Date: Wed, 30 Nov 1994 09:45:52 -0500 From: David B. O'Donnell THE DOCTOR'S WORLD After Setback, First AIDS Vaccine Trials Are Planned Even a weak vaccine would help slow the epidemic. By LAWRENCE K. ALTMAN, M.D. [New York Times 11/29/94] In a sharp turnaround driven by a desperate need to stop the AIDS epidemic, the World Health Organization is moving ahead with plans for the first large trials of the two most widely tested experimental AIDS vaccines. The United States rejected plans for testing the vaccines in this country in June. By a nearly unanimous decision last month, an advisory panel of experts gave the Geneva-based health organization a green light to design and carry out full-scale trials of the effectiveness of the two experimental vaccines against H.I.V., the AIDS virus. Both vaccines have gone through the first two stages of a three-stage testing system, evaluating safety and immunologic responses. The third phase tests the vaccines' ability to protect against the disease, and the trials now being planned could involve several thousand volunteers. The experiments are aimed at determining whether the vaccines can prevent infection with H.I.V., not whether they can prevent AIDS in people already infected with H.I.V. Developing an AIDS vaccine has been a top priority for public health officials around the world since shortly after AIDS was first recognized, in 1981. But the goal has become more urgent as the number of people infected with H.I.V. has surged. W.H.O. now estimates that 17 million people have been infected and that 4 million have AIDS. Even a vaccine with a low degree of protection would be valuable. Because so much preparation needs to be done, a full-scale study of AIDS vaccines could not begin until 1996 at the earliest, said Dr. Peter Piot, an infectious disease expert and W.H.O. official. No decision has been made on where to begin testing, but initial indications point to Thailand as the first site, with Brazil and Uganda as distant contenders, he said. In an interview, he said that scientists from the United States Army, American medical schools and W.H.O. have been working for several years with Thai doctors and health officials who are eager to do the trials in Thailand. The date and sites hinge on a number of scientific and political factors that could change before the first injections are given. In June, a panel convened by Federal health officials expressed a lack of confidence in the potency of the two vaccines and overwhelmingly rejected a proposal to conduct phase 3 trials in this country. Such trials would take longer and require more participants if conducted in the United States than in countries with a higher incidence of H.I.V., the panel said. Although the decision affected trials only in the United States, it created an impression that full-scale testing would have to wait for more promising candidates. The United States panel said, however, that because public health needs vary among countries, those with higher rates of H.I.V. infection might reach a different decision. More than 90 percent of AIDS cases occur in third world countries. The World Health Organization then asked its panel to decide whether the vaccines should be tested in one of these countries. The two most widely tested vaccines currently available are derived from a protein, known as gp120, on the surface of H.I.V. that attaches to a human cell, an early step of infection. The two leading contenders are made by Biocine in Emeryville, Calif., a joint venture of the Chiron Corporation, the Ciba-Geigy Corporation and Genentech Inc. "Panelists were not asked to discuss plans for a specific study because we did not have one," Dr. Piot said. Participants said that unless human trials are started soon, the most that could be expected over the next several years would be progress reports of vaccine experiments on a few chimpanzees and dozens of laboratory tests of uncertain importance in discovering whether a vaccine would work in humans. "Representatives of developing countries stressed their tragic and dramatic plight and said they could not wait an eternity to test an H.I.V. vaccine," Dr. Piot said. Experts from W.H.O. are now working with health officials and scientists in the United States to develop a protocol. The new venture was discussed this month at a meeting in Reston, Va., held by the National Institute of Allergy and Infectious Diseases. An important problem in conducting such experiments is determining how well people understand the concept of randomized trials, in which a participant receives either the experimental vaccine or a placebo, or dummy substance. In third world countries, researchers have traditionally relied on permission given by local health officials and tribal or community leaders. But such group permission "is not acceptable anymore," Dr. Piot said. To help develop meaningful informed consent processes for AIDS vaccine experiments in third world countries, W.H.O. convened a group of sociologists and anthropologists last week to design studies to determine how well people understand the concepts and how independent they are in making such decisions. The