Pathways of Discovery:
HIV Vaccine Research and Development
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YRG Care, a premiere HIV referral center in Chennai, Tamil Nadu,
India, actively educates communities about HIV vaccine research in
many venues. These young people are watching a play about adults
being encouraged to get tested for HIV as part of participating in a
clinical trial for a novel HIV vaccine.
Source: McCluskey/USAID |
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The HIV/AIDS pandemic continues to impose a global burden, especially
on developing countries. In the present as in the past, viral
infectious diseases are most effectively controlled – some even
eradicated – through prevention programs that include a vaccine.
No single approach to HIV/AIDS prevention is likely to have a dramatic
impact. Integrated approaches to prevention, detection, and
management that are tailored to specific populations yield the best
results. Reversing the course of the AIDS pandemic will require
carefully combined strategies that include behavioral, biomedical,
and even surgical methods to prevent HIV, as is the case with male
circumcision. An effective HIV vaccine would significantly advance
successful prevention strategies to control the AIDS pandemic.
Vaccine Research and Development:
A Complex Scientific Endeavor
Although vaccines have proven to be among the most efficient
tools to stop epidemics like smallpox, polio, and measles, their
development is neither easy nor rapid. Vaccines that are currently
administered routinely and are saving countless lives have taken up
to 50 years to discover and develop. The first HIV vaccine trial
began in 1987; since that time, many challenges have surfaced in
the pursuit of a safe and effective vaccine against the virus. If HIV
caused disease in animals the way it does in humans, testing vaccines
for their potential effects could be done in predictive animal
models. Since such a reliable model does not exist for HIV, the
only way to confidently prove the efficacy of a candidate vaccine is
to conduct clinical trials in people who are at risk for HIV infection.
The goal of all vaccines is to create an
immunological response that can either prevent
infection or minimize the symptoms and the
course of a disease. |
Necessarily, these trials are lengthy, complicated, and expensive
endeavors. Adding to their complexity is HIV’s high rate of genetic
variability, which may render a vaccine effective against only some
clades, or variants, of the virus. Ideally, a vaccine would provide
global protection.
USAID’s Approach to HIV Vaccine
Research and Development
As an agency committed to international development and a key
partner in the expansion of care and treatment to ease the grip
of the pandemic, the U.S. Agency for International Development
(USAID) brings valuable expertise and resources to the goal of
developing a globally relevant HIV vaccine. In addition to five
decades of experience in international development and field
presence in nearly 100 countries, USAID has in-house expertise
in clinical trial design and conduct, immunology, virology, product
development, pharmaceutical regulatory affairs, ethics, community
engagement and gender issues. Inevitably, more large-scale
human trials are needed in developing countries to understand
how the human immune system behaves after being stimulated
by a preventive HIV vaccine. USAID’s broad international partnerships
in HIV prevention, care, and treatment, and its perspective,
are fundamental to the eventual success of HIV vaccine
discovery and distribution.
International AIDS Vaccine Initiative
Since 2001, USAID has funded the International AIDS Vaccine Initiative
(IAVI), a nonprofit organization that acts as a virtual pharmaceutical
company to accelerate the development and clinical
testing of HIV vaccine candidates. This support is an important part of U.S. Government (USG) efforts to address the pandemic
from every conceivable direction.
IAVI facilitates collaboration among universities, governments, and
private-sector groups to ensure that the appropriate resources are
available for each phase of product development.
IAVI also provides analyses of important issues affecting the HIV
vaccine field, such as regulatory and licensing issues, normative
laboratory values in African populations, new strategies to engage
biopharmaceutical companies in HIV vaccine development, and
preparation for the manufacture and distribution of vaccines once
they are proven effective. Under a five-year cooperative agreement
initiated in 2006, USAID is supporting IAVI to strengthen
clinical trial capacity in developing countries, advance the development
and testing of novel vaccine candidates, enrich the pipeline
of next-generation HIV vaccine candidates, and analyze policy and
future access-related issues in the HIV vaccine field.
Partnership for AIDS Vaccine Evaluation
In addition, USAID collaborates with the National Institutes of
Health (NIH), the U.S. Centers for Disease Control and Prevention
(CDC), and the U.S. Military HIV Research Program (USMHRP)
through the Partnership for AIDS Vaccine Evaluation (PAVE). PAVE
is a voluntary consortium of USG agencies and key USG-funded
organizations involved in the development and evaluation of
HIV/AIDS preventive vaccines and the conduct of HIV vaccine clinical
trials. USAID is represented on the PAVE Executive Steering
Group. IAVI, USAID’s major partner for HIV vaccine development,
also is an affiliate of PAVE.
