PI Perspective #34
March 2002 View PDF En
español
A Potent Weapon in the Battle Against HIV:
Your Own Immune System
The goal of HIV vaccines is to teach the immune system new and
hopefully better ways to win the battle against the virus. There
are different types of immune responses, those we were born with
(innate immunity) and those we “learn” (acquired immunity).
HIV vaccines exploit the side of the immune system that is learned
(acquired) by providing information to cells in new ways in hopes
of enhancing their learning and making them more effective fighters.
A Little Background
The first line of defense against nearly every new disease is our
innate immune responses. It includes cells called dendritic cells
(DCs) and natural killer cells (NK cells). These cells are out surveying
the body looking for things that don’t belong and trying to
get rid of them. They’re a bit like a neighborhood watch,
looking for suspicious activity but not a specific perpetrator.
Our learned or acquired immune system is slower to respond at first,
but it is highly specific in its activity and can respond fiercely
and briskly once it has learned a task It includes specialized CD4+
T cells, CD8+ T cells and B cells. Unlike the innate immune response,
these specialized cells will walk right past a group of neighborhood
thugs (e.g. the flu virus, the fungal infection, etc.) to find a
specific wrong-doer (e.g. HIV). If they’re HIV-specific cells,
they will seek out and destroy HIV-infected cells or if they are
HIV-specific antibodies, they will seek out HIV floating in the
blood.
HIV-specific cells learn by seeing. Other immune cells show CD4+
cells bits and particles of HIV that they have found while surveying
the immune system for trouble. Once these other cells find a CD4+
cell that can learn about HIV (a naïve cell), the CD4+ cell
communicates with other cells and provides instructions on how to
respond. Depending on how HIV is shown or presented to the CD4+
cell, the cell will send out different chemical messages to activate
a response.
One type of response is antibody (also called humoral) responses,
which are generated by B cells. Generally these battle virus that
is free floating in the blood (outside of cells). Another type of
response is cellular responses, which are largely carried out by
CD8+ cells. These destroy HIV-infected cells (eliminates virus that
is inside of cells). Both humoral and cellular responses are believed
to be important in controlling HIV replication, though some scientific
debate remains about which, if either, is more important.
Vaccines and How They Work
The process of recognizing a new critter (i.e. an antigen, e.g.
HIV) and responding takes awhile. If the way the particle of HIV
was presented to the CD4+ cell wasn’t done right, the entire
process of antigen presentation, recognition and response could
be crippled or ineffectual. Once a robust and effective response
has been learned, however, the immune system marshals full force
against the critter to specifically contain and hopefully control
or eliminate it entirely. Vaccines teach these responses.
Preventive Vaccine
The goal of HIV preventive vaccines is to give people who are not
infected with HIV specific memory responses that can act swiftly
and effectively in controlling HIV if a person encounters the virus.
Ideally, a vaccine might prevent the establishment of HIV infection
altogether, although vaccines seldom achieve this goal. Instead,
they prime the immune system to act quickly to prevent the infection
from becoming serious or dangerous. Whether an effective vaccine
will block the establishment of HIV infection altogether or merely
alter the course of HIV disease in those who become infected is
unknown. Currently there are no proven effective HIV preventive
vaccines. If or when a vaccine is one day proven to have some benefit,
it’s highly likely that it will work best if combined with
proven HIV prevention efforts (e.g. safer sex, etc.).
Therapeutic Vaccine
The goal of HIV therapeutic vaccines is to educate the immune system
in hopes of shoring up a more potent and effective response against
the virus in a person living with HIV. Whether or not it is possible
to teach the immune system to better fight HIV remains to be seen.
Some scientists believe that if continued production of HIV itself
does not provoke an immune response sufficient to control the infection,
no therapeutic vaccine is likely to do so either. Still, researchers
are exploring strategies to improve HIV presentation and immune
recognition and responses. Therapeutic vaccination is only one area
of research aimed at trying to do this—others include gene
therapy, cell therapy, structured treatment interruption approaches,
passive immune therapy and cytokine therapy. Currently there are
no proven effective HIV therapeutic vaccines.
