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Therapeutic Vaccinations in HIV
Written by Michael Norton, PA, Boriken Family Health Clinic, NYC
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Introduction by Jules Levin
At the 41st ICAAC meeting in Chicago on December 16, 2001, Dr Lederman
delivered a talk about therapeutic vaccine research & application in HIV. Dr
Lederman is a noted researcher in the area of immunology in HIV. He is an
active researcher in the AIDS Clinical Trials Group. As you may know several
candidate drugs are being researched as therapeutic vaccines in HIV. The
Merck vaccine research program has perhaps received the most attention.
Mainstream newspapers such as the Wall Street Journal, and HIV community
newsletters and advocates have written much about this research effort into
finding a therapeutic vaccine for use in HIV. The hope and goal for this
research is that perhaps such a vaccine or a combination of vaccines could
slow HIV in persons already infected with HIV. It is being proposed that
perhaps such a vaccine could be used by persons on HAART, in addition to
HAART. One way in which such a vaccine could be used is to use it while on
HAART and to remain on HAART. The vaccine may help to control HIV and prevent
viral load rebound and help to increase CD4 cell count. A second way in which
such a vaccine could be used would be to allow patients to take a therapy
interruption. For example, if a patient is on HAART, perhaps vaccination
would control HIV so much that the patient could take an interruption but
continue to maintain control of HIV.
It is important to realize that researchers are looking very hard to find a
therapeutic vaccine for patients already infected with HIV. It's also
important to realize this research effort is in the early stages and we do
not know yet if it will be successful. The Merck research effort is ongoing
and perhaps we will have some early clues of its potential for success in
about a year. Dr Lederman talked about the challenges and hurdles of finding
such a vaccine. And Michael Norton's report below discusses the challenges Dr
Lederman talked about.
Report by Michael Norton
Therapeutic Vaccination = a vaccine given to someone who has already been
infected by the disease being vaccinated against. The purpose of the vaccine
is to enhance an immune system's inadequate response to that specific
disease.
Dr. Lederman reviewed the field of therapeutic vaccination as it related to
HIV. He stated the theory remains plausible by unproven. He cited two
important forces that continue to drive the need for an HIV therapeutic
vaccination:
- Virologic failure rate of HAART in most clinics continues to be greater
then 50% per year.
- Side effects to currently available antivirals limit their long- term
usefulness.
A literature search done by Dr. Lederman suggested the magnitude of the task
at hand. He found only one case where a therapeutic vaccine was employed
successfully today in medicine, a vaccine against the Herpes Simplex Virus
(HSV). HSV causes painful oral and genital ulcers. This therapeutic vaccine
against HSV, when given to individuals with HSV infection, was shown to
decrease the severity of subsequent outbreaks. Someone in the audience
familiar with organ transplant medicine also noted that a therapeutic vaccine
for Cytomeglovirus (CMV) exists. He stated that when given, prior to
transplant and subsequent immunosuppressive therapy, the therapeutic vaccine
meant to prime a response against CMV has been shown to decrease post
transplant CMV infections.
Therapeutic vaccinations against infectious diseases have received relatively
little interest when compared to the plethora of therapeutic vaccines being
explored for a variety of cancers (melanoma, breast cancer, prostate cancer,
and etc).
A new and possibly important concept has arisen in this field of HIV
therapeutic vaccination. Dr. Lederman cited unpublished work showing that
the nadir cd4 T-cell count (the lowest CD4 count a person has everhad) was
important in a response to diphtheria in a CTL assay. Patients with normal
cd4 T-cell numbers, and whose cd4 cell count remained normal, were able to
make a better response. But patients whose normal cd4 count did decline to a
nadir (a low level) did not make an equivalent CTL response. Because the
work is yet to be published it is impossible to critique this work. But put
another way here is what he said, having a normal (assume 500-1200 cells/mm3)
cd4 T-cells number at the time of vaccination didn't matter if in the past
cd4 T-cells had been below normal (assume below 500). So, if a patient
waited to start HAART until there cd4 count was 200, they may not be able to
respond to a vaccine even if their cd4 count increased on HAART to 800.
