Scientists Poised to Test AIDS Vaccines on Humans

Times Staff Writers

The pace of AIDS vaccine research has sharply accelerated, with many research teams around the world now poised to begin human testing of prototype vaccines in the coming months.

It now appears likely that human testing in the United States will begin before complete data on test animals are available--a significant departure from tradition. So far, the AIDS vaccines that have been tested in chimpanzees seem to be safe, but there is no evidence that they work.

"If you had asked me a year ago if we would be where we are now," said Dr. Robert T. Schooley, an AIDS researcher at Massachusetts General Hospital in Boston, "I wouldn't have predicted we would be at this point. But . . . things are moving at an ever-increasing pace."

The growing sense of urgency was clearly evident during a three-day conference last week at the National Institutes of Health attended by several hundred researchers, health officials and biotechnology experts from around the globe. The World Health Organization estimates that 5 to 10 million people already have been infected with the deadly AIDS virus.

The rush to launch limited human clinical trials also may mean that major social and ethical as well as key scientific and medical issues may go unresolved, at least for now.

Whatever the outcome of the upcoming vaccine trials, most researchers still say that a safe and effective vaccine is at least 5 to 10 or more years away.

Before the end of the year, it is "virtually certain" that such tests will get under way in the United States, said Dr. Gerald V. Quinnan of the U.S. Food and Drug Administration.

"I suspect they will start within the next six months," Schooley said.

The NIH meeting, which ended Friday, was designed to generate a consensus on how to proceed in the uncharted waters of AIDS vaccine development and to provide advice to the FDA, which must approve any human tests of vaccines in the United States.

But while endorsing an accelerated vaccine development and testing program, many researchers sounded cautionary notes.

They recommended, for example, that widespread human testing should not be allowed until potential vaccines had been proved successful in animals, according to Dr. Cladd Stevens of the New York Blood Center and Dr. Robert Couch of Baylor University.

How Vaccines Work

Vaccines work by inducing the body's immune system to produce protective molecules called antibodies, as well as special white blood cells that can eliminate foreign organisms.

It conceivably could take only a reasonably small group of humans to demonstrate that a vaccine is safe, at least in the short term. But showing effectiveness is quite another matter.

The best proof of any vaccine's efficacy comes when an inoculated person is shown to be immune from infection with the virus. Clearly, however, vaccinated humans cannot be deliberately exposed to the AIDS virus, since the risk would be too great.

In traditional vaccine experiments, volunteers are divided into two groups--one getting the test vaccine, the other a placebo. If, for instance, the vaccine group at the end of the trial period has a far lower rate of infection than the placebo group, that might constitute evidence of the vaccine's efficacy.

Yet ethics would dictate that all volunteers in an AIDS vaccine trial be warned to minimize potential exposure to the virus, such as through unsafe sex practices. But such warning may cloud the results; if members of both groups heeded such warnings--and thus avoided exposure to the virus--it would be difficult to sort out any protective effects of the vaccine.

Must Give Best Advice

"You have to ethically give any participants all the best advice you can on how to abolish their risk," one federal health official explained. "And you're basically relying on the fact that some will not listen."

The conference participants also said that all volunteers must be bluntly warned that test vaccines may not work at all. In addition, a person inoculated with an ineffective vaccine could become even more vulnerable to disease if they later become infected with the AIDS virus, according to Stevens. Sometimes ineffective vaccines can actually reduce immunity.

"We have to balance the urgency for developing drugs and vaccines against the need to do it in an orderly fashion to make certain that the information and safety and utility of these vaccines is valid before moving into the general population," Schooley said.

"The thing that has changed in the last year is the perception by many that this effort can be undertaken at a much more rapid clip than has been the case in the past with other diseases," he said.

Dr. Frank Young, commissioner of the Food and Drug Administration, has pledged to expedite regulatory action governing the development of AIDS vaccines, as has already occurred with the search for AIDS drugs. AZT, the first drug effective in prolonging the short-term survival of AIDS patients, was approved March 20 for marketing in this country, less than two years after tests on humans began. (Last September, a major test of the drug was halted by an independent board of scientists monitoring those trials because the results among those who got AZT were so dramatic. The board said medical ethics dictated that the drug also be given to members of the placebo group as well as to other AIDS patients.)

