AIDS Vaccine Tests Fraught With Peril

Sometime before the end of 1993, an American or Thai volunteer is likely to roll up his or her sleeve and receive the first injection in a large-scale test of a vaccine against the human immunodeficiency virus.

The long-awaited moment will mark a milestone in the global battle against AIDS. The rapid pace of AIDS vaccine research offers hope for millions of people around the world who are at risk of acquiring the deadly infection.

But the early tests, which are likely to involve thousands of people in the United States, Thailand and other countries and last at least several years, are fraught with peril as well as opportunity.

Despite the high public expectations and billions of dollars that have been invested in AIDS research, there are no guarantees that the initial AIDS vaccines will work. These early vaccines may be supplanted by more promising test vaccines even before the first large-scale trials are completed.

“It is very important that people understand that we are very unlikely to hit a home run at the first trial,” said Dr. Daniel F. Hoth of the National Institute of Allergy and Infectious Diseases, who envisions a decade or more of large-scale clinical trials before an optimum vaccine emerges.

Dr. Donald S. Burke of the Walter Reed Army Institute of Research said that at best the first large-scale trials will “show evidence that (the test vaccine) works and . . . why it is less than perfect. Having learned that, we can go and design vaccines that are better.”

AIDS vaccine experts are fearful that even a partial success in the first large trials will be viewed as a tremendous failure, which in turn would jeopardize the long-term prospects to achieve a safe and effective vaccine.

“Without a doubt . . . this is what makes everybody nervous, how well we can tolerate failure,” said Dani P. Bolognesi of Duke University Medical Center.

The key problems, examined by leading researchers at a medical meeting in Keystone, Colo., this year, range from the wide variation among different AIDS virus strains to concerns about product liability if volunteers in vaccine tests develop unanticipated side effects.

At the meeting, Phillip W. Berman, an AIDS vaccine researcher with Genentech Inc. of South San Francisco, said: “We are all looking for a vaccine which completely prevents HIV infection and disease. We would love a sugar cube you take once in your life and you will be protected forever. But I don’t think it is going to happen with HIV.”

Many of the U.S. vaccine trials will be coordinated by the National Institute of Allergy and Infectious Diseases. Earlier this year in a little-noticed announcement, the institute said that it “anticipates” beginning clinical trials of AIDS vaccines “as early as December, 1993, at domestic sites and shortly thereafter at international locations.” The institute has yet to announce how many trials it will oversee or where they will be conducted.

In addition, the Walter Reed Army Institute of Research is working with Thai researchers to plan large AIDS vaccine tests in Thailand, a country where the rate of HIV infection has been increasing dramatically. Researchers in Britain, France and Sweden are mulling over large trials, while the World Health Organization is helping to prepare vaccine trial sites in Brazil, Rwanda, Thailand and Uganda.

AIDS experts say that rapid progress must be made for any of the dozens of vaccines under development to be ready for large-scale tests in the next year or so. “Everybody is recognizing how hard this is going to be” to find a vaccine, Hoth said.

Over the next year, trial organizers will gather extensive data about the rate of new HIV infections among the populations in which the vaccines will be tested, as well as the AIDS virus strains that are being transmitted. Sophisticated laboratories and computerized data collection procedures will be put in place.

By the summer of 1993, decisions will have to be reached about the vaccine or vaccines to be tested, so that large quantities can be manufactured.

The picture appears brighter after the announcement last week that scientists from the University of Washington in Seattle have for the first time infected monkeys with HIV. This success, in a monkey species known as the pigtailed macaque, could speed the testing of experimental AIDS vaccines.

To maximize the chances for success, leading vaccine researchers may propose that several vaccines, perhaps from different manufacturers, be combined. A combination might also help protect against different HIV strains, which vary by as much as 40% in their genetic sequences.

But differing strains represent only one of the many hurdles facing vaccine researchers. Others include:

* The specific immune system response to HIV necessary to protect against infection is not known. In most cases, researchers have determined the protective immunity against a germ before embarking on large-scale vaccine tests.

* Most of the “successful” AIDS vaccine tests in animals have been conducted under conditions that “load the dice” in favor of success. For instance, animals have been exposed to the virus when their immune response is believed to be at its peak. Some of these experiments may not be relevant outside the laboratory.

* There has been little study of the ability of experimental vaccines to protect against HIV transmission through sexual contact, which is the most common route of infection.

* Researchers also do not know how best to administer a vaccine. They do not know how many doses to give initially, how often to give booster shots, or what chemicals, known as adjuvants, are best to package with a vaccine in order to strengthen its action.

* An AIDS vaccine might fail to prevent infection, but still may prevent the development of disease in an infected person. If this is the case, it might take a decade or longer to determine if such a vaccine was effective. This is because HIV-infected people can remain free of AIDS symptoms for many years.

Many vaccines, such as those against the polio virus, are injections or oral preparations of weakened or dead germs. But most of the AIDS vaccines under development contain only parts of the virus. Scientists disagree as to whether such “sub-unit” AIDS vaccines can be as effective as vaccines based on the complete virus. But there are concerns that injections of killed or weakened whole AIDS virus particles could be very dangerous because they might infect people with the virus.

Many AIDS experts believe that the galloping epidemic of new HIV infections, particularly in developing countries, is sufficiently acute that large-scale vaccine tests should go forward before such details are worked out in the laboratory.

The World Health Organization estimates that the number of HIV-infected people, now between 9 million and 11 million, will increase to between 30 million and 40 million by the end of the decade. Earlier this month, an international team, led by Harvard School of Public Health researchers, said the WHO figures were too low and that as many as 110 million people may be infected with HIV by 2000.