Neutralizing Antibody Consortium
USAID provides funds for the IAVI-sponsored Neutralizing Antibody
Consortium (NAC), which was established in 2002 on the
belief that the induction of broadly neutralizing antibodies capable
of preventing viral entry, and thus infection, is critical to the eventual
success of an HIV vaccine. Most vaccines work by neutralizing the
infectious agent with antibodies and then eliminating the agent
and/or infected cells. Because of HIV’s many ways of immune evasion,
the infection does not usually result in the body’s creation of
broadly neutralizing antibodies. Since nature has not been capable
of aborting HIV infection altogether, or been clear on how it rarely
controls HIV, we must be able to improve upon these responses.
Currently, it remains unclear how to generate broadly neutralizing
antibodies against HIV. IAVI established the NAC to delve into
novel strategies of structure-based designs by a consortium of
scientists with wide-ranging skills, supported by a generous supply of
core resources and a quasi-industrial approach to problem-solving
and management practices. Because relatively few broadly neutralizing
antibodies to HIV are known and characterized, IAVI initiated a
major undertaking in 2006 to generate more of them. “Protocol G”
was initiated at clinical sites worldwide to seek out the rare HIV-infected
individuals who seem to be making antibodies that can react
with a broad array of HIV viruses and who use their lymphocytes to
generate broadly neutralizing monoclonal antibodies (mAbs)/h.
How USAID Ensures
Scientific Review and Due Diligence
As an agency responsible for development assistance, USAID is
composed of experts who are accountable for the stewardship
of U.S. resources used to introduce and manage evidence-based
programs and practices through highly skilled implementing partners.
In addition to the internal, rigorous procedures that USAID
relies upon to approve funding for these cooperating agencies,
the Agency also looks to its partners and their processes for
vetting their respective scientific portfolios.
IAVI is a good example of an organization that systematically scrutinizes
its scientific agenda of research and development in search of
an HIV vaccine. IAVI’s Scientific Advisory Committee (SAC) is a formally
constituted committee reporting to IAVI’s Board of Directors
and, as such, advises the Board on scientific issues and is represented
on the Board by the SAC Chair. USAID has access to SAC
meeting reports, which provide the recommendations of the SAC
and how IAVI has approached each recommendation. This group
of internationally acclaimed immunologists, vaccinologists, and virologists convenes twice a year to review the R&D portfolio
under consideration by the organization. USAID receives its
proceedings and is confident in this method of intense examination
of scientific research while exercising its authority to call upon
additional independent external advisors as needed. All scientific
proposals reaching the level of IAVI’s SAC are pre-evaluated using
standardized selection criteria by a group of internal experts in vaccine
discovery and product development. A detailed scientific and
business due diligence is conducted for the proposals of interest,
the intensity of which depends upon the stage of the technology
platform and to what degree IAVI’s support is expected. The Chair
of IAVI’s SAC and its R&D management committee review each
proposal and offer their final recommendations to the senior management
team. Approval from IAVI’s Board of Directors is also
sought when projects require substantive organizational resources
and funding. The SAC subcommittees – Project Management
Committee and Clinical Trials Committee – provide ongoing oversight
of approved projects and their respective progress against
milestones on a quarterly and biannual basis.
• Since 2001, USAID has contributed $134 million to help discover an HIV vaccine. Currently, USAID is committing annual
funding of $28 million through 2011 for HIV vaccine R&D.
• USAID provides support for all phases of HIV vaccine applied R&D, infrastructure, and capacity building for clinical trial
conduct, public communications, and policy analysis through a partnership with the International AIDS Vaccine Initiative.
USAID does not support basic research.
• USAID plans involvement with the Global HIV/AIDS Vaccine Enterprise.
• USAID facilitates coordination between HIV vaccine clinical trial activities and HIV/AIDS prevention, care, and treatment
programs in developing countries. |
The Science Behind HIV Vaccine
Research and Development
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Source: Lydia Martin/Courtesy of Photoshare |
Using History to Inform the Future
It is possible that the first generation of HIV vaccines will be
unable to prevent acquisition of the virus, but will be able to
preserve the immune system by limiting the damage of the initial
infection by containing viral replication and by delaying the
progression to AIDS – both of which also may lead to less
transmission of HIV.
The search for an HIV vaccine is particularly challenged by
the complex properties of the virus, specifically its uncanny
ability to mutate and recombine, its ability to integrate into the
genome of host cells and create latent infection, and its ability
to avoid and escape immune responses by concealing the part
of its outer coat that induces protective antibodies.
