NEW YORK, NY February 07, 2004 — For most of the last 20 years, the bulk of AIDS research has focused on treating the deadly disease and its symptoms. More recently, scientists are increasingly trying to prevent it from occurring in the first place with vaccines. Today, more than 20 different AIDS vaccines are in different stages of development and testing around the world.

Ever since Nobel Prize Winners Watson and Crick visited his high school biology class, Martin Lowe has admired scientists. He never became a doctor or researcher, but he does his part by volunteering for all kinds of experimental treatments. When he tells friends he's participating in an AIDS vaccine trial, they seem to respond more emphatically than usual.

LOWE): I've received reactions ranging from, You shouldn't do this, you're going to get AIDS from taking this vaccine, to Oh, this is great, I'd like to volunteer myself, give me the number.

Lowe thinks he's perfectly safe. He trusts the FDA rules protecting human subjects. And he knows he can't get AIDS from the synthetic DNA used in the vaccine trial. And while he feels, Sure, there's a one-in-a-gazillion chance something could go wrong

LOWE: You have to think are you just gonna bite the bullet and do it?

Other AIDS vaccine trials have had difficulty recruiting volunteers, but this one at Rockefeller University in Manhattan has attracted a surplus - more than 400 people for some 45 spots. Dr. Sarah Schlesinger is not sure why. Maybe because AIDS has touched the lives of an exceptionally high proportion of New Yorkers? Regardless, she is pleased with the size and diversity of the volunteer pool, and gratified by people's enthusiasm.

SCHLESINGER: We reimburse people $100 per visit, and we really thought we were going to get a lot of students and a lot of young people, but we've been really delighted in that the real motivation has been really highly altruistic and really with a sense that they want to do something to change the epidemic.

Trials like this one are small and preliminary. Researchers need to know the vaccines or drugs they're testing are safe and at least maybe do what they're supposed to, before running large-scale trials. Only one AIDS vaccine out of dozens has made it to the Big Time. It was produced by a company called VaxGen, who tested it on thousands of people on two continents. The trial cost hundreds of millions of dollars, and when it failed, it made front-page news. Still, vaccine researchers say they learned a lot from VaxGen's expensive dud. Dr. David Ho, director of the Rockefeller-University-affiliated Aaron Diamond AIDS Research Center, or ADARC, followed the VaxGen trial closely.

HO: I'm impressed by the mechanics of the trial. This involved, multiple centers working together to follow a common trial protocol and to follow them for several years and to determine how many people become infected in each group, vaccine versus placebo.

The VaxGen trial also showed researchers some things not to do. Ho says the VaxGen scientists basically were in denial. They knew their vaccine produced anti-bodies. The problem was these antibodies did not kill the AIDS virus. Ho says they then made the costly decision to change their hypothesis, mid-stream, without getting new data.

HO: They said, Well, could the non-neutralizing anti-bodies still be protective?' And despite lack of any data, they, went ahead, and unfortunately for them and the field, it failed.

Doctors Ho and Schlesinger hope their new vaccine will teach the body to respond more effectively against HIV than earlier vaccine candidates. Unlike almost all others currently being tested, the Rockefeller-ADARC vaccine contains parts of all five HIV genes. But how does injecting these genes into the blood get an immune response? Schlesinger and Ho think the answer lies with cells called dendritic cells. These cells are a relatively recent discovery, and scientists are still trying to figure out how exactly they work. They seem to coordinate the body's response to invading pathogens - viruses, germs, pollen grains that make you sneeze. Schlesinger says they sort of see the big picture -- like someone helping out the five blind men in the old story, with each one feeling a different part of the elephant and trying to figure out what it is...

SCHLESINGER: and one describes the side as a wall, and the other describes the ear as feeling like leather, and the trunk is a hose. So if you get a response to each of those parts, you're much more likely to eliminate the elephant than if you just get a response to the leg. Not that I want to eliminate the elephant! Believe me, we're very fond of elephants.

Probably only one or two of HIV's five genes needs to be knocked out to de-activate the virus - sort of like hitting the elephant's head or heart. Because they don't know which gene is the head or heart, scientists are trying to get the dendritic cells cells to respond to all of them - and put together the big picture for anti-bodies and white blood cells. But even if the trial doesn't work completely - and it almost certainly won't -- Schlesinger would be happy if the vaccine at least protected some people from HIV. That way, scientists could get some benchmarks for immune response, what they call correlates of protection. Currently, there's nothing for them to measure in the blood to know if a vaccine is working, the way they can with tetanus or polio or rabies.

SCHLESINGER: If I give you a tetanus shot, I can come back in two weeks and draw your blood and measure your antibody titers, and we know you're protected from tetanus. So that's a huge difference. So if we have a proportion of people who are protected from infection by the vaccine, we can then study them to see what it is that's different -- and that would be a huge break-through.

Since the time a curious English country doctor named Edward Jenner injected a young boy with a mild version of smallpox called cowpox, vaccine research have been primarily empirical - trial and error. That hasn't worked so far with AIDS, leading scientists back to basic, nuts-and-bolts, molecular research - what's called rational vaccine design. In the end, though, Schlesinger suspects AIDS will be conquered by serendipity.

SCHLESINGER: We won't know what works until it works, and then we'll be done. There was a huge industry in polio research and many different strategies being tried, and all of a sudden something worked, and it was over. We can only hope that someday isn't too far away. Pasteur said chance favors the prepared mind, we can only hope our minds are prepared enough, but in the end we're gonna have to be very, very lucky.

Schlesinger began AIDS research early on in her parallel career as the mother of four boys. She hoped they would be protected from AIDS before they hit manhood. Now, her oldest son is 16, and she has seen too many AIDS victims not to worry about him. Her youngest, however, is 9, so maybe there's still time. Not that she's counting on it. All four sons have had to blush early and often, while their researcher mom lectures them on safe sex.

Some links:

Rockefeller University -- http://www.rockefeller.edu/

Aaron Diamond AIDS Research Center -- www.adarc.org/

International AIDS Vaccine Initiative -- www.iavi.org/

AIDS Vaccine Advocacy Coaltion -- www.avac.org/

HIV Vaccine Testing Network -- http://www.hvtn.org/

General AIDS Information, National Institutes of Health -- http://aidsinfo.nih.gov/vaccines/

General AIDS Information, Centers for Disease Control -- http://www.cdc.gov/hiv/dhap.htm