Therapeutic HIV Vaccines: Things to Consider
Many HIV vaccines have already been tested in people living with
HIV without compelling results. Studies conducted by the AIDS Clinical
Trials Group compared several HIV therapeutic vaccines, including
products developed by Genentech, Chiron Corporation, MicroGenSys
and others. These studies showed that some products were more effective
than others in inducing immune responses but it was wholly unclear
if the responses had any impact in controlling HIV replication.
In the early 1990s, Genentech proceeded with a large study of its
therapeutic HIV vaccine, rgp160. Results suggested that the vaccine
made no impact on HIV disease progression and there was some indication
that people who received the vaccine did slightly worse than those
on the placebo. Genentech stopped the study and abandoned efforts
in this arena. (Note: This vaccine was later sold to VaxGen, who
modified it and is researching it as a preventive vaccine called
AIDSVax.)
Results of a large study of Immune Response Corp.’s (IRC)
vaccine, the HIV-1 Immunogen (also known as Remune) suggested that
the product had little to no impact on CD4+ cell counts or viral
load. Unfortunately the study was not large enough to detect differences
in the rate of HIV disease progression among those receiving the
vaccine compared to the placebo. Pfizer Corporation, which was the
principal investor in IRC, abandoned further development efforts
of this product.
Many therapeutic vaccine products have been shown to elicit HIV
antibody responses and some induce HIV-specific cellular responses
in animal, test tube and human studies. Reports from complete and
ongoing research will often highlight results from previous studies
highlighting a product’s immunogenicity. Immunogenicity is
the degree to which the vaccine induces immune responses. Whether
or not these responses will have any impact on HIV disease is unknown.
Both the Genentech and the IRC vaccines were shown to induce at
least transient and modest levels of HIV-specific immune responses
but neither showed measurable benefits in people living with HIV.
Whether larger and more lasting responses will make a difference
remains to be seen. Ongoing studies should soon begin to provide
answers to this question as some new vaccines, such as that from
Merck, produce dramatically higher and longer lasting levels of
these responses than any previous vaccine.
Some HIV vaccines have been shown to prevent infection in animal
studies, including the Genentech vaccine referred to above. The
new Merck DNA vaccine did not prevent infection, but it did appear
to alter the course of the disease in animals that were later infected
with an aggressive animal virus. Prior vaccination did not prevent
the animals from developing disease, but it appeared to significantly
slow disease progression. A few other vaccine products have shown
similar results in animal studies. Humans do not react the same
way to vaccines as animals. While results from animal studies may
provide encouragement to vaccine developers to move forward into
human studies, they may tell us very little about how the product
will (or won’t) work in humans. Also, not all animal models
are the same—the types of animals used in a study are presumed
to give better or worse information about what the human experience
might be like. The kind of virus used to infect the animals in the
studies might also make a difference in terms of how the information
applies to the human setting.
One aspect of the excitement over animal study results of the Merck
DNA vaccine may have to do with the kind of animal used in the studies.
The animals used are known to develop a very aggressive form of
AIDS following infection. That the product slowed disease in the
animals was encouraging. Animals used in other studies do not develop
disease following infection with HIV, so some researchers have been
less enthused about results of studies where infection was blocked
in those models. Of greater interest in the Merck studies is a compilation
of new data showing that when the vaccine is used with the right
adjuvant (a booster), it produces the strongest cellular immune
responses yet seen from a vaccine. Still, researchers are not willing
to predict whether it will work well enough to prevent infection
altogether or provide therapeutic benefit to those infected already.
The way researchers report therapeutic vaccine study results can
be a little misleading and generally this is not intentional or
deliberate. The only way, truly, to report on initial findings of
small studies of candidate vaccines is to discuss the immunogenicity
of the product and any safety concerns. Generally speaking, when
you hear or read that a vaccine product or a treatment strategy
enhances HIV-specific immunity (either cellular or antibody) it’s
wise to remember that we’ve no idea if that is functional
immunity or what level of this type of immunity is needed to make
a clinical difference.
