Box 1. The struggle for an HIV vaccine

In part because HIV targets and undermines the immune system and in part because of its rapid capacity to mutate its antigens, many ingenious efforts to develop protective vaccines against it have proved fruitless. Just this past September, for example, officials at NIAID and Merck called a halt to two clinical trials to evaluate Merck's V520 HIV vaccine (a trivalent vaccine of gag, pol and nef, one in South Africa and the other at sites in Australia, Brazil, Canada, the Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico and the United States. An independent Data Safety Monitoring Board had concluded that the V520 "could neither prevent HIV infection nor reduce the amount of virus in those who became infected with HIV." Moreover, volunteers who participated in this study, referred to as the "Phambili," HVTN 503 in South Africa or HVTN 502 or STEP at the other sites, are also being counseled about the possibility that vaccine recipients "may have an increased susceptibility to acquiring HIV infections."

Against such a backdrop, it is "not immediately obvious why an immunomodulatory product is suitable for HIV-infected, immunocompromised patients," says Charles Nicolette, vice president for R&D of Argos Therapeutics (Durham, NC, USA). Moreover, according to his review of the recent scientific literature, "immunotherapy has a complete lack of efficacy in terms of controlling the viral load among HIV-infected patients, even in cases where immunity is augmented," he adds, alluding to dozens of published reports. "The story is the same in every case."

"Maybe they were all looking at the wrong antigens," Nicolette continues. Instead of looking for a single antigen, Argos goes after HIV-infected individuals, extracts a medley of viral antigens from each person, reverse engineers and amplifies by PCR messenger RNA (mRNA) molecules corresponding to those viral antigens, and then uses electroporation to load that mRNA into dendritic cells. The cells are introduced into each patient to induce an individually tailored immune response to whatever "quasi-species" of HIV that he or she is carrying, according to Nicolette. Following phase 1 studies, which uncovered no unusual safety problems, plans call for administering such cocktails early in 2008 to HIV-infected individuals who are taking antiviral drugs and then measuring viral loads when drug therapy is temporarily halted, he says. "We expect to have a full data set by the fourth quarter of 2009."

Other HIV-immunomodulatory products under development are closer to being conventional vaccines—at least, in the sense that products are not being separately tailored to suit each infected individual. Among the "dozens of designs" being followed and evaluated, Wyeth (Madison, NY, USA) researchers are looking at a DNA-based HIV-therapeutic vaccine that consists of two plasmids, one encoding HIV immunogens and the other encoding interleukin-12 (IL-12) to act as an adjuvant, according to John Eldridge, vice president of applied vaccines research at Wyeth (Pearl River, NY). The underlying idea is to use therapeutic vaccines with antiviral drugs to "bring the immune system back up and maybe halt antiretrovirals if the immune system can control the virus and reduce damage," he says.

Elsewhere, The Vaccine Research Center at the National Institutes of Health (NIH; Bethesda, MD) is testing a 'prime/boost' vaccine incorporating the plasmid DNA technology of Vical (San Diego, CA) to prime the immune system and the adenoviral vector (Ad35) technology of GenVec (Gaithersburg, MD) as an immune booster. A phase 1 trial with both a single-dose arm and a dose-escalation arm began in June.

Among the several companies developing therapeutic vaccines for HIV, "it's difficult to say somebody is ahead," Eldridge says. "Many people are working with very difficult targets." Although at least one of those other vaccines is in phase 1 clinical trials, plans call for evaluating the Wyeth vaccine in rhesus macaques in a one-year study that has yet to begin. "Although it's difficult to extrapolate from [the STEP prophylactic vaccine trial in South Africa] to a therapeutic, that trial gives us pause, and we're not sure what's going on or what to predict," he says. Still, none of the animal studies involving those therapeutics "predict any damage."