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Merck Study Volunteers to be told who got HIV vaccine
  By Carol M. Ostrom
Seattle Times health reporter
Nov 14, 2007
Volunteers in a failed worldwide AIDS-vaccine study headed by Seattle researchers will be told whether they were given the experimental vaccine - and may face a higher risk of getting HIV than those who got a placebo.
"In our deliberations about this, the central point was: 'What's best for the participant?' " said Dr. Ann Duerr, an associate director of the HIV Vaccine Trials Network, based at Fred Hutchinson Cancer Research Center, and one of the sponsors of the so-called "STEP vaccine" study.
The study was halted in September because the vaccine wasn't working; last week the researchers announced that a deeper analysis showed that certain volunteers who got the vaccine were more likely to contract HIV, though they are not yet sure why.
About 100 volunteers were from Seattle. Other sites include 15 other U.S. cities, as well as some in Canada, Peru, Brazil, Australia, Jamaica, Haiti, Puerto Rico and the Dominican Republic.
In total, 3,000 volunteers - men and women between ages 18 and 45 considered to be at high risk of HIV infection - will now be encouraged to return to their study sites for "risk-reduction" counseling and study-related tests, said the study's sponsors.
Skewed data?
The vaccine, being developed by Merck pharmaceutical company, used a disabled form of a common cold virus to deliver three synthetic HIV genes into the body in hope of stimulating an HIV-targeted immune response.
The decision to "unblind" the study also focused on whether it would be more beneficial for follow-up research to maintain the study's "double-blind" design, in which neither researchers nor volunteers know who got the real vaccine.
And that decision was neither simple nor easy, said Duerr, who is also a professor at the University of Washington.
"There was a huge spectrum of opinions," she said. "This issue isn't really black and white."
The fear is that volunteers, if they know whether they got the medication being studied or a placebo, might change their behavior enough that information collected afterward would be tainted.
"Unblinding the patient has the potential to bias the data in the future," noted Garret Anderson, an assistant professor of biostatistics at the University of Washington. Anderson was a co-investigator of a huge study of hormone-replacement therapy in women that was halted in 2002 when it found the hormones had adverse effects. The research was later unblinded.
In the end, researchers realized that "this isn't the last trial we'll do," Duerr said, and that keeping the trust of potential volunteers was paramount.
"It's very important that we keep faith with the community," she said.
Mitchell Warren, executive director of the New York-based AIDS Vaccine Advocacy Coalition, applauded the decision. Not only will it increase the chances of getting volunteers for future studies, he said, but it may actually help with future data collection from the trial's participants because it signals that the researchers are putting their safety first.
"In many ways unblinding may be a great motivator to keep people coming back," he said.
AIDS vaccine's failure deals big blow
Other clinical trials delayed as researchers ensure mistakes are not repeated

By Stephanie Desmon Baltimore Sun reporter
November 14, 2007
The failure of Merck & Co.'s once-promising AIDS vaccine has cast a pall over research efforts and forced delays in trials of other experimental vaccines as scientists ponder what went wrong.
After more than two decades of work, vaccine researchers were hoping to be further along. Even if other vaccine initiatives eventually succeed, the arduous process of development and testing means that there won't be an immunization to prevent HIV for at least another decade, one top federal researcher says.
The Merck vaccine not only failed to protect participants in the trial, it also might have put them at a greater risk of contracting the virus, company officials said last week.
"The recent Merck trial results were a big blow to the field," said Dr. Gary Nabel, director of the National Institutes of Health's Vaccine Research Center in Bethesda.
He said few in the field believed that the vaccine would provide total immunity, but "it had absolutely no effect. We thought maybe it would have a little effect and maybe that would point us in some direction we could follow up on."
Instead of looking forward to the next vaccine candidate, scientists at the NIH and elsewhere must first look back to make sure that mistakes are not repeated. A large clinical trial involving human subjects being done by Nabel's center has been pushed back to mid-2008 while a half-dozen smaller trials in earlier testing phases have been paused.
The Merck results don't mean researchers are at a dead-end, several insisted. In the 1930s, two major vaccines for preventing the polio virus failed "miserably," said Mitchell Warren, executive director of the nonprofit AIDS Vaccine Advocacy Coalition.
