November 3, 2009
Therapeutic Vaccines: Steady Wins the Race
by David Evans
Recent news of modest success with a preventive HIV vaccine has led some to wonder whether we’ve moved any closer to a compound that can train the immune system to better control the virus—a therapeutic vaccine. AIDSmeds talked to two HIV vaccine experts to find out where we are now and where we’re going.
On September 24, researchers from the Thai government and the U.S. military made a surprising announcement. For the first time, an experimental HIV vaccine showed evidence of offering modest protection from infection with the virus. But the optimistic news was soon shrouded in skepticism, when critics began pointing out that the results were barely statistically significant—and not statistically significant at all in one important analysis—and that the vaccine failed to offer any benefit for those who did become infected in the study.
Rama Amara, PhD, an associate professor of microbiology and immunology at the Yerkes National Primate Center of Emory University in Atlanta, explains that a preventive vaccine is designed to provoke the development of antibody- and/or cellular-immune responses to the virus, which in turn stop an infection from taking root. “When you are talking about therapeutic vaccine studies,” he says, “you’re looking at a vaccine that would reduce viral load in people who are already infected.”
It has been suggested that a vaccine that effectively prevents infection might also double as a therapeutic vaccine, given that it would spark the same components of the immune system needed to control HIV in the absence of antiretroviral (ARV) therapy. Unfortunately, as immunology advocate Richard Jefferys of the New York City–based Treatment Action Group explains, the strategy employed in the Thai trial failed to lower viral loads or protect CD4 cell counts in vaccine recipients who did become infected. In other words, any preventive results that arrive from this trial won’t necessarily have much relevance for researchers developing a therapeutic vaccine.
Fortunately, the hopes of a therapeutic vaccine don’t hang on the results of the Thai study. (That trial included a combination of Sanofi Pasteur’s ALVAC plus VaxGen’s AIDSVAX to first prime, and then boost, the immune response to HIV.) The search for a vaccine strategy that can spark the immune system against HIV, potentially doing away with the need for antiretrovirals or curing the infection altogether, has been ongoing for decades—and both Jefferys and Amara say there are reasons to be optimistic.
Promising therapeutic candidates are currently in clinical trials, with others gearing up for testing in humans. What’s more, at a recent vaccines conference, researchers reported for the first time that a therapeutic vaccine succeeded in lowering viral loads to undetectable levels in the absence of any other medications in some people. There’s still a lot of work to be done, but Jefferys indicates progress has been made.
One of the constant struggles with this research has been the lack of good tests to predict, before moving into human testing, how well a therapeutic vaccine candidate might elicit the right immune responses to the virus. Jefferys says this is one area where there is reason for hope. “There’s a researcher at National Institute of Allergy and Infectious Diseases, named Mark Connors, who has developed what he thinks is a pretty good test of CD8 cells’ [ability] to kill virally infected cells, and that seems to be a pretty strong correlate of immunologic control,” Jefferys says.
There’s also the issue of developing the right vaccine strategy. Amara says he’s quite encouraged by the results of the research he’s been engaged in for the last five years. He and his colleagues have been studying whether exposing the immune system to pieces of HIV DNA, along with a booster shot of a modified strain of the Vaccinia virus, helps lower HIV levels in monkeys.
Amara and his team first treat the monkeys with ARVs to lower HIV levels. They then give the monkeys a series of shots of their vaccine and booster. From there, the researchers stop administering the HIV drugs and watch what happens with the virus.
In studies completed thus far, Amara says, the monkeys’ virus levels rebound, but to levels significantly lower than they were before they were given the ARVs. This, in turn, may translate into a much slower rate of HIV disease progression and a decreased need for ARV treatment.
A company called GeoVax, in Atlanta, plans to study this approach in humans starting sometime in 2010. But Amara is quick to spell out the fine print—this particular strategy might only work in those who started ARV treatment very soon after becoming infected with the virus, as it relies on a well-preserved immune system to work. Fortunately, his lab is working on a second compound based on an immune molecule called PD-1 that helps revive exhausted CD4 cells. He hopes that this newer compound, combined with the vaccine, could be effective for a much larger percentage of people living with the virus.
Further along in development is Vacc-4x, a therapeutic vaccine being developed by Bionor Immuno, a Norwegian company. Preliminary results from a Phase IIa study were reported at the XVII International AIDS Conference in August 2008 in Mexico City. The clinical trial involved 38 patients who kept their HIV under control using ARV therapy while also receiving a series of low-dose or high-dose Vacc-4x immunizations during a period of 26 weeks, followed by an interruption of their HIV treatment.
According to Bionor, the majority of study volunteers were able to remain off ARV therapy for an average of 31 months before seeing their CD4s once again fall to a level requiring that treatment be restarted.
Jefferys remains somewhat skeptical and isn’t convinced that Vacc-4x will win U.S. Food and Drug Administration approval as a strategy to keep people living with HIV off ARV therapy. “The vaccine didn’t have a striking effect on viral load [during treatment interruption],” he says. Jefferys cautions that where there is ongoing HIV replication—even if CD4s are slow to drop—there may be inflammation, which contributes to an increasing risk of certain non-AIDS-related complications.
In fact, Bionor is no longer looking at the prospect of using Vacc-4x to keep patients off ARV therapy, but rather to boost CD4 cells in treatment-experienced HIV-positive individuals with suppressed immune systems while remaining on antiretroviral therapy.
“We are hopeful that Vacc-4x will provide meaningful benefit to people with HIV who have no alternative therapies,” says Per Bengtsson, MD, PhD, Bionor’s senior vice president for development and chief medical officer. “The Thai study has re-energized the research community to search for effective vaccines to counter HIV.”
Also of interest are personally tailored vaccine strategies, such as the one that made a splash earlier this month at AIDS Vaccine 2009, the annual meeting of the Global HIV Vaccine Enterprise, in Paris. AGS-004, being developed by North Carolina–based Argos, customizes immune system cells from each individual, using HIV fragments known as messenger RNA, to maximize an HIV-positive person’s immune response to the virus. To do this, dendritic cells are removed from the body and combined with mRNA taken from the same individual’s HIV. The data presented at the Paris conference showed that the vaccine, when given just before an ARV treatment interruption, kept viral loads at least 1 log—more than an 80 percent reduction—below pre-ARV therapy levels in 13 of 16 patients.
Jefferys says that the more we learn about people who are naturally able to control HIV replication, called elite controllers, the better able we will be to mimic their immune responses in other people.
Whether a successful immune-based therapy will be in the form of a therapeutic vaccine or a similar approach, Jefferys and Amara feel that the goal is achievable.
Search: Therapeutic vaccines, preventive vaccines, Thai vaccine study, Rama Amara, Richard Jefferys, Treatment Action Group, Bionor, Vacc-4x, dna prime, MVA, PD-1
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