Therapeutic Vaccines: Ready for Prime (and Boost) Time?
We are all waiting for an effective vaccine -- one that will prevent HIV infection and relegate AIDS to the same fate as diseases such as smallpox, polio, and diphtheria. At present, this is just wishful thinking because, for many reasons, HIV research has not come close to producing an efficacious vaccine. In the meantime, people continue to become infected with HIV and require lifelong antiretroviral treatment.
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.
A therapeutic vaccine is a relatively new immune-based approach that differs from a preventive, or prophylactic, vaccine in that it is not used to prevent infection, but is given to people who already have a disease. One goal of an effective therapeutic vaccine is to strengthen the immune systems of people infected with HIV, enabling their bodies to better fight the virus and lessen their need for antiretroviral therapy. A therapeutic HIV vaccine could theoretically be given during early infection to delay the initiation of antiretroviral therapy and reduce the risk of transmission; during chronic infection to lessen or eliminate the need for antiretroviral therapy; or in cases of advanced disease to slow disease progression and prolong survival.
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.
The news from the recent AIDS Vaccine 2004 conference, held August 30 - September 1 in Lausanne, was decidedly mixed. There were some positive findings reported from laboratory and animal studies, but not from clinical trials. Two presentations are illustrative of the news from the conference and the state of most HIV vaccine research to date.
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.)
One part of the solution to finding a better therapeutic vaccine may be to employ a strategy being used with preventive vaccines: prime-boosting. This strategy was developed because of the lack of protection against HIV seen in previous preventive vaccine research. In this approach, two doses of the vaccine are given: the first one activates ("primes") the immune system, and the second "boosts" it. The best vaccine candidates to use with prime-boosting are currently being identified, so the results of clinical trials are years away.
Meanwhile, researchers from France and Brazil appear to have taken the whole-killed virus approach to a new and far more robust level. In an article published in the December 2004 issue of Nature Medicine, Wei Lu and Jean-Marie Andrieu of the Université René Descartes in Paris and colleagues reported that their therapeutic vaccine reduced plasma HIV viral load by a median of 80% after four months in a cohort of 18 Brazilians (16 females, average age of 27 years). At the end of one year, eight subjects had maintained a durable viral load reduction of over 90%. Four of these eight had a viral load between 400 and 900 copies/mL, though none had an undetectable viral load. In addition, HIV-specific CD4 cell counts increased in several subjects, particularly between the first and fourth months of treatment with the vaccine, then generally returned to baseline levels after one year. The vaccine was also very well tolerated; no adverse events were reported other than increased lymph node size.
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.
The scientific obstacles to HIV vaccine development are daunting. And a lack of financial incentive for pharmaceutical companies to develop vaccines has been a major economic hindrance. However, there is reason for renewed hope with the G8 countries' recent endorsement of the formation of the Global HIV Vaccine Enterprise program to speed HIV vaccine development and increase and coordinate vaccine research efforts. Study of immune-based therapies could be energized through such an arrangement.
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.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.