Despite these difficulties, scientists are making advances in
defining early events in HIV transmission. These critical findings
may lead to understanding what enables protection from HIV
acquisition and replication in, for example, those who are highly
exposed yet uninfected, and those known as “elite controllers”:
individuals who control HIV replication for several years in the
absence of highly active antiretroviral therapy, known as
HAART. Their immune systems provide convincing evidence
that an effective vaccine against HIV is possible, despite the scientific
challenges being faced.
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Antibodies that are created by B-cells can:
attach to free virus and prevent viral entry
into T-cells
neutralize newly released virus particles
bind to infected cells and trigger their elimination
Cytotoxic T-cells are coordinated by helper T-cells and can act by recognizing viral proteins (HLA-1) attached
to the surface of infected cells and effectively destroy
the cells. The viral proteins are attached to the cell
surface by HLA molecules, which are part of a person’s
genetic signature.
Photo Source: Courtesy of R. Bruce Walker |
Much work is being done to understand the potential effect of vaccines designed to produce protective cytotoxic and
memory T-cells that might hold HIV “at bay” by limiting viral replication, thereby preserving the immune system of the infected
person. There is serious emphasis on which vectors might enhance HIV-specific immune responses by introducing
the vaccine antigens into the body to create functional and long-term defenses in the human immune system.
Several groups are striving to elicit effective antibody responses that can neutralize HIV before it can enter the host T-cell.
Others are characterizing how the genetic makeup of each person plays a role in seemingly being less susceptible to HIV
and being able to delay the onset of AIDS. These studies may hold the promise of providing scientific insights into defining
the correlates of protection from HIV and, as such, defining what will be required of a vaccine to create a similar immunity
against HIV. USAID provides substantive support to many of the scientific responses to these extraordinary challenges
through its strategic partnership with IAVI and allegiances with related organizations interested in discovering an
effective HIV vaccine.
Future Directions
Through its key partnership with IAVI and interactions with other
organizations, USAID engages in HIV vaccine R&D and related
activities. As the Global HIV/AIDS Vaccine Enterprise evolves
into a growing global initiative to coordinate resources, share
technology and data, and foster greater collaboration, USAID
looks forward to contributing its developing-country expertise
to this valuable endeavor. USAID also facilitates linkages between
HIV vaccine clinical trial activities in Africa and Asia and HIV/AIDS
treatment, care, and prevention services under the U.S. President’s
Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS,
Tuberculosis and Malaria.
“We must never lose sight of what a
vaccine against HIV could accomplish. So many
have suffered for so long; the least we can do
is patiently focus our hopes and hard works
on the science that can lead us to a promising
vaccine capable of diminishing this epidemic.” |
Margaret M. McCluskey, RN, MPH,
Senior Technical Advisor for HIV Vaccines,
USAID Office of HIV/AIDS
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As promising vaccine candidates are identified, USAID will provide
support through IAVI to assess how the availability of an HIV vaccine
might contribute to changing risk behavior, and how these effects
can be countered. USAID is planning for the introduction of
HIV vaccines in developing-country settings. These activities will
eventually include engaging host-country governments to register
the new products, managing supply chain and logistics of vaccine
delivery, developing protocols and training health care workers
through partnerships that pre-exist in current USAID networks.
Although there is little doubt about the potential for an effective
HIV vaccine to curb the pandemic, the road to one is long and
arduous. Given the challenges, it is likely that no single candidate
will provide a definitive solution to the pandemic. The likely scenario
is one of discovering and mobilizing a variety of new tools to
stop HIV, each with its own limitations. When used in combination
with other approaches, such as consistent condom use and partner
reduction where possible, we may be able to turn the tide against
the growing epidemic.
USAID is an established technical assistance and development
agency with a reputable history of supporting programs to improve
public health. Vast improvements in public health are not
accomplished in a hurry. Indeed, it will take time to discover and
develop a safe and effective HIV vaccine. USAID has the foresight
to support HIV vaccine research while preparing for the introduction
of this invaluable tool in tandem with governments, nongovernmental
organizations, and the private sector, which are
also faithfully pursuing the promise of a vaccine to control AIDS.
Glossary of Key HIV Vaccine Terms
Adaptive immune response - a "learned" response in which the
immune system responds specifically to an invader, such as a virus,
and retains the ability to respond more quickly in the future (called
immune memory). Vaccines can induce immune memory.
Antibody - (also called immunoglobulin) an infection-fighting
protein, made and secreted by B-Iymphocytes, in blood or secretory
fluids that recognizes, neutralizes, and helps destroy pathogenic microorganisms (e.g., bacteria, viruses) or toxins. Antibodies are made
in response to stimulation by antigens. Generally, each antibody
binds only to the specific antigen that stimulated its production.
Antibody-mediated immunity - (also known as "humoral
immunity") protection provided by antibodies as opposed to
cellular immunity.
