIV exposure and infection, NIAID-funded
investigators and others are comparing long-term HIV survivors
with people who have become easily infected or sick. Leading
areas of research include genetics, individual variations in the
immune response, and exposure to or infection by less deadly
variants of HIV. Any patterns found in the data may help
investigators decode what contributes to protective immunity
against HIV.
HIV Transmission Complicates Protection
Unlike most other viruses, HIV can be transmitted and can
exist in the body not only as free virus but also in infected
cells. Thus, a vaccine against HIV may be required to stimulate
the two main types of immunity. Humoral (antibody-mediated)
immunity defends against free virus when B immune cells produce
custom-made proteins, called antibodies, including neutralizing
antibodies that inactivate the virus. Cellular (cell-mediated)
immunity directly or indirectly results in the killing of
infected cells by immune cells. A major unanswered question is
how important each type of immunity is to protection from HIV.
Data on long-term HIV survivors and those generated from animal
model and human clinical trials of experimental HIV vaccines may
offer clues to the answer.
Another factor complicates the attempt to define HIV
protection. Eighty percent of HIV transmission worldwide occurs
sexually, according to the World Health Organization. Thus, an
effective HIV vaccine also may have to stimulate mucosal
immunity. Immune cells found in the lining of the respiratory,
digestive and reproductive tracts and in nearby lymph nodes
provide the first line of defense against HIV and other
infectious organisms. Unfortunately, relatively little is known
about how the mucosal immune system works. NIAID has increased
its commitment to research on laboratory tools and animal models
that will enable scientists to learn more about how HIV and other
pathogens elude the defenses of mucosal cells and the immune-
modulating proteins, called cytokines, that they stimulate.
Adjuvant Research Revived
One hopeful note is the renewed interest in adjuvants,
substances formulated with vaccines to boost specific immune
responses. Interest in adjuvants has revived because new-
generation vaccine candidates containing only part of HIV and no
live virus stimulate less potent immunity than traditional
vaccines made from live-weakened or whole-inactivated viruses.
Some adjuvants also stimulate mucosal immunity.
An adjuvant may work well with several different
experimental vaccines. Thus the Food and Drug Administration
(FDA) licenses the vaccine formulation, or the antigen-adjuvant
combination, for human use rather than the adjuvant alone.
The activity of the adjuvant alum was first described in
1926, and alum remains the only adjuvant in use in FDA-licensed
human vaccines. Alum increases the strength of antibody
responses generated by the vaccine antigen. New, experimental
adjuvants can increase the type, strength and durability of
immune responses evoked by an experimental vaccine. For example,
some vaccine antigen/adjuvant combinations can induce cell-
mediated immune responses, even if the vaccine antigen by itself
does not.
NIAID-funded scientists are evaluating a panel of promising
adjuvants in monkeys to help identify the suitable candidates to
incorporate in experimental human HIV vaccines. In 1993, NIAID
began the first Phase I HIV vaccine adjuvant trials in humans.
Various adjuvants paired with two different vaccine candidates
are being compared to determine the best vaccine formulations to
pursue.
Protection Against Genetic Diversity
Another unique problem confounding HIV vaccine development
is the extensive genetic diversity among different HIV strains.
Other successful virus vaccines have had to protect against only
one or a limited number of virus strains. At least five genetic
subtypes, or clades, of HIV exist, each of which includes many
related but unique strains.
Strain diversity arises through genetic mutation or
recombination. Because HIV genes mutate much faster than human
genes, many variants of one HIV strain may arise within an
infected person. Also, whenever a drug or immune response
destroys one variant, a distinct but related variant can emerge.
Moreover, variants may thrive in different tissues. Any of these
changes may yield a variant that can escape immune detection.
Generally, an individual appears to be infected by only one
HIV strain, but a preventive vaccine will need to generate immune
responses that protect noninfected individuals from all different
clades of HIV to which they may be exposed. Conserved regions of
HIV genes that may exist in more than one clade would be
desirable to find. A cocktail vaccine containing several
proteins or peptides from different HIV strains may be the most
effective way to invoke broad-based immunity.
Immune System Breakdown
Perhaps the most difficult challenge vaccine researchers
face is that the major target organ of HIV is the immune system
itself. HIV infects key cells that regulate the immune response,
modifying or destroying their ability to function. After
infection, HIV incorporates its genetic material into that of the
host cell. There the virus can hide indefinitely until the cell
receives an activation signal and makes new viruses. Other cells
act as HIV reservoirs, harboring intact viruses that may remain
undetected by the immune system.
