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Originally published November 8, 2007 at 12:00 AM | Page modified November 8, 2007 at 9:49 AM

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Failure of AIDS vaccine punctures soaring hopes

The resounding failure of an AIDS vaccine that was tested with great fanfare in Seattle and around the world has left researchers with plenty...

Seattle Times health reporters

The resounding failure of an AIDS vaccine that was tested with great fanfare in Seattle and around the world has left researchers with plenty of theories — but as far as ever from the long-sought holy grail in the fight against the pandemic.

Researchers gathered in Seattle on Wednesday for a three-day conference admitted they were both startled and disheartened by the revelation that the much-hailed "STEP Study" vaccine may actually have put volunteers at an even greater risk of developing HIV than reported last month. HIV-negative men who received the test vaccine actually ended up with more cases of infections than men who got placebo injections.

The vaccine had been only the second ever to reach wide testing in humans, and early phases had shown so much promise that scientists spoke excitedly as recently as last winter of finally finding an elusive vaccine.

This latest blow has prompted some even to question whether any vaccine will ever be successful against HIV, a virus that has killed 25 million people worldwide.

What went wrong?

The STEP study, launched in early 2005, was halted in September, more than a year early, because the vaccine simply did not work. It neither prevented HIV infection nor reduced the virus levels of those who got infected. Now researchers are trying to determine whether the vaccine itself actually made men more susceptible to acquiring HIV.

The study included 3,000 men and women between ages 18 and 45 who were considered at high risk of HIV infection. One hundred volunteers were from Seattle. The rest were from 15 other U.S. cities and from Canada, Peru, Brazil, Australia, Jamaica, Haiti, Puerto Rico and the Dominican Republic.

The pharmaceutical company Merck, which was developing the vaccine, co-sponsored the trial with the Vaccine Trials Network, an international research collaboration based at Seattle's Fred Hutchinson Cancer Research Center. It was funded by the federal National Institutes of Health.

The vaccine used a disabled form of a common-cold virus to carry three synthetically produced HIV genes into the body. It was hoped that those genes would spur the body to unleash an HIV-targeted immune response using so-called "killer" T cells.

Neither the cold virus nor the HIV genes could reproduce, so volunteers could not catch a cold or become infected with HIV directly from the vaccine.

Researchers knew in September that men who were receiving the vaccine were catching HIV at a higher rate than the men who received the dummy shots.

In an initial review, they found 24 HIV infections among 741 men who received at least one dose of the vaccine. That compared to 21 HIV cases among 762 men in the placebo group.

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A smaller sample, limited to those who had received at least two vaccinations, found 19 infections in the vaccine group and 11 in the placebo group.

That was enough to pull the plug on the trials Sept. 21.

After further analysis of the full research data in October, researchers discovered that the gap in infection rates was even wider. And a pattern was spotted: Especially vulnerable were volunteers who had more immunity to the particular cold virus used in the vaccine because of earlier exposure to it.

Although 40 percent of the volunteers were women, only one woman developed an infection, so the review focused only on the men.

The September analysis had looked only at subjects with no or low immunity to the cold virus.

Among the 392 men who received the experimental HIV vaccine and had high immunity to the cold virus, 21 became HIV infected compared to nine among the 386 men in the placebo group.

And a subset of that group showed even more contrast: Among the men with the highest levels of immunity to the cold virus, seven were infected out of 163 men who got the vaccine, compared to only two cases out of 157 men in the dummy-injection group.

In the entire study, 49 of the 914 men in the vaccine group and 33 men of 922 in the placebo group tested HIV-positive.

Sifting for clues

Investigators are still analyzing the data to figure out whether the higher infection rate among the vaccine group is coincidence, said Dr. Larry Corey, the lead scientist for the HIV Vaccine Trials Network.

It would take further tests to figure out whether the vaccine somehow aided HIV infection instead of averting it, the scientists said Wednesday. It's also possible that other factors are at work, such as differences in circumcision rates, geographic variations and sexual habits, Corey said.

Regardless, the results marked an abrupt reversal of fortune for a project once regarded as one of the leading hopes in the AIDS battle. In early tests, the vaccine had triggered such vigorous immune responses that researchers in 2005 decided to double the number of volunteers.

Since the discovery, the STEP volunteers have been notified about the potential increase in infection risk. But they have not been told whether they received the vaccine or placebo during their participation in the study.

The trial's co-sponsors are deliberating whether to "unblind" the trials and divulge that information. A decision may be released this month.

The decision will depend on whether the researchers think volunteers would be better off knowing, said Margaret Johnston of the National Institute of Allergy and Infectious Diseases, one of the trial's co-sponsors. Another consideration, she said, is that unblinding the study would make it harder to keep studying subjects from the international trials, because people's behavior could change after they find out whether they got placebo or vaccine.

Learning from failure

Meanwhile, disappointment among the researchers and others who had been watching the effort has been palpable this week, even in a field accustomed to dashed hopes.

Dr. Frank Plummer, a leading researcher and adviser to the Public Health Agency of Canada, said it's both troubling and interesting that the would-be vaccine, which stimulated the immune system, failed.

"One wonders if stimulating the immune system may make people more susceptible," he said. "If that turns out to be true, then one wonders if we can make a vaccine for this thing."

At the same time, they were looking for bright sides.

Dr. Seth Berkley, an infectious-disease specialist who heads the International AIDS Vaccine Initiative, emphasized that other major vaccines have taken years to perfect. Polio, for instance, took 47 years. Chicken pox took 42.

"I don't think anybody thought this vaccine would be the proverbial home run," Berkley said.

He said the failure raises new questions to fuel research. Among them are what form of HIV virus should be used as a vaccine, and what type of cold virus could be effective in delivering it into the body.

And it's the nature of science to take "two steps forward, and one backward," said Dr. Alan Bernstein, who is taking over as director of the Global HIV Vaccine Enterprise, an international collaboration partially funded by the Bill & Melinda Gates Foundation.

He predicted that this failure may clear the way for other researchers to get funding and try something else.

"Science is not a series of eureka moments," Bernstein said.

"If every time a scientific experiment didn't work, we gave up, we would have no scientific progress."

Kyung Song: 206-464-2423 or ksong@seattletimes.com.

Copyright © 2007 The Seattle Times Company

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