icon star paper   HIV Articles  
Back grey_arrow_rt.gif
After 20 years, AIDS vaccine still seems a distant dream
  By Steve Sternberg, USA TODAY
Sept 29, 2004
When AIDS was young, researchers pinned their hopes of ending the epidemic on the speedy discovery of a vaccine. Twenty years later, they realize their work is still just beginning.
This recognition comes from a steady drumbeat of discouraging results, most recently this month at the 2004 AIDS Vaccine Conference in Switzerland, and in July at the 15th International AIDS Conference in Bangkok.
"We're dealing with a very formidable scientific challenge," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). "This is probably going to turn out to be the most difficult vaccine to develop in the history of vaccine research."
Unlike other viruses, AIDS doesn't produce immunity in people who are exposed to it because it attacks the immune system itself. People who are already infected with one strain of HIV are still vulnerable to infection with others, a catastrophe known as "super infection."
As a result, most of the vaccines tried so far have failed to live up to expectations, researchers say. The most widely publicized flop was VaxGen's prototype AIDSVAX, which failed last year in large-scale human trials of 8,000 people in North America and Thailand after years of costly research.
Almost two dozen prototype vaccines are being tested in humans, compared with seven just two years ago. Eleven of them are in the U.S. government-sponsored HIV Vaccine Trials Network. Many of them use kaleidoscopic combinations of HIV genes or proteins — diced up so they can't reproduce and give people AIDS — packaged in a wide array of weakened viruses. So far, researchers say they haven't found any combo that reliably generates potent enough immune responses.
As a result, they say, AIDS vaccine research is at a crossroads, with once-promising approaches falling by the wayside and little certainty about where to go next.
"Part of any investigation into the unknown is running into dead ends. That's how science is done," says Emilio Emini, director of vaccine research for the International AIDS Vaccine Initiative (IAVI). "It's not as if we're running out of ideas. Failures teach you to modify your path."
The vaccines now in trials include vaccines made with bits of pure genetic material from the AIDS virus, stripped of the sections that would allow HIV to reproduce itself and spring to life. These so-called DNA vaccines, once viewed as promising, have since proved disappointing. Others are Trojan-horse vaccines, made by stuffing viruses with inactivated HIV proteins that researchers hope will send the immune system into overdrive.
Many basic questions also remain unanswered. For instance, no one knows what immune responses best guard against HIV infection.
Below is list of vaccine trials. Table will be posted in article on NATAP website later today.
  And no one has figured out how to produce a vaccine that can prompt the immune system to generate antibodies capable of killing the AIDS virus, before it establishes a toehold in the body. These so-called neutralizing antibodies are critical to the effectiveness of every other vaccine.
"A lot of labs are working very vigorously on this," says Paul Spearman of Vanderbilt University.
Most vaccines now in development activate a very different arm of the immune system, one designed to rid the body of infected cells. While these vaccines won't block infection, researchers hope they'll serve as a kind of immune therapy able to keep the virus in check, stave off symptoms and prolong life. Vaccines tested so far haven't produced a potent enough response.
Some human trials to watch are:
--A third test of AIDSVAX is now underway in Thailand, involving 16,000 people. This study uses AIDSVAX as a priming dose for a second prototype vaccine made from a combination of harmless HIV genes and canarypox virus by the drug firm Aventis. This study has been criticized as a waste of time and resources. "There is substantial evidence that this vaccine combination is not likely to be protective," says Charles Rinaldo of the University of Pittsburgh.
--A small-scale human effectiveness trial of a Merck vaccine slated to begin in about 1,500 people by the end of this year. Another Trojan-horse vaccine, it packages an HIV gene in an ordinary cold virus. Tests have shown such vaccines are safe, but they won't prevent infection. Instead, they help the immune system hold HIV in check.
--Preliminary tests of a prototype vaccine developed by the NIAID Vaccine Research Center. This one packages multiple HIV genes, from different strains of the virus, in genetically engineered cold viruses.
Spearman calls the latter vaccines the most exciting of those now in development.
When one approach doesn't work, drop it and move on, says IAVI director Seth Berkley. Berkley says he is poised to pull the plug on a once widely promoted vaccine his organization sponsored in trials in London and Nairobi, Kenya. Those studies found the vaccine activated the immune system in just 20% of those who received it.
There's no way to avoid such missteps because monkey studies of HIV vaccines have turned out to be powerless to predict how well the vaccines will work in humans.
The failure has prompted a profound shift in research strategy, says Lawrence Corey, director of the HIV Vaccine Trials Network.
Rather than winnowing out likely winners by testing them in animals, researchers are going to have to mount costlier small-scale trials in humans, Corey says.
It will take patience, says Gary Nabel director of the NIAID Vaccine Research Center. "Nothing happens overnight," he says, "especially in medicine."
  icon paper stack View Older Articles   Back to Top   www.natap.org