Understanding how HIV disease evolves, especially during
early infection, is a high priority research area for the
Institute. Scientists at NIAID and elsewhere have shown that no
true period of biological latency exists in HIV infection. After
entering the body, the virus rapidly disseminates, homing to the
lymph nodes and related organs where it replicates and
accumulates in large quantities. Paradoxically, the filtering
system in these lymphoid organs, so effective at trapping
pathogens and initiating an immune response, may help destroy the
immune system by infecting the steady stream of CD4+ T cells that
travel there in response to HIV infection.
Early HIV infection is an example of one area of
investigation where basic research in immunology, epidemiology
studies of long-term survivors, and animal model and human
clinical trials all can contribute to a greater understanding of
the immune system breakdown and ways vaccines may be designed to
prevent or slow down the progress of HIV disease.
Animals Model Studies - Imperfect But Important
Animal model studies can answer critical questions that may
pose undue risk to humans or cannot be answered using computer
modeling or laboratory tests. For example, animals can be
inoculated with an experimental vaccine and then challenged with
HIV to test the vaccine's effectiveness--a study that would be
unethical to conduct in humans.
Although chimpanzees can be infected with HIV, they have not
yet been observed to develop disease. Moreover, they are
expensive to maintain.
Most large-animal AIDS research is conducted with macaque
monkeys. They can be infected with simian immunodeficiency virus
(SIV), a retrovirus similar to HIV that causes an AIDS-like
disease. The genetic and physical structures of SIV differ
enough from those of HIV, however, that extrapolating the results
of SIV experiments to humans must be done carefully.
Despite the lack of an ideal animal model, important
information has been obtained from both monkeys and chimpanzees.
Experiments in both primates have demonstrated the feasibility of
developing a protective vaccine. Moreover, two new animal
models--infection of pigtail macaques with HIV and of rhesus
macaques with a chimeric SIV-HIV virus--may become valuable
alternatives to chimpanzees for evaluating candidate HIV
vaccines.
In late 1992, NIAID-funded investigators first reported
results from their experiments with a live-attenuated SIV vaccine
made by deleting the SIV nef gene. The vaccine demonstrated
durable protection against high intravenous doses of a lethal SIV
different from that used in the vaccine. These findings provide
hope that safe and effective human HIV vaccines can be developed.
CLINICAL RESEARCH
Important immunologic targets on HIV and on infected cells
have been identified. For example, scientists now know that
gp120, the principal envelope protein of HIV and the main target
for antibodies and some cellular immune responses, contains the
cell attachment site called CD4. For
these reasons, vaccines based on genetically engineered HIV
envelope proteins--gp160 and one of its cleavage products, gp120-
-have been the most well-studied to date.
As of May 1993, about 23 experimental HIV vaccines were in
various stages of human testing around the world. Vaccine
approaches in development or in clinical trials include:
þ subunit vaccine - a piece of HIV, such as the envelope
proteins gp160 or gp120, produced by genetic engineering.
þ recombinant vectors - a live bacterium or virus such as
vaccinia (used in the smallpox vaccine) that can transport into
the body a gene that makes an HIV protein.
þ vaccine combinations - use of a recombinant vector vaccine
to induce cellular immune responses followed by booster shots of
a subunit vaccine to stimulate antibody production.
þ peptide vaccine - chemically synthesized portions of HIV
proteins (peptides) known to stimulate immunity.
þ virus-like particle vaccine - a non-infectious HIV look-
alike that retains all or part of the HIV envelope but only some
of the interior components.
þ anti-idiotype vaccine - antibodies generated against
antibodies to the virus.
þ naked DNA vaccine - direct injection of genes coding for
HIV proteins.
þ whole-inactivated virus vaccine - HIV that has been
inactivated by chemicals, irradiation or other means so it is not
infectious.
þ live-attenuated virus vaccine - live HIV from which one
or more apparent disease-promoting genes of the virus have been
deleted.
Clinical Trials of Preventive HIV Vaccines
In August 1987, NIAID opened the first clinical trial of an
experimental HIV vaccine at the NIH Clinical Center in Bethesda,
Md. The trial eventually enrolled 138 noninfected healthy
volunteers. The gp160 subunit candidate vaccine tested caused no
serious adverse effects in this safety trial.
From the beginning of that first trial until May 1993, about
two dozen preventive HIV vaccine trials have been initiated
worldwide. These Phase I trials, which enroll noninfected
participants, seek information on the vaccine's safety and
preliminary information on its ability to stimulate immune
responses.