(editorial note: This potential development has yet to be researched and
proven but is a concern being raised by Lederman and others). This may have
implications for patients when considering the guidelines of when to start
HIV antivirals. Perhaps waiting until cd4 T-cells nadir to 350 or even 250
cells/mm3, as some are now suggesting, will prevent future benefit if a
therapeutic vaccine is eventually approved for use.
Editorial note: And it appears that at this point in research and our
understanding of therapeutic vaccines & immunology we don't know exactly what
that CD4 cell count nadir is‹is it 100 Cd4 cells or 350.
The problems that exist for the development of an effective therapeutic
vaccine for HIV are intimately tied to our limited understanding of basic HIV
pathogenesis (how HIV destroys and evades the immune system). Consider
long-term non-progessors, those individuals who seem to be able to live with
HIV for decades without any measurable loss of immune function. A
fundamental question remains unanswered. How do these people keep from
succumbing to HIV? Is it the breadth of peptide recognition by their immune
system? Is it that they recognize key peptides most people don't?
(editorial note: peptides are on HIV and if a person's immune system can
recognize them, perhaps they can attack).
Because our understanding of the human immune system is in its infancy we
simply don't know which one, or ones, if any of the following components are
essential to HIV control.
--Cd4 CTL response
--Cd8 CTL response
--NK (natural killer cell) response
--Neutralizing antibody response
(editorial note from Jules Levin:) different vaccines in research are
exploring these various approaches. For example, the Merch vaccine effort is
exploring improving the CTL response. While other vaccines are looking at
improving the antibody response. Popular opinion is that the CTL approach
will prove more effective but we don't know that yet. Perhaps, a combination
treatment approach of 2 or more vaccines will be most effective. And this
combination might include 2 CTL vaccines or perhaps 1 CTL vaccine and an
antibody vaccine approach).
Guiding future work in this field are the past failures. The ineffective
Remune vaccine. The ineffective transplanting of T-cells between identical
twins where one was HIV infected and the other not.
Dr. Lederman concluded by reminding us of the challenges ahead:
-- The lack of precedent. We have had very limited success developing such
vaccines. In the report above reference is made to successes with herpes &
CMV.
-- Patients with HIV infection have immune deficiency as a result of HIV
infection. The degree of immune deficiency may limit the number of HIV
infected individuals who will benefit from a therapeutic vaccine even if one
were available. (editorial note: Perhaps, benefit will occur but it could be
limited by HIV's effect on the immune system. HIV may cause too much immune
system decline to respond to vaccine, for some individuals. Despite cd4
increases from HAART, the low Cd4 count experienced before HAART may preclude
a response to a vaccine). We don't know the answers to these questions yet.
-- HIV strain variability may mean limited usefulness worldwide.
HIV-infected individuals in different parts of the world have different
strains. We do not know if the vaciine will work for all strains. Initially,
the vaccines will be tested against one strain or just a few, but then it
will have to be tested against other strains.
-- Currently, no reliable assay (test) exists for the evaluation of a
therapeutic vaccine making the discovery and development process exceedingly
slow.
Editorial note: despite the challenges and hurdles researchers face in
finding a therapeutic vaccine, it's important to place this effort into
perspective. We have come a long way in treating HIV in 20 years, and science
research has taken us there. At some point in the early days, everyone
thought death was around the corner for most. We went from having no
treatment for HIV in the 80's to having AZT monotherapy. Shortly after that
we added d4T and ddI, and 3TC. Dual NRTIs were next. In 1996, protease
inhibitors and HAART emerged. Shortly after that NNRTIs became popular in
HAART. And since then our understanding of how to these these drugs has made
strides, despite the difficulties we have had to face along the
way--lipodystrophy, adherence, etc. I think everyone recognizes that we need
to improve treatment for HIV. We don't know for sure what lies ahead. I for
one have confidence and hope that we can and will make greater strides in
treating HIV, and that good scientific research & dedication to that effort
by leading researchers will lead the way. Let's wish these researchers the
best of luck and please continue the dedicated effort.
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