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The search for an AIDS vaccine, 20 years on

PHILADELPHIA, Pennsylvania (CNN) -- Twenty years after the first cases of AIDS appeared, researchers are still looking for a successful vaccine against HIV. The next breakthrough could be sparked by information shared by the more than 1,000 men and women meeting this week in Pennsylvania.

Researchers, clinicians, epidemiologists, public health officials, pharmaceutical/biotechnology industry representatives and policy makers from around the world are attending the AIDS Vaccine 2001 conference, which gets under way Wednesday evening.

Drug-resistant HIV rate to climb  

Sponsored by the Foundation for AIDS Vaccine Research and Development and several other U.S., French and United Nations health organizations, the gathering is aimed at sharing of information regarding the development, delivery, evaluation, production and implementation of AIDS vaccines and immunotherapies.

Vaccines under trial

Of the 20-25 AIDS vaccines currently in clinical trials, only AIDSVax by VaxGen is in large-scale human trials.  It's currently being tested in 7,900 people in the United States, Europe and Thailand.

The trial is scheduled to continue until late 2002, but VaxGen will do an interim review this fall.  If the results show a certain level of protection, the trial will be stopped and VaxGen will apply for FDA approval.

But many researchers don't think AIDSVax will be the magic bullet.   Dr. Gary Nabel, the director of the Vaccine Research Center at the National Institutes of Health, says, "The VaxGen product is a protein derived from the virus, it does elicit an antibody response to this protein, but it turns out this protein is not identical to the protein on the virus itself."

Still, in some places where the virus rages, many experts agree some protection is better than none at all.  

Designing vaccines

Because no one has ever kicked HIV on their own, researchers don't know what to replicate in the lab.

Look at smallpox, for example.  In 1796, English physician Edward Jenner noticed that milkmaids who had previously had cowpox were resistant to infection with smallpox.  The milkmaids were a protected population that could guide researchers with smallpox vaccine design.

Several years ago there was similar hope from a group of prostitutes in Nairobi, Kenya.  Despite guaranteed exposure to HIV, some of the women remained uninfected.   A vaccine was created on that model and is in trials now. 

Researchers determined that the women were exposed to a low enough level of the virus so that it didn't infect but instead protected them. It was like a natural virus; it taught the immune system that the virus was an enemy without overwhelming the immune system.

But there's a downside. Several of the women took a break from the sex trade and,  upon returning, became infected with HIV -- leading researchers to question how long any protection may last.

There are more reasons why an AIDS vaccine has been particularly difficult to design. The virus is constantly changing, so what may be a good vaccine target today, could be different tomorrow.  Furthermore, the virus camouflages itself from the immune system.

Immune responses

There are two ways the immune system fights infections:  an antibody response and a cellular response.

A typical vaccine presents a marker, like a protein, of the virus, bacteria or fungus to educate the immune system, showing it what the enemy looks like.  Then when the disease appears and the marker is present again, the immune system recognizes it as an enemy and launches an all-out attack, blocking infection.  This is an antibody response; it occurs before cells are infected.

A cellular immune response kills cells that are already infected.   Nabel says future vaccines will most likely target both responses.  "To the extent that we can combine the cellular arm and the antibody arm, we are likely to do much better," he predicts.

Several AIDS vaccines in clinical trials seem to trigger a cellular response.  One designed by Merck is in the first stage of human trials. Similar vaccines by the Yerkes Regional Primate Center and Harvard expect to be in human trials soon.

Animal studies with these vaccines show they don't necessarily kill all infected cells.  If this carries over to humans it may mean the vaccine doesn't necessarily block infection, but it may kill enough of the virus that the disease doesn't make you sick.

"We're now thinking that we'll take our victories where we can," Nabel says.  "If we can convert this lethal infection into a benign one, a latent infection, then that would be a major step forward."

Vaccines for other countries

Another catch with HIV vaccine is there are several different types, or clades, of the virus around the world.  The type most common in the West, where most vaccine development is under way, is different from the types in Africa, India and China, where the disease is having the greatest impact.

It's not yet known if a vaccine that works against the clade in the United States will work against the clade in South Africa.  The different clades of the virus differ at the genetic level, however; Nabel says there is a relatedness of those viruses at the protein level, so a vaccine that is based on proteins could possibly carry over.

The polio virus, for example, does not change like HIV does, but there are different strains.  By using a vaccine cocktail of three different strains, the major strains of polio worldwide can be vaccinated against with one vaccine.

Nabel says it is conceivable it will take a vaccine cocktail to defend against all the clades of HIV worldwide.

Next large-scale trial

The next vaccine closest to large-scale human testing is a vaccine made by Aventis that uses canarypox, a bird virus that is harmless to humans, to deliver selected HIV genes into the body.  The genes then trigger the immune response.  It's being tested in combination with a protein vaccine.

Nabel says that although it's the farthest along, it's not definite the vaccine will be the next for large-scale trials.

"It looks better than current generation vaccines," Nabel says, "but I think it's too early to say whether it meets the level that we need to see for it to move forward.  We need a little more data."   Vaccines that use the pox-type viruses to deliver the vaccine tend to trigger a better cellular immune response.

"I would say the data at this point shows that it induces a cellular immune response in a certain proportion of patients, but not all patients," Nabel says.  "That's why we need to gather a little more data and understand the process before further decisions are made."

Once a large-scale trial is started, experts estimate it takes another three to five years just to collect the data.  Given VaxGen's vaccine is the only one in a phase three trial and many researchers have limited expectations for it, Nabel estimates it will probably be another five to 10 years before we have a solid AIDS vaccine.

• AIDS Vaccine 2001
• United Nations Programme on HIV/AIDS
• Journal of the American Medical Association HIV/AIDS Resource Center

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