NIAID's AIDS Vaccine Clinical Trials Network is the largest
cooperative vaccine clinical trials group in the United States.
Between 1988 and August 1993, more than 1,300 men and women have
participated in HIV vaccine trials conducted at its five medical
center sites located in Seattle, Baltimore, St. Louis, Nashville
and Rochester, N.Y.
To date, all the vaccine candidates tested have been well-
tolerated, generally producing only mild side effects typical of
most vaccines. The most thoroughly tested candidates stimulate
production of antibodies, although levels decrease within a
relatively short period of time. Initial formulations and
dosages of these vaccines produced few or low levels of
neutralizing antibodies, and rarely elicited cytotoxic T cells,
which are invoked through cell-mediated immunity to kill HIV-
infected cells. With the newer protocols that have increased
vaccine dosages, changed immunization schedules, tested
experimental adjuvants, and used recombinant proteins shaped more
like those of native HIV, more promising data have begun to
emerge.
In December 1992, NIAID launched the first Phase II
preventive HIV trial worldwide. Earlier trials enrolled
noninfected people at low risk of HIV infection and primarily
sought data on safety. The Phase II trial includes noninfected
volunteers with a history of high-risk behavior--injection drug
use, multiple sex partners or sexually transmitted diseases.
Participants are counseled repeatedly to avoid any behavior that
puts them at risk of HIV infection. The trial will help
determine if these distinct populations, representative of people
likely to be enrolled in large-scale efficacy trials, respond
differently to the vaccines. The trial also will gather more
detailed data on the safety and ability of the vaccines to
stimulate immune responses.
As experimental HIV vaccines continue to grow in number and
kind, clinical trials are expected to yield more valuable
information about the relative effects of different vaccine
formulations and different methods of delivery on the immune
response.
Therapeutic Vaccines - A New Strategy
Traditionally, vaccines are used to stimulate immune
responses that protect noninfected individuals from acquiring
infection or disease upon subsequent exposure to the virus. For
HIV infection, delaying or preventing the onset of AIDS symptoms
in an infected individual through therapeutic immunization are
desirable goals as well. Any agent that requires infrequent
administration and might prolong the disease-free state of those
infected would be beneficial to the public health. Also, if the
agent reduces the amount of virus in an infected individual, the
risk of HIV transmission to sexual partners or to a pregnant
woman's fetus or newborn also might be decreased.
Can vaccines boost immune responses to HIV or reduce the
amount of HIV in infected people? Experience with therapeutic
vaccines is very limited. As of early 1993, NIAID and other
sponsors had initiated more than a dozen therapeutic HIV vaccine
trials worldwide, including some larger more advanced trials, to
answer this question. So far, the vaccine candidates being
tested seem to be well tolerated, but longer follow-up is needed
to generate more data for interpretation.
Most therapeutic HIV vaccine trials have enrolled people who
are HIV-infected but otherwise healthy and free of AIDS symptoms.
In the first half of 1993, NIAID launched the first trials in the
world to test therapeutic HIV vaccines in three additional
populations: pregnant HIV-infected women and infants born to
them, and asymtomatic HIV-infected infants and children. Early
1993 also marked the opening of NIAID's first therapeutic HIV
vaccine trial to include people with more advanced disease.
FUTURE DIRECTIONS
Although the challenges are daunting, scientists remain
optimistic that safe and effective HIV vaccines can be developed.
Basic researchers have made tremendous strides in understanding
how HIV causes disease, recently describing how throughout the
long symptomless period of HIV infection, the virus gradually
ravages the lymph nodes and related organs, a process
imperceptible by the patient who generally feels well during this
time.
Furthermore, novel ways to present HIV proteins to the
immune system continue to be designed and tested, as do new
antigen/adjuvant vaccine formulations. A growing number and
variety of experimental vaccines are entering clinical tests in
primates and humans, and more trials are exploring whether
changing immunization schedules, increasing booster doses, or
using a combination vaccine strategy can stimulate stronger, more
durable immune responses. Together, progress in basic and
clinical research is moving scientists closer toward identifying
products suitable for large-scale HIV vaccine efficacy trials.
Prepared by:
Office of Communications <br>
National Institute of Allergy and Infectious Diseases<br>
National Institutes of Health<br>
Bethesda, Maryland 20892<br>
Public Health Service<br>
U.S. Department of Health and Human Services
October 1993
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