“We are moving rapidly because we have a serious problem,” Bolognesi said. “If this weren’t as serious as it is, we could probably take a lot more time to get the information.”

Compared with the time it has taken to develop other widely used immunizations, the pace of AIDS vaccine research has been quick.

The first human tests of AIDS vaccines began in 1987, three years after the virus was discovered; dozens of small trials are in progress. These Phase I tests have focused more on safety considerations than the possible protective effects of a vaccine. Those asked to volunteer have primarily been healthy individuals at very low risk of acquiring the infection.

In contrast, the large-scale AIDS vaccine trials that are planned will target people at high risk of becoming infected. Some participants will receive the test vaccine while others will get placebo injections. Neither the participants nor the physicians conducting the trial will know who is receiving which injections.

The use of placebo injections places researchers in a somewhat conflicting position. On one hand, they are obligated to educate all trial participants about how to protect themselves against HIV infection and to stress that they are not immune to HIV infection simply because they are participating in a trial.

Yet if educational efforts are very effective, most trial participants might avoid behavior that puts them at risk of infection. If very few people become infected, it may be impossible to tell if a vaccine really works.

The preliminary vaccine trials have bolstered the idea that combining vaccines may be the best route to take, said Bolognesi of Duke University. So far, some of the most impressive test results have been obtained with a combination that includes a recombinant vaccine made by Bristol-Myers Squibb. This vaccine incorporates a gene from the AIDS virus into the vaccinia virus, which is used to vaccinate against smallpox. A booster injection, made by MicroGeneSys, follows the primary injection.

The combination “induced an immune response that was much greater than any achieved in previous (small) trials using a single AIDS vaccine,” Dr. Barney S. Graham of Vanderbilt Medical Center in Nashville said at the international AIDS conference last year.

But there is concern that an AIDS vaccine using the vaccinia virus might cause health problems if it fails to work and people become infected with HIV after taking it. Although the vaccinia virus is harmless to individuals with normal immune systems, it can cause serious illness or death in people with weakened immune systems, such as people with HIV infection.

Moreover, some AIDS vaccine manufacturers fear that people who participate in AIDS vaccine trials might sue if they later become ill. Bristol-Myers Squibb recently said it would not provide researchers with additional supplies of their experimental vaccine for further testing, federal officials said.

The decision, which Bristol-Myers Squibb acknowledged reflected liability concerns, does not necessarily mean that this vaccine or a similar product will not be involved in large-scale vaccine trials. But, experts said, it increases the pressure on the federal government and industry officials to work out solutions to the liability problem before it becomes a greater stumbling block.

Federal officials will meet this summer with industry representatives to try to resolve the issue, said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

In addition to scientific and legal concerns, the large-scale AIDS vaccine trials will raise ethical issues, particularly for the trials conducted in developing nations.

An AIDS vaccine should be “reasonably available to the citizens of the country (where it is being tested) at the completion of successful testing,” said Dr. Robert J. Levine of Yale University, who is a leader of an international project to develop ethics guidelines for AIDS vaccine testing.

Some worry that AIDS vaccines will be too expensive for developing nations to afford. The World Health Organization is working with vaccine manufacturers to find ways to solve this problem, said Dr. Michael Merson, the director of the organization’s AIDS program. According to Merson, the ideas under discussion include the creation of a global fund to purchase AIDS vaccines, a special pricing mechanism for vaccines in developing countries, and special tax breaks or other advantages for companies that supply AIDS vaccines to developing nations.

Most AIDS officials believe that despite the uncertainties, now is the time to press forward toward large-scale AIDS vaccine tests.

“There is always a risk,” Hoth said. “But the key thing is that the risk of waiting is much greater than the risk of proceeding. That’s really the bottom line. At some point in life, even in science, with all the elegant things that we understand, you have to jump in and swim and just do it.”

Clinical Tests of AIDS Vaccines

These are some of the companies with AIDS vaccines that are now in human clinical trials :

* Bristol-Myers Squibb (New York City)--The gene for the AIDS virus envelope protein, known as gp160, is inserted into live vaccinia virus, which has been used for vaccination against smallpox. Being tested as a vaccine in uninfected people.

* Chiron Corp. (Emeryville, Calif.)--Genetically engineered AIDS virus envelope protein, known as gp120. One version is made in yeast cells, another in mammalian cells. Being tested both as AIDS vaccine and as a treatment for infected individuals.

* Genentech Inc. (South San Francisco)--Genetically engineered gp120 AIDS virus envelope protein, made in mammalian cells. Versions have been developed against two different AIDS virus strains. Being tested both as an AIDS vaccine and as a treatment.

* Immuno AG (Vienna)--Genetically engineered gp160 AIDS virus envelope protein, made in mammalian cells. Being tested both as an AIDS vaccine and as a treatment.

* Immune Response Corp. (San Diego)--Inactivated AIDS virus particles, known as HIV-immunogen, from which the envelope protein has been removed. Approach developed by Dr. Jonas Salk, the polio vaccine pioneer. Being tested as an AIDS treatment for infected people.

* MicroGeneSys Inc. (Meriden, Conn.)--Genetically engineered gp160 AIDS virus envelope protein, produced in a virus grown in the cells of an insect. Being tested both as an AIDS vaccine and as a treatment.

* Pasteur-Merieux of France--The gene for the gp160 AIDS virus envelope protein is inserted into a live canary pox virus, which does not reproduce in humans. Tests in uninfected people starting soon. Participants will also receive booster shots of the gp160 protein.