San Francisco Chronicle - July 18, 2008
Sabin Russell, srussell@sfchronicle.com.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the decision to call off the proposed study was his alone, but followed months of meetings to debate the merits of proceeding with the experiment.

After the Merck vaccine failed, Fauci first delayed and then scaled back the proposed $160 million test of the NIH vaccine. The trial was to be known as PAVE 100.

Backers of the scaled-back study still hoped for the go-ahead, but Fauci rejected the plan and asked study designers to propose a still "smaller, leaner, meaner" version of PAVE 100 that would cost less than $45 million.

His decision took vaccine advocates by surprise. "We supported the scientific premise of the trial and believed that it was being designed in such a way that participants' safety would be protected to the fullest extent possible," said Mitchell Warren, executive director of the AIDS Vaccine Advocacy Coalition in New York.

Until the failure of the Merck candidate last fall, the NIH was just months away from launching its own study with 8,500 volunteers. Both vaccines were designed not so much to prevent HIV infection as to stir up an immune response that would keep any infection in check - mimicking natural control of the virus that small numbers of people appear to have.

An early look at the results of the Merck trial in September showed its vaccine failed on all fronts. It didn't protect against infection, and those who were vaccinated and infected anyway had no better immune control over HIV than those who had been given a placebo.

Hope remained that the newer vaccine would be different. It had succeeded in studies with laboratory monkeys, whereas the Merck vaccine failed in similar animal trials. Also, the NIH vaccine was made of bits of viral DNA designed to stir up an immune response, while the Merck vaccine relied on an older technology that injected bits of protein. DNA vaccines are thought to be potentially more powerful.

But both vaccines rely on a hobbled version of a common cold virus to stir up the immune system, and the surprise result of the Merck study was that some volunteers who had previously been exposed naturally to such cold viruses appeared to become infected with HIV at a higher rate. Most puzzling was that the infection rate was highest for men exposed to the cold virus and who were also uncircumcised.

After Fauci postponed the launch of PAVE 100, a new trial version was cobbled together that would be conducted only in the United States among volunteers who had not been exposed to the cold virus and were circumcised. Only 2,400 volunteers would enroll, and costs would be trimmed to $63 million.

Martin Delaney, founder of Project Inform in San Francisco, said the flaws of the Merck study were not addressed in the revised proposal. "There were a lot of people counting on this study. It was big-time funding for the next five years," he said. "But in the end, it was some of the weakest science I had ever seen." The NIH vaccine, he said, was not that different from the one that had failed.

Dr. James Kublin, director of the HIV Vaccine Trials Network, the Seattle organization that was to have run the PAVE 100 trial, acknowledged that he had strongly supported going through with it. "We're willing to accept the decision and move forward," he said. "We can design a study that will provide critical information and ideas for the next round of research."

Fauci ultimately turned down a plan that would have generated mountains of data from each volunteer's response to the vaccine, as measured by a variety of biological markers.

Instead, he wants to carry out a study that would answer just one fundamental question: whether the vaccine works. Specifically, the study needs to find out as quickly as possible whether those who are vaccinated and subsequently become infected can control the level of virus in their bloodstream better than those who become infected but had been given a placebo.

His scaled-down test proposal will still do that. In order for that to work, Kublin said, at least 30 volunteers will have to become infected over five years. Just how many volunteers will need to be enrolled to come up with 30 infections has yet to be determined.

Dr. Susan Buchbinder, director of HIV research for the San Francisco Department of Public Health and a leader of vaccine trials in the city, said Fauci's decision was a "balanced approach" that takes into consideration some of the lessons learned from the Merck trial.

"This isn't a barrier to research," she said. "It's a fork in the road, and the decision is just to take one fork and not the other."

AIDS vaccine failures

Dozens of potential AIDS vaccines have been studied, but only two have made it to large-scale trials, and both have failed.

February 2003: A study of 4,500 North American and European volunteers found that a vaccine produced by Vaxgen, a Brisbane company, did not protect against infection by HIV, the virus that causes AIDS.

November 2003: The Vaxgen vaccine also fails in a study of 2,500 injection drug users in Thailand.

September 2007: A nine-country study of 3,000 volunteers found that a vaccine by Merck & Co. failed to protect against HIV infection or control the virus as hoped in those infected.

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