Ending of HIV vaccine trial jolts industry

It wasn't a definitive blow, but it sure sent shock waves through the AIDS world when Merck & Co. Inc. decided late last month to pull its HIV vaccine trial.

Merck had assembled the latest thinking on a 20-year quest to attack the elusive virus. Its researchers had spent more than a decade devising the best ways to take down a supremely canny organism.

And then nearly three years into an international trial, the company, which created the vaccine in West Point, Montgomery County, pulled the plug because the vaccine did not seem to be working. More people among the vaccinated group were getting the virus than those receiving a placebo.

Mark B. Feinberg, Merck's vice president for Medical Affairs for Vaccines & Infectious Diseases, estimated that roughly 90 percent of vaccine studies were using major elements of Merck's approach.

So the pullback created a collective gasp. Was HIV-vaccine research careening down the wrong path?

"I must admit I was shocked when I saw the outcome. It was the most promising vaccine we had," said Hildegund C.J. Ertl, an immunologist at The Wistar Institute in Philadelphia who is preparing to test another HIV vaccine.

It is too early to know what Merck's study means. The firm is still collecting data and promises to share its results.

"To paraphrase some of my colleagues, the trial shows a failure of a specific product but not a failure of the concept," said Gary J. Nabel, director of the Vaccine Research Center of the National Institutes of Health, who is also involved in another HIV vaccine trial.

"It would be truly remarkable" to develop a vaccine in less than 10 years, Nabel added.

It will not be for lack of trying. With the end of the Merck trial, the world has seen only two completed tests of HIV vaccines, a direct result of weak investment in the 1990s, said Seth Berkley, president of the International AIDS Vaccine Initiative in New York. (A third trial by Sanofi Pasteur Inc. in Thailand will wrap up in mid-2009, but it is not expected to provide strong results.)

But the world now is spending $759 million a year on HIV vaccines, up from about $150 million annually in the 1990s, he said. More than 90 percent is coming from governments.

The increased funding overall has enabled about 30 vaccines to enter human trials, including several involving researchers in the Philadelphia area.

A successful HIV vaccine will likely take multiple swipes at the virus, not just one, said Michael A. Horberg, director of Kaiser Permanente's HIV/AIDS Policy, Quality Improvement, and Research Initiative. "It's going to require a few synergistic strategies in the same way the virus is treated with multiple drugs."

Vaccines remain a holy grail in the world of HIV. The virus, spread through sexual contact and infected needles, rivals the largest epidemics in history, killing more than 25 million people worldwide since 1981, including 550,000 in the United States.

The virus represents one of the most confounding targets in medicine. It mutates quickly, so vaccines cannot keep up. Its outer envelope, swathed in sugar molecules, is difficult to attack. And HIV strikes the very cells that the immune system throws up against it.

Traditional vaccines that work by exposing people to a weakened or killed microbe have failed in HIV.

So scientists, noting that many long-term survivors have high counts of killer T cells, have turned to stimulating the immune system to generate those cells.

Merck's vaccine represented a state-of-the-art example of the new cell-based approach. It used a human cold virus altered so it could not replicate. Researchers placed one of three HIV proteins inside its shell in hopes of triggering an immune response.

The U.S. government paid for most of the testing. Merck paid for some sites and for making the virus, but would not disclose how much it spent.

The trial, designed to see if the vaccine would prevent HIV infection and reduce the virus in those infected, failed on both counts.

HIV levels were similar in both the treated and untreated groups. And among those whose received two doses of the vaccine, 19 developed an HIV infection compared with 11 in the group that got the placebo.

Those results startled many researchers, because the vaccine had triggered a strong response in early studies of healthy volunteers.

But the trial may yet prove useful. "The information is going to help us develop vaccine in the future," said Ian Frank, director of the HIV Vaccine Trials Unit at the University of Pennsylvania, which enrolled 125 women into the Merck trial. "I don't think people should be overly disappointed. We're really at the very earliest stages in this process."

Penn is getting ready to test two more vaccines. One by Nabel's group at the NIH, called PAVE100, will be closely watched. It uses five proteins of the HIV virus compared with Merck's three.

Another promising approach comes from the lab of David B. Weiner, a Penn pathology professor whose group has been a leader in using DNA to stimulate an immune response against HIV.

Weiner has been working on the concept since 1989, trying to make it more potent. He stresses that these new trials - his group's second attempt at producing more potent immune responses - are meant to see if the platform is strong enough for larger clinical testing.

"We now have a line in the sand. We need to do better than" the Merck trial, Weiner said. "We should be testing different hypotheses so when they fail, we can refocus on things that have a better chance of working."

Ertl at Wistar said she thought she, too, might have an answer.

Her group recently received a $13.3 million grant over five years to test a vaccine based on chimpanzee cold viruses.

Ertl said she thought the Merck virus might have stumbled because of its reliance on a human cold virus.

The immune system may have recognized the cold virus and quashed it before it could work. A chimp's virus likely would not elicit the same reaction, she said.

But John W. Shiver, who heads Merck's basic research in vaccines, said the company's failed effort took that into account.

Shiver, who is credited with several research advances, said he did not think any current approach would work. He said he thought a new burst of creativity was needed.

"It's a virus of change. It's different in every person," he said. "That makes making an HIV vaccine a huge challenge."