AIDS vaccine trial called disappointing, but not futile

Although the study found no efficacy in the general population, experts say it was a valuable exercise and will aid future AIDS research.

By Victoria Stagg Elliott, amednews staff. March 17, 2003.

The news that the first AIDS vaccine to enter phase III clinical trials failed to provide protection against the virus in the general population left those involved desperately hunting for a silver lining.

According to trial results, which were released in February, the reduction in infection among the more than 5,000 study participants was barely 4%, hardly the mark of an effective vaccine and not a statistically significant finding.

Links
See related content

In the wake of this news, the landscape appeared bleak. Physicians involved in the trial had to face their patients' dismay as well as their own. Frustrated researchers vowed to continue the search. And stock of VaxGen Inc., the company sponsoring the trial, took a nosedive.

"We wanted it to work," said Jerry Cade, MD, who ran the trial at the University Medical Center of Southern Nevada in Las Vegas, where he is director of the HIV program. "It was very disappointing."

But many maintain that the trial was far from a futile exercise. It's hardly unusual for a drug or biologic to fail at some point, although with so much riding on the success or failure of this one, it attracted more attention than most. Most importantly, because this was the first phase III trial of an AIDS vaccine, what was learned is particularly crucial for the future of research in this area.

At the most basic level, researchers learned how to design an AIDS vaccine trial and retain more than 90% of enrolled participants -- a significantly higher retention rate than most clinical trials.

Reduction in infection was barely 4%.

"We can do these kinds of studies," said Peggy Johnston, PhD, assistant director for AIDS vaccines at the National Institute of Allergy and Infectious Diseases. "We can do them well, and we can get good answers."

Researchers also wrestled with the ethical quandary of giving high-risk people a vaccine that may not work and may encourage more high-risk behavior -- a reality that complicates efforts to communicate and affirm risk-reduction strategies known to work.

In response, the Centers for Disease Control and Prevention stepped in and ran intensive behavior modification counseling programs at several clinical trial sites. Data about the CDC's efforts are expected to be published before the end of the year and may also lead to better public health programs to control virus' spread.

Ironing out the wrinkles

The issue of behavioral counseling may also play a role in one of the most controversial and confusing quandaries created by the release of the results. Specifically, researchers found significantly higher response rates to the vaccine among non-Caucasians. Subset analysis indicated a 67% reduction in infection among nonwhite study participants, including a 78% reduction among African-Americans, according to a VaxGen news release. What this finding exactly means is now the subject of debate.

For instance, many are calling for additional analysis to determine if behavioral change as a result of the CDC's efforts was more significant in these populations

Meanwhile, AIDS activists had a different take. They accused VaxGen of raising false hopes. Other experts, too, were quick to point out that the sample sizes in these subgroups are not large enough to draw conclusions.

The trial retained more than 90% of participants.

"I worry when people start taking these little sets of data and analyzing them and trying to make something out of them," said Arthur J. Ammann, MD, who worked on vaccine development in the 1990s and is now president of Global Strategies for HIV Prevention. "Emphasizing a small subpopulation analysis is bad science."

Those involved say the subset analysis is intriguing and should be pursued further, although the results from a second similar trial in Thailand -- all test subjects are Asian -- should clarify whether the results from the initial trial are a statistical fluke or due to genetic differences.

"It's a little premature to start saying we have to do studies that recruit a larger cohort of people of color to be able to definitely answer this question, but that may be what is going to need to be done," said Kenneth Mayer, MD, who led the study at the Miriam Hospital in Providence, R.I. "But first we need a more thorough analysis of the data that we already have."

Race, by itself, has not been a significant factor in vaccine response before, although researchers are hopeful that if this bears out, the result will not be a vaccine for minorities but rather -- through an understanding of the genetic basis of the response -- lead to a vaccine for all.

"The next question is: If this does hold up, then why?" said Dr. Johnston. "That could be a very important key to the AIDS vaccine field. If we could figure out an immunological or a genetic reason why certain individuals respond and are protected and others don't, that's almost the holy grail of vaccine development."

Experts are also hoping the results may increase minority participation in clinical trials, a longstanding challenge because of the legacy of the Tuskegee syphilis study.

"You've got to get more diversity in these trials," said Dr. Ammann.

Waiting for the science

For the moment, however, scientists are waiting for the scientific release of the data, which was announced in a teleconference in accordance with the U.S. Securities and Exchange Commission rules for publicly traded companies rather than the traditions of science.

Analysis of the VaxGen data through all sorts of lenses will continue. Those participants who received the vaccine, not placebo, and who became HIV-positive during the trial are being monitored to discover if the vaccine impacts the course of the disease. The NIH also collected numerous specimens from trial participants for future analysis.

Many experts, however, are ready to move on. They're looking to the other vaccines at various stages of development with great hope and optimism because research into a vaccine appears, finally, to be going somewhere.

"At least it happened," said Dr. Cade. "There was such inertia in this country about doing any AIDS vaccine research for such a long time. We're hoping to participate in more trials, and we'd love to have a vaccine that works."

VaxGen Inc., is reviewing the data with the Food and Drug Administration and plans to submit papers to academic conferences and journals over the next year.

"We're disappointed that there wasn't broader efficacy, but vaccine development goes in steps, and this is a step forward," said Jim Key, spokesman for the company.

ADDITIONAL INFORMATION:

Study examines whether antiretroviral has a role in prevention

Researchers at Johns Hopkins University in Baltimore are investigating whether regular low doses of an antiretroviral currently used to treat AIDS and prevent mother-to-child transmission can be used to prevent infection among adults whose behavior puts them at high risk for infection.

Early results from the phase I/II trial of nevirapine involving 33 patients were published in the journal AIDS this month.

So far, the trial found that a 12-week regimen of the pills taken once a week, twice a week or every other day produced levels of the drug in the blood that could prevent infection.

No serious adverse events were reported. Over the short period, there were also no new infections.

"This is a new concept for the prevention of HIV infection," said J. Brooks Jackson, MD, lead author and director of pathology at Johns Hopkins.

"We want to see if long-term, low doses of one of these drugs can prevent new HIV infections in people at high risk. HIV infection rates are fairly steady in the United States, but skyrocketing elsewhere. We can't afford to wait for a vaccine."

Researchers expressed concern that the drug could damage the liver or that chronic use could make the drug less effective against an actual HIV infection, but considered the potential benefits worth the risks.