When considering therapeutic HIV vaccine human study results, look
for:
Was the study controlled (did some people receive vaccine and others
receive placebo)? This will help you to sort out if any observed
increases in CD4+ cell count or decreases in HIV levels were associated
with the vaccine or merely the use of anti-HIV therapy. If the study
was not controlled it may not be possible to sort out other factors
that might be influencing the outcome.
Did the report include information on both HIV-specific immune responses
as well as viral load? Again, if the study was not controlled it
is not really possible to say decreases in viral load were due to
the vaccine product being researched. It’s possible for the
vaccine to be immunogenic (e.g. inducing HIV-specific immune responses)
while anti-HIV therapy could be the factor controlling HIV replication.
Discussion
HIV vaccines are experimental. None have proven to be effective
in preventing HIV infection or disease progression in humans. Several
candidate vaccines are garnering interest from researchers and activists
alike, including the Merck DNA vaccine and the GlaxoSmithKline HIV
vaccine. Excitement for these products are due to the fact that
they are moving forward into human studies and preliminary research
suggests that they do something slightly different or novel compared
to previously tested approaches. Whether or not these products will
prove useful remains to be seen and is wholly unknown.
Generally speaking, HIV vaccines are believed to be relatively
safe. Likely, vaccines will be given periodically, such as monthly,
and side effects might predictably primarily be pain, redness and/or
swelling at the site of injection and perhaps fever, fatigue and/or
joint pain and stiffness—as one might expect with any vaccine.
In some HIV vaccine studies, more serious reactions have been observed
(in a few rare cases there have been ulcerations at the injection
site). It’s quite possible that people with autoimmune diseases
(e.g. lupus, arthritis, etc.) will be excluded from initial studies—as
stimulating the immune system with vaccination has shown to worsen
some of these conditions. It’s even possible that stimulating
the immune system with an HIV vaccine could worsen HIV disease progression.
Results of previous studies don’t suggest this is a major
concern, but it is possible.
Initially, new therapeutic HIV vaccines will be researched in conjunction
with anti-HIV therapy. Some proposed study designs includes the
use of therapeutic vaccine or placebo in a structured anti-HIV therapy
interruption model. The hope is that the HIV-specific immune responses
induced by the vaccine will suppress HIV rebound following therapy
discontinuation longer than what might be observed among people
not receiving the vaccine. If you’re considering participating
in such a study it’s important to understand the potential
risks of structured treatment interruption.
When HIV mutates and becomes resistant to the effects of drugs,
this is called HIV drug resistance. When HIV mutates and becomes
resistant to the effects of the immune system this is called immune
escape. At least one previous study suggests that the virus can
mutate around the immune response. Theoretically, it’s possible
that HIV can become resistant to new, functional and potent HIV-specific
immune responses. How much this will present a problem for therapeutic
or preventive vaccines remains to be seen.
Finally, the potential of HIV vaccines is great. Despite years
of research, however, this remains a field of study in its infancy.
Many small studies have built the foundation for recent advances
and researchers, activists and people living with HIV alike await
the results of studies of new vaccine approaches to see where the
next steps in this important area might lead.
Bottom Line
- There are currently no proven effective therapeutic or preventive
HIV vaccines.
- Therapeutic HIV vaccine research is still in its infancy.
- Many studies have reported information that is not encouraging.
- We don’t yet know if the ability of a vaccine to induce HIV-specific
immune responses tells us, in and of itself, if the vaccine (or
the immune responses) is useful in treating or preventing HIV.
- New vaccines, including the Merck DNA Vaccine, have garnered much
interest among activists, researchers and people living with HIV.
Only results of human study will tell us if this enthusiasm is warranted.
Initial studies are underway.
- HIV vaccines researched to date have had minimal side effects, primarily
pain, redness and swelling at the injection site and sometimes transient
fever, fatigue and joint stiffness.
- In previous studies therapeutic vaccines were delivered monthly,
by injection.
- In the short-term, it’s likely anti-HIV therapy will be required
in therapeutic HIV vaccine studies.
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