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Next on AIDS' frontier: After a promising vaccine fails in trials, researchers channel efforts and optimism toward other possibilities.

Los Angeles Times - March 3, 2003
Jane E. Allen, Times Staff Writer

The first AIDS vaccine to undergo advanced human trials has proved a failure, its makers acknowledged last week. But researchers and advocates are not giving up.

Vaccines using other strategies remain in the pipeline, keeping alive the hope that at least one will someday tame the global spread of the human immunodeficiency virus. About 19 are currently in human trials, researchers say.

They caution, however, that large-scale progress isn't expected any time soon. Most are in early studies designed to show that they're safe and can mobilize the body's disease-fighting systems. Others haven't gotten even that far.

"We have a field of them that are doing pretty well in animal studies," said Martin Delaney, founder of Project Inform, an AIDS treatment, information and advocacy group in San Francisco. "But the nature of vaccine research is that if you had the perfect vaccine tomorrow, it would take you almost 10 years to prove it and get it to the regulatory stage."

AIDS has killed about 22 million people since it was first identified more than 20 years ago. Currently, an estimated 42 million people are infected with HIV, with 15,000 new infections each day, most in Asia and Africa.

Antiviral medications can prolong the lives of those with HIV and AIDS, but they're expensive and unavailable in many of the nations hardest hit by the disease. Therefore, the ultimate goal is to prevent new infections using vaccines.

Vaccines against polio or influenza give people a weakened or inactivated virus, which then teaches the body to recognize and defeat the real thing. But because HIV is so infectious, researchers are using only parts of the virus to avoid producing AIDS. They're testing various genes and proteins that might rev up the immune system, as well as the most effective means to inhabit human cells.

The Aidsvax vaccine, from VaxGen in Brisbane, Calif., was the only vaccine ever to get through Phase III trials, which test for effectiveness in large numbers of people. In the five-year trial, doctors injected 5,108 gay men and 309 women, all HIV-negative, with a genetically engineered protein from the surface of the AIDS virus, called gp120, hoping to stimulate the formation of antibodies that would neutralize HIV.

As last week's long-awaited announcement revealed, Aidsvax failed to produce the hoped-for disease protection, although there were suggestions it may have some effect in African Americans and Asians. VaxGen has a modified version of the same vaccine in Phase III trials of intravenous drug users in Thailand. Results are due by year's end.

Another hopeful

Another vaccine scheduled to enter Phase III trials in Thailand uses a two-step process. Participants will get an initial shot of a vaccine from a weakened canary pox virus (a bird virus in the same family as smallpox) that has been engineered to carry HIV genes into the body. It will be followed by a booster shot with Aidsvax. The trial of the vaccine, made by the French pharmaceutical company Aventis Pasteur, is sponsored by the National Institutes of Health and Thailand's public health ministry. The timing is uncertain because officials are expected to review the latest Aidsvax data before proceeding.

Such a two-part vaccine tries to fire up two types of immunity: antibody and cellular. Vaccines that produce antibodies aim to lock out the enemy, preventing HIV from entering disease-fighting T-cells and turning them into HIV factories.

Vaccines that promote cellular immunity are intended to bomb the HIV factories, telling the body to dispatch immune cells to destroy virus-infected cells. The attack would keep infected cells from turning out millions of copies of HIV that could infect other healthy cells.

Today, several research groups are trying to make a better antibody-inducing vaccine -- to either use alone or more likely in combination with a cellular immunity vaccine, said Dr. John P. Moore, who runs an AIDS research laboratory at Weill Cornell Medical College in New York City.

The antibodies produced by Aidsvax didn't prevent infection. But the International AIDS Vaccine Initiative, a nonprofit vaccine research program in New York, in collaboration with the National Institutes of Health, has established a multimillion-dollar international consortium of scientists from leading laboratories to accelerate the development of the right vaccine components to generate effective antibodies.

Of the many vaccines in early human trials, two that try to generate cellular immunity are garnering particular interest, said viral immunologist Wayne C. Koff, senior vice president of research and development at the International AIDS Vaccine Initiative.

One, made by pharmaceutical giant Merck & Co., shuttles HIV genes into the body using adenovirus, a cold virus that has been modified so it can't reproduce. Early results show adenovirus seems to stimulate a bigger and more prolonged immune response than other viruses used to ferry genes into target cells, said Koff. However, he noted, that as many as 80% of people worldwide have antibodies to adenovirus.

The other closely watched vaccine, being tested in Britain, Kenya and Uganda, has two parts: an initial shot of HIV genes and a booster shot of modified vaccinia Ankara (MVA), which resembles the virus in smallpox vaccines, containing other HIV genes.

One-two punch method

AIDS activists and researchers also have hopes for another combination vaccine (using an initial shot of HIV genes and a booster using adenovirus) and a GlaxoSmithKline vaccine made from three different HIV proteins. Both are being studied by the NIH.

The International AIDS Vaccine Initiative is working with France's AIDS research agency on a vaccine that gets into cells using a lipopeptide -- a small protein fragment with a lipid tail. And IAVI has been conducting pre-clinical trials on a vaccine from Targeted Genetics Inc. in Seattle that's made from adeno-associated virus, which appears to give persistent immunity with one shot, said Koff.

Meanwhile, the AIDS community is waiting.

"I'm hopeful. The problem is timing," said Delaney. "In the best case, you're going to see something seven or eight years from now."
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