studies are to be conducted in the next few months, Dr. Piot said. The quest for a vaccine in the midst of a raging epidemic almost inevitably touches off a clash between a pragmatic approach of testing what is available as soon as possible and a more academic approach of waiting for substantial evidence from laboratory and animal studies. W.H.O., a United Nations agency, has cited ethical reasons for insisting that AIDS vaccine trials must be conducted in the country where the product was developed. The aim is to prevent exploitation of people in the third world for the benefit of those in the developed world. Dr. Piot said that in going against the United States' decision, W.H.O. is not deviating from its basic principle, because the panel explicitly said that no scientific or ethical short cuts could be taken. "We certainly stick to the idea that the first two phases of AIDS vaccine development must be done in the country of origin of the product," Dr. Piot said. But the policy does not necessarily affect the third phase. For example, Dr. Piot said, "it would be absurd for scientific reasons to insist on testing experimental vaccines for malaria in the United States or Europe, where the disease does not exist." Panelists from developing countries criticized such policies as discriminatory, because they felt they interfered with their sovereign right to test experimental vaccines in their countries, particularly when they have more H.I.V. infections than most developed countries. The trials will follow standard scientific guidelines. Some volunteers will be injected with an experimental vaccine and others with a placebo. Neither the volunteers nor the researchers will know which injection any of the volunteers received until the trial is completed several years later. Still, before W.H.O. approves a protocol for the vaccine trials, many questions need to be answered. One is, how should an AIDS vaccine's effectiveness be measured? Another is, which strains of H.I.V. should be used in making the vaccine? The two most extensively tested vaccines are derived from strains detected in the United States. H.I.V. is arguably the wiliest virus known, and no one knows whether a vaccine made from one strain will protect against different strains. For that reason, some scientists favor testing a vaccine made from the most prevalent strains in the country where the trials are being conducted. If modifications of the vaccine are needed, it could take longer to begin the trials. Since 1988, when the first injections of an experimental AIDS vaccine were given in the United States, more than 1,500 volunteers have enrolled in 18 federally sponsored trials involving 13 experimental vaccines. No vaccine has been tested in a phase 3 trial. The current vaccines are made by genetic engineering techniques and cannot directly cause AIDS because they contain only a portion of the virus. No one expected that the first such vaccines would prevent infection in every recipient, and so far, 12 participants in phase 1 and phase 2 trials are known to have become infected with H.I.V. Five of the infected participants had received a full course of the vaccine. Regardless of where the phase 3 trials are held, considerable time will be needed to insure that volunteers and members of the community fully understand what will happen in a trial. Dr. Piot said his panel's deepest concern was to avoid creating a false sense of security among participants in trials who might engage in unsafe sex or inject drugs on the assumption that a vaccine was fully effective. If enough volunteers relaxed their guard against H.I.V., the incidence of H.I.V. could rise in the community. Although the concern is theoretical, Dr. Piot said, "we are taking it seriously," The World Health Organization will take steps to augment community efforts for H.I.V. prevention through education and counseling and to measure the impact of a vaccine trial on a community. "We want to make sure that we are not exposing more people to H.I.V. than before the vaccine trial," Dr. Piot said. A theoretical possibility is that the vaccines might increase the chance of H.I.V. infection by producing immune responses known as enhancing antibodies. None have been found so far. But there are limits to the available tests to detect such responses, and the number of people tested has been small. Many issues will be debated before the trials begin. Dr. Piot said W.H.O. is encouraging debate "because, with the urgent need for an effective vaccine, we cannot afford a failure due to scientific or ethical problems." {Table} Choosing a Place to Test AIDS Vaccines Some sites being considered for the third phase of testing for vaccines against H.I.V. the virus that causes AIDS. Country \ Sites \ Population \ Estimated Incidence \ H.I.V. subtypes BRAZIL \ Rio de Janeiro, Sao Paulo, Belo Horizonte \ Men who have sex with men \ 6% \ B/C/F UGANDA \ Rakai \ Rural Adults \ 3% \ D/A UGANDA \ Kampala \ Military \ 6% \ D/A UGANDA \ Kampala \ Women \ 3% \ D/A UGANDA \ Gulu \ Women \ 3% \ In doubt THAILAND \ Chiang Mai \ workers \ 3% \ E/B THAILAND \ Bangkok \ Intravenous drug users \ 5% \ B/E ##30##