As the smoke of hope dissipates for the eradication of HIV from the human body and the limitations of antiretroviral medications become all too apparent, efforts are being renewed to examine a role for immune-based interventions to help control HIV infection and potentially reduce ongoing exposure to antiretroviral medications. One way of intervening is to take vaccines that were originally designed to prevent infection and give them to people who are already infected with HIV. Strictly speaking, this is called a therapeutic immunization.
Although other methods of stimulating the immune system are also being considered, therapeutic immunization is likely to be less expensive and more easily tolerated than other immune boosting therapies. Despite healthy skepticism of how useful they'll be, many researchers as well as HIV-positive persons are enthusiastic about their promise.
Robert Redfield, M.D., Director of Clinical Research at the Institute of Human Virology in Baltimore, points out that models of therapeutic immunization in other diseases have already proven benefit. "The rabbit herpes model in the seventies, rabies, and a post exposure mechanism for immunization against smallpox in humans all have shown efficacy in moderating the course of disease."
Dr. Redfield continues. "If you look carefully at the hepatitis B vaccine study, published in the New England Journal of Medicine, several of the persons enrolled tested positive for surface antigen, indicating that they were incubating hepatitis B; yet, after administration of the vaccine, none got intercurrent infection. There are also examples in leishmaniasis in humans as well as animal anthrax data. Do I think this will work for HIV? I would have to say yes. The only questions are what are the right antigens and how best to deliver them."
This sentiment is echoed by Pat Bucy, M.D., Ph. D., an immunologist and Professor of Pathology & Medicine from the University of Alabama at Birmingham. "Will a therapeutic immunization work? I think the answer is yes -- but how big an effect it will have and what fraction of the population of HIV-infected individuals will have a significant benefit from this approach needs to be worked out in clinical trials."
Jim Kahn, M.D., an Associate Professor of Medicine at University of California San Francisco Medical Center and provider of HIV care at San Francisco General Hospital, is equally optimistic. "Could a therapeutic vaccine make it a more tolerable situation for our patients? Yes, I believe an immunization could help re-stimulate the immune system to recognize constitutively expressive cells [cells that are making HIV proteins and are flagging themselves for destruction]."
Dr. Kahn continues. "We've spent a lot of time on some candidate vaccines and have learned several important lessons. Not only have antibody-based vaccines proved insufficiently protective, they have not been of benefit therapeutically. I think now is the time to concentrate on the cellular side of the immune system." Dr. Kahn is currently enrolling low-risk HIV negative people into a phase I safety trial of Merck's so-called "naked DNA" vaccine, and plans are in the works to evaluate this in HIV-positive people.
Dr. Bucy elaborates on the potential for therapeutic immunizations. "What we are currently missing is an understanding of what it is that controls viral replication off therapy." A "setpoint" -- a relatively flat viral load over time -- has been shown to occur in most people in the absence of therapy. A sort of natural equilibrium happens.
According to Dr. Bucy, "there is no commonly accepted model as to what drives this setpoint that is achieved relatively early in infection -- although widely variable between persons -- yet is sustained until the CD4 count drops below 200 in end stage disease. At that time, the whole immune system begins to decompensate [fail to provide protection against common bugs like PCP], and viral load begins to rise." The setpoint phenomenon has been demonstrated in invaluable historical natural history studies of untreated persons.
"So the question remains, why did the viral burden stay at such a relatively low level? What is the mechanism? To me, there are two theoretical choices -- the target cell limitation theory and the theory of immune control." The target cell limitation theory was popularized in a 1996 article with, according to Dr. Bucy, little supportive data.
This theory says that the viral "ceiling" is maintained due to the finite number of target cells that HIV has available to infect. Since activated CD4 cells are those most susceptible to infection, their number would be limited at any given time. Dr. Bucy feels that this is difficult to believe considering the enormous variation in viral load during the flat "setpoint" period among different individuals with the same CD4 count. He says, "I find this conceptually hard to swallow."
This theory doesn't pay much attention to other cells of the immune system that are vulnerable to infection by HIV, such as macrophages. Perhaps more tellingly, it fails to fully account for the rapid increase and rise in viral burden late in infection when there is less fuel (CD4 cells) for the fire. It could be argued that the immune system is in a general state of chaos at this point, and the entire population of dwindling CD4 cells is indiscriminately activated. Nevertheless, studies of general immune suppressing agents have yet to show a true antiviral effect.
Therefore, we are left with the theory of immune control to account for the stabilization of viral load through a relatively long period of chronic infection. Dr. Bucy draws the analogy of a lawn being mowed regularly by the immune system. The grass continues to grow, but is kept in check by the immune system. This implies that if such control could be enhanced -- the grass mowed to a lower height -- people could perhaps go longer without the destabilizing side effects of antiretroviral chemotherapy and prolong the period of symptom-free infection.
Since antiretroviral therapy slows down viral replication -- offering T-cells protective cover from infection by HIV -- a vaccine could kick-start CD4 cells that are specific for HIV antigens and the CD8 "killer" T-cells, also known as cytotoxic lymphocytes (CTLs), would be primed as well.
Dr. Redfield explains. "We are left with defining the clinical goals of therapeutic immunization. In the late eighties and early nineties, our goal was mid-level and early -- to modify the rate of progression. Now that we are in the era of maximal suppression, we have different goals such as the durability of suppression." In other words, could an immunization delay time to the development of drug resistance? Could immunization allow for the use of less drugs or, alternatively, time off treatment with less immune destruction?
Such worthwhile goals would seem to argue for some urgency in testing a wide variety of vaccines among the HIV infected population. One could especially imagine their utility in the developing world, with an estimated 90% of the world's 40 million infections. As Dr. Bucy points out, there is a huge number of candidate vaccines all at the same or similar stage of development. Dr. Redfield also feels the pipeline is healthy with candidate vaccines. "Merck, GlaxoSmithKline and Aventis are all actively pursuing testing their vaccines therapeutically." Dr. Redfield sees the commitment of the powerhouse pharmaceutical houses as "much more positive than the early days of minimally financed biotech companies."
Nevertheless, the path to FDA approval of a candidate vaccine for treatment is a little less clear since Pfizer recently abandoned its Remune trials. Upwards of $100 million had already been spent on Remune, the "Salk" HIV vaccine; yet, as published by Jim Kahn from UCSF and Steve Lagakos from Harvard in the Journal of the American Medical Association, it had failed to show clinical benefit.
Dr. Bucy laments the current pace. "Slow is costly. For every year that things are not done, hundreds of thousands of lives are lost in the balance. In the scheme of things at this stage of the HIV pandemic, I think the lost opportunity cost has to be factored into decisions about testing such agents in humans."
Unfortunately, studies are often designed that are burdensome to the participant who is relatively healthy -- high CD4 counts and maximally suppressed virus. Dr. Bucy says, "Potential trial participants have to balance possible benefit, still theoretical, with issues of time spent coming to the clinic. I can't say I blame them, but as a consequence progress is not being made."
Likely, the buzz behind some of the newer agents will make enrollment much more robust. Two new approaches are Merck's "naked DNA" vaccine and the Tat toxoid vaccine. Merck's vaccine, being tested as both a preventive and therapeutic vaccine, consists of genes extracted from HIV; the hope is that it may be better able to counteract the random changes in different HIV strains. The Tat toxoid vaccine, licensed from Aventis by the Institute of Human Virology in Baltimore, is a slightly modified version of HIV's Tat protein and has been shown to produce anti-Tat antibodies in early studies. The community as a whole could only benefit if its members enroll in these trials.
Jeff Gustavson is an HIV- and HCV-positive activist who lives and swims in San Francisco.