"The world didn't say, let's abandon the search," he said. Two decades later, two vaccines were developed that led to the eradication of polio in the United States.
Merck was the only pharmaceutical company developing a vaccine - spending 10 years, untold millions of dollars and some top scientific talent toward that end - and a company official said last week that it has no other vaccine candidate in development. That removes a major player, though government money and foundation dollars are likely to keep flowing to others doing vaccine research.
The Merck failure also raises important scientific questions. In analyzing the results, the company said 49 cases of HIV infection were seen among 914 male volunteers after they got the vaccine, compared with 33 cases of HIV infection among the 922 male volunteers who got a placebo.
The vaccine used a disabled form of a common cold virus to carry three synthetic fragments of HIV genetic material into the body's cells. The cold virus was believed to be the perfect vector because it replicates very quickly inside the cells it infects.
But because some people already have some immunity to the common cold, the vector might have led to the vaccine's failure. If the immune system failed to respond when the cold virus arrived carrying the vaccine, then it might not have known that the vaccine was there at all. In the Merck trial, those vaccine recipients with the highest immunity to the cold virus were some of the most likely to get HIV.
"It's unequivocal that the vaccine cannot cause infection," Dr. Keith Gottesdiener, vice president for clinical research at Merck, said last week. "But it raises the possibility of increased susceptibility of the volunteers. We don't yet understand the reasons."
There are two dozen groups around the world actively pursuing an AIDS vaccine. Only two major clinical trials have taken place and neither has succeeded.
Scientists have taken two basic paths toward an AIDS vaccine. Some researchers have taken a more traditional route by trying to prompt the body to make neutralizing antibodies to fight off the virus before infection can take hold. Others take a tack similar to Merck's in trying to trigger a cellular response to HIV once it has invaded, forestalling disease at that point. Many researchers agree that a combination of both will probably be needed to create a successful vaccine.
A vaccine in the pre-clinical trial stage at the University of Maryland School of Medicine's Institute of Human Virology, which received a $15 million grant this summer from the Bill & Melinda Gates Foundation, is based on antibodies, an approach considered the more difficult of the two. Officials there declined to comment on the impact of the Merck failure.
Each approach uses a different methodology to get there. Some are similar to the one employed by Merck, raising questions about whether those will also raise the risk of infection in volunteers who receive them. But scientists say many of the cellular-based vaccines should be different enough to be able to move forward safely.
For example, the NIH vaccine, being overseen by Nabel and up next for clinical trial, includes a cold virus vector like Merck's, but it is in a booster dose given after three shots that do not include the cold virus. Nabel said that minimizes the chance of a repeat of what appears to have happened with the Merck vaccine.
Nabel said the majority of vaccine candidates in development are, like Merck's, based on the cellular model, because the antibody approach has thus far proved "much tougher to solve." Still, he said, "we desperately need the antibodies."
Meanwhile, condoms, circumcision and AIDS-prevention education are not working fast enough to halt the spread of AIDS. According to the NIH's National Institute of Allergy and Infectious Diseases, approximately 40 million people live with HIV, primarily in the developing world. This year, there have been an estimated 4.3 million new HIV infections.
In Baltimore, public health officials have struggled to contain the epidemic, especially in the hardest-hit neighborhoods.
"There is this sense that if we had a vaccine we could end this epidemic," Warren said. "When you have a setback, people might get so discouraged and say, we might never get an AIDS vaccine so let's just give up.
"It's not at all the end of the line."
Dr. John G. Bartlett, chief of infectious diseases at the Johns Hopkins School of Medicine, said that fighting AIDS thus far has been a losing battle and that hearing of another vaccine failure is "disheartening; it's really depressing."
"We're all going to be better off if we get this vaccine," he said. But, he added, "The AIDS vaccine program has been a disappointment from the beginning. Some people will say we're right where we were in 1985 and, in some ways, we are."
Nabel insisted that the knowledge about the AIDS virus and the immune system gained since 1985 - the year after HIV was discovered - has grown exponentially.
"At the end of the day, the search for a vaccine is a marathon, not a sprint," said Dr. Seth F. Berkley, president and CEO of the nonprofit International AIDS Vaccine Initiative. "The great challenge is to keep the world focused on the long-term prize."
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