'It's a Tough Issue'

Referring to the fast-track on AZT, Young said in a recent interview: "We will do the same with vaccines. With vaccines, we have to be very, very careful. It's a tough issue--that's why you'll see me pulling all the stops out."

Another major concern expressed by many scientists at the FDA-sponsored conference was that competition among manufacturers to develop a vaccine might impede the free exchange of vital scientific information.

One researcher who is working with a biotechnology firm, for example, was asked to sign a secrecy agreement as a condition of his participation in the company's search for a vaccine.

Young said the FDA will strive to ensure a free flow of information.

"We'll be meeting with individuals contemplating vaccines much earlier than we ordinarily would," he said. "We promise to meet with sponsors as early as we can and as frequently as we can, and we will hold a number of conferences. We will leave no stone unturned to be facilitators, experimenters and analyzers of work--not just work done here but on the international scene as well."

Virus Very Dangerous

The development of an AIDS vaccine is more complicated than for other diseases, such as hepatitis B or measles. This is because the molecular basis for immunity to the AIDS virus is not known and because the virus is so dangerous that conventional vaccines using a killed or weakened virus are considered out of the question.

As a result, researchers are experimenting with a variety of novel approaches, including the use of recombinant DNA technology. Among the most widely discussed are vaccines made from the proteins on the outer coating of the AIDS virus and live-virus vaccines, made by inserting genes from the AIDS virus into a second live virus such as vaccinia, or cowpox virus, which normally is used to immunize humans against smallpox.

The recombinant live-virus approach has triggered debate about its potential hazards. One fear is that such a vaccine might cause recipients with weakened immune systems to develop a serious infection with the vaccinia virus, similar to infections seen in AIDS patients.

At last week's meeting, a frequent topic of discussion was Dr. Daniel Zagury, the maverick immunologist from the Pierre and Marie Curie University in Paris who injected himself with a recombinant vaccinia AIDS vaccine in November and is now testing the vaccine on a small number of volunteers in Zaire--the first such human tests.

Criticized for Secrecy

Several speakers criticized the secrecy in which Zagury is conducting his experiments, which have the approval of the government in Zaire. For example, the initial recipients of a vaccinia AIDS vaccine in the United States would probably need to be isolated in a special hospital room for 10 days to two weeks to evaluate their potential to transmit the live virus to others, according to Dr. John La Montagne of the National Institute of Allergy and Infectious Diseases.

Zagury attended the meeting but declined an invitation by the conference organizers to discuss his research. When asked in an interview about the criticism, Zagury said he "would not do anything different." He added: "We do not necessarily play by the American rules but we all have the same goal."

Given the social stigmatization and discrimination associated with AIDS and the mere infection with the virus, the possibility of a vaccine raises yet another potential dilemma.

Those inoculated with a vaccine are expected to produce antibodies against the AIDS virus--meaning that they would test positive on the standard ELISA blood test for AIDS infection. This, conference participants pointed out, could cause problems for the inoculated individuals because the blood test might not distinguish them from those actually infected with the AIDS virus.

'Marked for Life'

"If at some point this person wants to buy life insurance, or give blood, that person will have an ELISA test to explain," one health official said. "We have to be certain we're not doing a disservice to those individuals who participate. You're asking people to accept an inordinate social risk--those people will be marked for life. Even if you give them a piece of paper saying they were in a vaccine trial, in our society, he's marked for life."

AIDS, or acquired immune deficiency syndrome, destroys the body's immune system, leaving it powerless against certain cancers and otherwise rare infections. The virus can also invade the central nervous system, causing severe neurological disorders. It is transmitted through anal and vaginal sexual intercourse, through the sharing of unsterilized hypodermic needles, and by woman to fetus during pregnancy.

In this country, AIDS has primarily afflicted homosexual and bisexual men, intravenous drug users and their sexual partners. As of Monday, a total of 33,158 Americans had contracted AIDS, of whom 19,192 had died.

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