The use of antiretroviral therapy has led to dramatic declines in the morbidity and mortality associated with HIV/AIDS, but treatment failure still occurs for a sizable percentage of people within one year of starting therapy (see "Mortality Trends" in this issue). Studies have shown that drug toxicity is the number one reason why people wish to, or need to, stop their antiretroviral therapy. Further, antiretroviral drugs appear incapable of eradicating HIV and cannot completely restore the immune systems of those infected. This has led to the idea of combining immune-based therapies, such as therapeutic vaccines, with current antiretroviral regimens to potentially achieve long-term management of HIV infection. It is also hoped that therapeutic vaccines might extend the benefits of anti-HIV therapy, while minimizing their adverse effects, by allowing for periods of antiretroviral treatment interruption.
The idea of a vaccine, whether preventive or therapeutic, is to strengthen the immune response by showing the immune system a disease-causing microbe, or a piece of one, to allow the system to recognize it and build up defenses against it. When a vaccinated person later encounters the same microbe, ideally the body's defenses will be primed for it and be able to mount a strong and rapid immune response, preventing a harmful infection.
The use of a therapeutic vaccine approach against viruses has been shown to be effective, such as for rabies and hepatitis B virus (HBV), if used soon after infection. Preclinical and animal studies of HIV-like viruses have shown that a therapeutic vaccine approach can be safe -- which means "generally well tolerated" and without significant adverse events -- and effective, by enhancing immune responses without increasing viral load levels. Most results so far for HIV therapeutic vaccine development in humans have been disappointing, similar to those reported for HIV preventive vaccines. But a recent study showed promise for a whole-killed virus approach different from Remune (see table below) that deserves further investigation.
One study designed to show the feasibility of using a therapeutic vaccine as part of a treatment interruption strategy in people with chronic HIV infection was reported by George Pavlakis, MD, PhD, of the National Cancer Institute and colleagues. In this study 31 monkeys were infected with SIV (the monkey form of HIV) for up to 70 weeks before being given multidrug antiretroviral therapy. Fifteen of the animals also received a therapeutic vaccine that used specific pieces of viral genetic material to increase the animals' immune responses while on treatment; the other 16 were not vaccinated. Treatment was stopped after 20 weeks, then the animals were studied for 7-18 months. The results showed that the monkeys that had received the therapeutic vaccine had a statistically significant reduction in viral load compared with the unvaccinated animals. Although this seems like good news, there is no guarantee that similar results would occur in a human clinical trial.
A case in point was the presentation by Luc Perrin, MD, from the University Hospital in Geneva of results from the international QUEST study. Participants in this trial began antiretroviral therapy relatively soon after infection with HIV. Those people responding to anti-HIV therapy underwent a structured treatment interruption to see whether virological suppression would continue. Some of the subjects stopping therapy received one of two HIV vaccines, an ALVAC canarypox vaccine or Remune, in an attempt to keep them off treatment longer. Unfortunately, the people who received the vaccine and those who did not had similar rates of viral rebound during the treatment interruption. (Both the ALVAC product and Remune have also been studied as preventive vaccines, with little success.)
These data are striking because none of the study participants were taking antiretroviral therapy before or during the study, all of them had continuously high viral loads for six months before the first of their three vaccine injections, and CD4 cell levels were falling among the group before immunization began.
The unique therapy of Drs. Lu and Andrieu involved using dendritic cells, which are immune cells found in the skin and mucous membranes. Dendritic cells target invading organisms, then carry pieces of these organisms to the lymph nodes, where the body's more vigorous cell-mediated immune response is activated. HIV normally attacks dendritic cells and ultimately paralyzes the body's cell-mediated immune response. But in this experiment, dendritic cells were removed from each subject and allowed to process whole, inactivated HIV in vitro (in the laboratory). After these dendritic cells were reintroduced into each subject, the results suggested that protective, cell-mediated immune responses against HIV were then properly triggered. This scenario hints at the possibility that the body, with help from a vaccine, could theoretically keep HIV in check without antiretroviral drugs.
While data from this study are tantalizing, future research on this dendritic cell and whole-killed virus approach requires randomized studies involving larger cohorts and a group of control subjects to prove its efficacy.
Although not ready for clinical use, therapeutic vaccines remain a promising avenue of research while investigators look for direction (see "Open Clinical Trials" in this issue). Encouragingly, a recent study of the potential contribution of a therapeutic vaccine to overall HIV care found that even a modestly effective vaccine would result in meaningful increases in life expectancy in people living with HIV.
|Remune: Down but Not Out|
The fight against HIV in the arena of vaccine development appears to be still in the first rounds, with no clear winner emerging. One early vaccine candidate still under investigation is Remune, which has been studied both as a preventive vaccine and as a therapeutic vaccine in people already infected with HIV. Like other HIV vaccines, Remune (HIV-1 immunogen, also known as the Salk vaccine, after its inventor, Jonas Salk) was designed to stimulate an infected person's immune system to attack HIV. Remune is made up of inactivated HIV virions (virus particles) that have had their outer envelopes removed. It is an example of a whole-killed virus vaccine, which means that the virus has been modified to make it incapable of infecting cells and replicating. Thus it is potentially safer than some other types of vaccines.
In its initial development as a preventive HIV vaccine, Remune experienced a series of setbacks, including data showing ineffectiveness and legal and financial troubles for its developer, Immune Response Corporation. As a result, this vaccine has become controversial among scientists, with most believing that it does not work and that research efforts would be better directed elsewhere.
Although Remune has not been shown to protect against initial HIV infection, there have been some positive results when it is used as a therapeutic vaccine. Data from a clinical trial presented in 2002 showed that the incidence of antiretroviral failure was reduced by 37% in people who also received treatment with Remune. More recently, the results of a small but well-controlled study at Massachusetts General Hospital showed that Remune restored HIV-specific immune responses in people chronically infected with the virus. More importantly, these responses were similar to anti-HIV immune activity seen in long-term nonprogressors -- people who have been HIV positive but asymptomatic for years without treatment. Whether these effects will ultimately have any clinical benefit, however, is not yet known.
The recent clinical findings are certainly welcome news, but Remune might have taken too many body blows in the past for it to be seen as a future vaccine contender. According to the noted AIDS immunologist Bruce Walker, MD, "Remune has now been shown -- in the only carefully controlled, double-blinded study ever conducted -- to have a positive and measurable biologic effect. Were this any other vaccine but Remune, people would be far more excited." Despite the general lack of enthusiasm, these results are encouraging, and at this point in vaccine research, we should, as Dr. Walker warns, "be testing anything that falls into the category of possible benefit."
Remune may have suffered an early knockdown, but it appears to be pulling itself off the mat. Whether it has the strength to go the distance to win FDA approval is anyone's bet.
John Hawes (firstname.lastname@example.org) is a freelance science writer who frequently writes about HIV/AIDS.
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