AIDS Vaccine Proving to Be an Elusive Goal

WASHINGTON — Even today, the memory makes scientists cringe. On a spring day in 1984, Health and Human Services Secretary Margaret Heckler, surrounded by prominent AIDS researchers and public health officials, announced that the virus responsible for causing AIDS had been found.

Brimming with optimism, she declared that a vaccine would be ready for testing within two years.

It was a remarkable display of scientific hubris that most AIDS specialists would prefer to forget.

“No viral vaccine has ever been made in two years,” said Haynes Sheppard, a researcher with the California Department of Health Services. “Vaccine development is part science, part art and part luck--and if we don’t get lucky, it might take a very long time.”

In the recent euphoria resulting from the introduction of life-extending AIDS drugs, it is easy to forget the more frustrating side of AIDS research: that 13 years after the discovery of the human immunodeficiency virus, there is still no effective preventive vaccine on the horizon.

“One must keep in mind that there were no breakthrough AIDS drugs for many years--and then, suddenly, there were,” said Sheppard, one of hundreds of AIDS researchers who met at the National Institutes of Health last week for an update on vaccine progress.

The news is not all bad.

Researchers have gained new information from animal studies about the breadth of the immune response to different candidate vaccines. And at least one human trial is poised to expand to 420 volunteers to begin testing two promising experimental vaccines simultaneously, an approach known as “prime-boost.”

But none of the dozens of products under scrutiny has proved compelling enough for a large-scale efficacy trial, in which tens of thousands of high-risk individuals would be studied to see whether a vaccine actually protects them against infection.

There are many complex reasons why it is taking so long; chief among them is that HIV is a formidable and crafty foe.

Multifaceted Enemy

One of the biggest challenges facing researchers is the fact that the major target of HIV is the immune system itself. The virus infects the critical T-cells that regulate the immune response, weakening their ability to function. (The virus uses these cells as “virus factories” to copy itself.)

Also, HIV mutates, meaning that any effective vaccine must protect against all strains, both within infected individuals and among different populations.

This cannot always be accomplished, as the influenza vaccine has shown. There are two basic types of flu, but different variations appear every year, requiring new vaccine formulations.

Furthermore, because HIV can be transmitted--and can exist in the body--both as free virus and within cells, a successful vaccine must be able to elicit at least two kinds of immune response.

First, it must stimulate “neutralizing” antibodies that will destroy any free virus before it has a chance to infect the body’s cells. Second, as a backup, it must provoke the production of killer T-cells that “poison” any cells that have become infected.

The soon-to-be launched “prime-boost” trial, sponsored by the National Institute of Allergy and Infectious Diseases, will attempt to stimulate both responses by using two compounds at once.

One vaccine, vCP205, is made from a weakened canary-pox virus used to carry specific HIV genes into the body. It will be given to provoke the production of the killer T-cells. The second compound, rgp120, is a genetically engineered copy of an HIV surface protein. It will be given to provoke the antibodies.

It still might not be enough.

Because AIDS is most often a sexually transmitted disease, an effective vaccine also will probably have to stimulate an immune response from the mucosal immune cells that line the reproductive tract. This aspect of vaccine development is proving especially difficult.

“We don’t understand the principles of mucosal immunity particularly well, and haven’t been successful in developing vaccines directed at mucosally transmitted pathogens,” said Dr. Robert T. Schooley, who chairs the executive committee of NIAID’s AIDS Clinical Trials Group. “For example, we have no effective vaccines for syphilis or for gonorrhea.”

There is much debate over the best ways to proceed.

In developing vaccines, researchers typically look to which immune responses protect against infection--known as “correlates of immunity”--and try to create a product that will elicit those responses.

Put another way, scientists study the immune responses of people who have suffered and recovered from viral illnesses. In developing vaccines for chicken pox and polio, for example, researchers learned much from cases of people who recovered.

Dispute Over Next Step

However, unlike other viral diseases, no one is known to have recovered from HIV and become immune. In fact, it is not known whether a natural protective state against HIV even exists.

Some wonder whether it might be valuable to launch a large human trial of a marginal experimental vaccine, hoping that a few individuals would develop immunity so they could be studied.

“Do we really want to blow $30 million on a candidate vaccine that we’re not sure will work to get more information about correlates of immunity?” Sheppard asked. “Some believe it’s not worth it. Others believe it’s absolutely critical to get to the next level of protection. That’s where some of the tension is.”

Unfortunately, only limited information can be obtained from animal studies. There is no ideal animal model for studying HIV vaccines. Chimpanzees can become infected with HIV, but only one chimpanzee is known to have become ill. Moreover, chimpanzees are an endangered species.

So most HIV animal studies use macaque monkeys. They can be infected with simian immunodeficiency virus, which is similar to HIV and causes an AIDS-like disease. But results cannot always confidently be applied to humans.

During last week’s forum, Dr. Opendra Narayan of the University of Kansas Medical Center in Kansas City reported that he had developed a live-virus candidate vaccine that appeared to protect a small number of macaques from exposure to a lethal, lab-created hybrid virus that contained an HIV component.

Fears of Mutating Virus

The virus, dubbed SHIV, was made by combining SIV with a piece of HIV taken from its envelope, or outer coat.

Researchers would be delighted to end up with a live-virus vaccine but have shied away from that approach because of serious concerns about safety.

Historically, the best vaccines are often made from live, attenuated viruses. These are living viruses that have been altered to make them harmless, or capable of causing only mild disease.

But AIDS researchers worry that a live-virus vaccine, even crippled in some way, might find a way to repair itself once in the body or, even worse, meld with another HIV strain to form a more dangerous “mosaic” virus.

HIV is a retrovirus--its genetic material is RNA rather than the usual DNA. Upon infecting a cell, it undergoes a special process to turn its RNA into DNA, integrating with the DNA of the host (human) cell.

“We don’t know how the body would handle” an attenuated vaccine, said Dr. Larry Arthur of the National Cancer Institute. “Theoretically, once you’re infected with a retrovirus, you’re infected for life.”

“I’ve always been a strong proponent of attenuated vaccines,” he added. “There are certainly enough areas of the world with high-risk people that would warrant testing one. But there is a big potential safety risk.”

Arthur has been developing DNA-based vaccines, which use pure--but noninfectious--genetic material from HIV.

Other strategies under study include using a live but harmless “vector,” such as a bacterium or another virus, to “carry” an HIV protein gene; using chemically synthesized pieces of HIV proteins, known as peptides, and using a noninfectious HIV look-alike.

No one has yet put a live HIV vaccine in humans, although some experts point to a fascinating case in Australia as evidence that such a trial might not prove as dangerous as many people think.

More than a decade ago, a handful of individuals received transfused blood from an Australian infected with a genetically impaired strain of HIV. One recipient died, but it was unclear whether AIDS was the cause.

None of the others has developed AIDS, raising the possibility that giving individuals a live vaccine using HIV with this same genetic defect might, at least, be safe.

But would it result in immunity?

“Some say: ‘Look at these people, they don’t get sick. Given the apparent failure of other approaches, do the trial,’ ” Sheppard said. “But others say: ‘No. Safety issues are paramount. We just can’t do it.’

“And who knows who is right?”