Antigen - any foreign substance that enters the body and is recognized
by a component of the immune system (I.e., antibodies, cells),
causing an immune response. Antigens are often agents such as invading
bacteria or viruses (see immunogenicity).
B-cells or B-lymphocytes - white blood cells of the immune
system derived from bone marrow and spleen. B-cells develop into
plasma cells, which produce antibodies (see memory cells).
Cell-mediated immunity - (also called cellular immunity) the
branch of the immune system that targets host cells infected with
microorganisms. such as viruses, fungi, and certain bacteria. It is
coordinated by helper T-cells and Cytotoxic T-cells (as opposed
to humoral immunity, which is driven by antibody responses).
Clade - a subtype or strain of HIV. Different HIV clades exist in
various regions of the world as groups of related viruses. Clades are
defined by the degree of genetic similarity of the viruses that make
them up.
Correlates of immunity - (also called correlates of protection)
the specific immune responses that provide protection from a
certain infection. The precise correlates of immunity for HIV are
as yet unknown.
Cytotoxic T-cells (CTL) - a lymphocyte able to kill foreign cells
or cells of one's own body that have a new antigen on their surface:
CTLs can destroy cancer cells, cells infected with viruses, fungi, or
certain bacteria. CTLs can destroy infected cells. whereas antibodies
generally target free-floating viruses in the blood. One type of
CTL carries the CD8 marker. CD8 T-cells may be CTL or may also
release substances that inhibit the growth of viruses. Also known
as killer T-cells.
Genome - the complete DNA present in an individual cell or virus.
Helper T-cells (CD4s) - a group ofT-celis that produce antibodies
and activate killer T-cells. These immune cells. which carry the CD4
cell surface marker. are the primary targets of HIV, Helper T-cells
are the chief regulatory cells of the immune system, controlling
activities such as turning antibody production on and off.
Humoral immunity - protection provided by antibodies
(as opposed to cell-mediated immunity). Also known as "antibodymediated
immunity."
Immune system - the body system, made up of many organs and
cells, that protects against infection, disease and foreign substances
or antigens. This response may neutralize or eliminate the antigens
and provide immunity.
Immunogenicity - when attributed to a test vaccine, defines the
product's ability to cause the body to produce antibodies or T-cells
that may protect against an infection. disease. or foreign substance.
Innate Immunity - a relatively nonspecific response that protects
against a whole class or type of invaders but does not generate
immune memory (see adaptive immune response).
Killer T-cells - a group of T-cells that is activated by helper T-cells
and has the ability to destroy cells infected by foreign invaders (such
as viruses). Also known as cytotoxic T-cells, they may belong to the
CDS group.
Lymphocytes - the diverse set of white blood cells (each with
different functions) that are responsible for immune responses.
There are two main types: B-cells (responsible for producing antibodies)
and T·cells (which orchestrate various aspects of the immune
response and carry out specialized functions such as destroying cells
infected with pathogens). These cells are produced in the bone marrow
and thymus, respectively.
Memory cells - T-cells or B-cells that have been exposed to a specific
invading organism and remembers the organism. Memory cells
help the immune system respond faster when they encounter invading
organisms for the second time. Memory cells are long-lived subsets
ofT -cells and B-cells that have been exposed to specific antigens
and can "recall" them (and then quickly mobilize an immune response),
even if infection occurs many years later.
Mutation - a change in the genetic material (DNA) inside a cell
that results in a new characteristic. HIV is a virus that mutates
frequently as it replicates (reproduces itself), often resulting in
a stronger and/or drug-resistant virus.
Neutralizing antibody - an antibody that prevents a virus from
infecting a cell, usually by blocking viral entry points (receptors)
on the virus.
Preclinical - testing of a vaccine or drug in cells or animals
before testing in humans.
T-cells - one of two main types of white blood cells critical to
the immune system. They include CD4+ and CDS+T-cells. The "T"
stands for the thymus, where T-Iymphocytes mature.
Virus - a microorganism composed of a piece of genetic material
(RNA or DNA) surrounded by a protein coat. To replicate, a virus
must infect a cell and direct the cellular machinery to produce
new viruses.
Vector - a bacterium or vi rus that does not cause disease in
humans and is used in genetically engineered vaccines to transport
encoding genes into the body to induce an immune response.
Examples include adenoviruses, vaccinia, and canarypox.
The above definitions are a combination of glossaries compiled by
the U.S. National Institute of Allergy and Infectious Diseases and by
IAVI, edited by USAID. For more definitions and answers to FAQs,
see the following:
Download the PDF version of this issue brief [PDF, 551KB]
The U.S. Agency for International Development works in partnership with the U.S. President's Emergency Plan for AIDS Relief.
October 2008
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