The Quest for an Effective
HIV Vaccine Presents New Possibilities, Challenges
A vaccine that prevents HIV infection remains an important goal
in the fight against AIDS, but the current top HIV vaccine candidates
may not work in this way, say scientists at the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National
Institutes of Health (NIH). Rather, the first successful preventive
HIV vaccines, if administered prior to HIV infection, may reduce
HIV levels in the body, thereby delaying the progression to AIDS
and the need to start antiretroviral drugs. These vaccines may
also reduce the chance that a person infected with HIV would pass
the virus on to other people, according to NIAID Director Anthony
S. Fauci, M.D., and Margaret I. Johnston, Ph.D., director of NIAID’s
Vaccine Research Program in the Division of AIDS.
In a review article in the May 17 issue of The New England
Journal of Medicine, Drs. Johnston and Fauci examine the
daunting challenges posed by HIV, the evolution of HIV vaccine
research, the role T cells may play in HIV vaccine effectiveness,
and how the first successful HIV vaccine may fit into a comprehensive
HIV/AIDS prevention effort.
Vaccines typically work by mimicking the effects of natural exposure
to a specific microbe. Because of initial exposure, the immune
system develops the ability to recognize the specific microbe and
can protect the human body against it if it reappears. HIV, however,
has thwarted scientists’ efforts thus far to develop a classic
preventive vaccine for the virus because of its ability to integrate
into target cells and evade clearance by the immune system. The
interaction between HIV and the immune system is complex, and how
different HIV-specific immune responses help to control infection
is only partially understood.
“The development of an HIV vaccine is a complex research challenge
because the virus is unusually well-equipped to elude immune defenses,” says
Dr. Fauci. “Much progress has been made; however, we must continue
research efforts to improve our understanding of HIV and how it
evades the immune system, to design new vaccine candidates and
to assess the most promising ones in clinical trials.”
Dr. Johnston adds, “An important research challenge is to determine
if these so-called T-cell vaccines that primarily induce a cellular
immune response can have a beneficial effect by reducing viral
levels and preserving critical cells needed to control infection.
There will be a tremendous public health challenge as well, in
an HIV vaccine that does not completely prevent the virus from
establishing itself in the body.”
Once HIV enters the body, it infects crucial CD4+ T cells, replicates,
spreads throughout the body and establishes HIV reservoirs in lymphatic
tissues. Within weeks of exposure, virus levels peak and then decline
to levels that may remain low for months or years. It is believed
that CD8+ T cells — so-called killer T-cells — are
responsible for this reduction in HIV levels; however, their ability
to continue to suppress the virus declines over time as the virus
mutates and the immune system is progressively destroyed.
The infection of CD4+ T cells occurs very early in HIV disease,
and virus persists indefinitely. Other viruses also replicate robustly
but, unlike HIV, most do not establish a permanent reservoir of
infected cells in the body. The window of opportunity to prevent
long-term HIV infection may close permanently once a pool of latently
infected cells is in place, Drs. Johnston and Fauci note. Neutralizing
antibodies, which can attach to and eliminate free virus, only
appear after HIV levels have declined substantially. Further, the
effectiveness of these antibodies is stymied because of the rapid
genetic changes that occur in HIV’s outer envelope protein, which
allow the virus to escape detection.
While early efforts to develop an HIV vaccine focused on the viral
envelope, an improved understanding of how HIV causes disease has
brought increased attention to the role that T cells could play
in an HIV vaccine by spurring cellular immunity. Numerous animal
and human studies have confirmed how important cellular immunity
is in the early and later stages of HIV infection, even though
the virus is never completely eliminated. Vaccines that induce
strong cellular immune responses may have some benefits, say the
authors. In non-human primate models of HIV infection, T-cell vaccines
have reportedly decreased the total amount of virus produced during
early infection, caused a reduction in virus levels following the
acute stage of infection, or produced some combination of these
effects. In many of these animals, disease progression was also
delayed.
Based on the scientific evidence, several questions remain, say
Drs. Johnston and Fauci: Can a vaccine that does not prevent HIV
infection but reduces virus levels and preserves a segment of uninfected
CD4+ T cells from destruction benefit the immunized individual?
Might people immunized with T-cell vaccines before HIV exposure
remain disease-free for a prolonged period once they are infected?
Additionally, T-cell vaccines may reduce secondary HIV transmission
if they can help the immune system keep viral replication at a
very low level for a long time. Studies have suggested that people
with high levels of virus — namely those in the early and
late stages of infection — are most likely to infect their
sexual partners. A preventive vaccine given before exposure to
HIV might stifle the initial burst of virus, better control virus
levels and potentially reduce that person’s ability to infect other
people, Drs. Johnston and Fauci assert.
Vaccines of this type present several complications, however.
T-cell-mediated control of HIV infection may not stave off disease
forever. Additional human studies would be needed to determine
if the vaccine also reduces the spread of HIV. Finally, an HIV
vaccine that delays but does not completely prevent disease could
not stand alone as a preventive measure; the public health community
would need to include it as part of a broader HIV prevention program,
so that recipients would minimize, or ideally, not engage in high-risk
behaviors, according to the authors.
Currently, several vaccines that induce primarily T-cell responses
are in or will soon enter expanded human clinical trials to determine
if they impact HIV infection. Researchers also continue to give
high priority to creating an HIV vaccine that induces broadly neutralizing
antibodies, which might prevent the establishment of HIV infection.
Although rare, such antibodies do exist, giving hope to scientists
that a vaccine to induce such antibodies can be designed.
Drs. Johnston and Fauci conclude that a vaccine that prevents
HIV infection by clearing the virus before cells become latently
infected remains the goal. In addition, they believe that even
a vaccine that does not prevent infection could prove beneficial
if it prolongs the disease-free period and possibly even reduces
virus transmission. If such a vaccine is shown to be successful
and is eventually licensed, it would need to be delivered as part
of a comprehensive, multifaceted HIV prevention program.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies. News releases, fact sheets and
other NIAID-related materials are available on the NIAID Web site
at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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