Science, Policy Issues Put AIDS Vaccine On Slow Track

The start of a clinical trial with an AIDS vaccine developed by French company Pasteur-Mérieux Connaught made front-page news in several major papers in September. The vaccine, composed of three HIV genes inserted into a canarypox vector, was administered to 420 human volunteers in a Phase II trial that tested the vaccine's safety and ability to provoke an immune response. Some researchers view the undertaking as one more trial of a technology that is unlikely to result in a useful compound. Others believe that HIV-vaccine candidates should be in Phase III trials, large-scale trials that test the efficacy of a drug. Yet not a single HIV-vaccine candidate has reached that point. 'GREAT NEED' : Chiron's Margaret Liu does not share other scientists' concerns that the market for an HIV vaccine is unattractive to industry. There are many reasons why HIV-vaccine development is not further along. Among the factors holding back vaccine development are differing attitudes among scientists. Some researchers believe everything must be known about the virus and its effects on the immune system before a vaccine can be produced, while others argue it is urgent that researchers take candidates already available and put them into Phase III trials. "Some of the basic scientists say we don't have enough information for the move into developing a vaccine candidate for clinical trial," says Helen Miramontes, a member of the President's Advisory Council on HIV and AIDS, and an associate clinical professor of nursing at the University of California, San Francisco. Some well-known scientists, like Robert C. Gallo, director of the University of Maryland's Institute of Human Virology and one of the discoverers HIV, have had a change of heart regarding vaccine development. He believes that obstacles, such as the numerous forms of the virus (nine subtypes are now known) and its rapid mutatation rate, can be overcome. "All of us at the Institute believe this [development of an HIV-vaccine in the next 10 years] is feasible," Gallo wrote in a recent newsletter from his institute (R.C. Gallo, Bench Talk, 2 :1, July 28, 1997). Other obstacles, however, hamper vaccine development. These include lack of sufficient research funding; lack of economic incentives for pharmaceutical companies to pursue a vaccine, especially because such a vaccine is more likely to have its major use in poor nations; and a government infrastructure unprepared for such an undertaking. The National Institutes of Health has been the world leader in funding HIV research. According to Seth Berkley, president of the International AIDS Vaccine Initiative (IAVI), a New York- and Washington, D.C.-based nonprofit advocacy and development group, about $4 billion is spent annually worldwide on AIDS research. Of this, "less than $125 million is spent on the broad area of vaccines and less than $50 million of this on actual vaccine development," he stated to the President's Advisory Council on HIV and AIDS Research Subcommittee in October 1996. NIH's AIDS budget for FY1997 is $1.5 billion. Less than one-tenth-$130.8 million-is for AIDS vaccine research, which may include both basic research and more advanced clinical work. 'HIGH COST' : CDC's William Heyward says a lengthy research period is unacceptable for vaccines against a disease as devastating as AIDS Some scientists are concerned that the United States government has not encouraged HIV vaccine development. "There's a disproportionately low amount of resources going into HIV vaccines," declares medical epidemiologist William Heyward, HIV vaccine coordinator for the Division of HIV/AIDS Prevention at the Centers for Disease Control and Prevention (CDC). "As with most prevention efforts, a small investment can have enormous cost-benefit returns, not only this country, but the world." 'CLOSE PARTNERSHIP' : NIAID director Anthony Fauci says government and industry will need to work together to develop an effective vaccine. Even National Institute of Allergy and Infectious Diseases (NIAID) director Anthony Fauci acknowledges that government spending on research for AIDS therapeutics traditionally has been-and still is-greater than the money spent on AIDS vaccine research. President Clinton also noted the problem when he announced a national goal to "commit ourselves to developing an AIDS vaccine within the next decade" at Morgan State University's commencement exercises in May. He promised increases in the federal budget for AIDS-vaccine research and the creation of an NIH AIDS vaccine research center, jointly administered by NIAID and the National Cancer Institute (NCI). This presidential commitment was a long time in coming, says infectious disease epidemiologist Donald P. Francis, a founder of VaxGen Inc., a Genentech Inc. spin-off in South San Francisco, Calif. "We did not see a really serious federal response to AIDS vaccine development until the president finally mentioned it this year," he states. "That is 16 years after the discovery of the AIDS epidemic and 14 years after the discovery of the virus." In June 1996, NIH's Vaccine Research and Development Area Review Panel, headed by Dani P. Bolognesi, the director of Duke University's Center for AIDS Research, found vaccine research and development efforts "in crisis." The report was critical of NIH's AIDS vaccine development efforts. It cited insufficient funding, a peer-review method that discourages research, and poor-quality research on animal models. It also noted a lack of coordination among programs as a major stumbling block to developing a vaccine with NIH support. The report suggested that NIAID take a leadership role in AIDS vaccine research. NIAID has slowly been taking this leadership role, according to Fauci. NIH began to increase its HIV-vaccine research resources three years ago. William Paul, the outgoing director of the Office of AIDS Research (OAR), is credited with beginning to restructure NIH's AIDS research program, which has been resident in many of NIH's institutes, but especially in NIAID and NCI. Early last month, Paul announced his resignation to return to his laboratory at NIAID, where he plans to pursue research on HIV-vaccine development. As overseer of NIH's AIDS budget, Paul advocated the establishment of the NIAID-NCI Vaccine Research Center. There are now $20 million in new funds budgeted for the center. Additional funds for a new building will be in the FY1998 budget. FEASIBLE : Some well-known scientists, including Robert Gallo, have new hope for HIV-vaccine development. Government involvement in the vaccine-development process traditionally has been in the beginning research phases. Heyward explains that vaccines available today "went through development anywhere from 10 years to 40 years." For some vaccines-such as rotavirus, which "has good palliation and treatment, and very low mortality" and is mainly a disease of infants-such a lengthy research period is acceptable, Heyward explains. "However [with AIDS], we're dealing with a disease that has very high cost" in terms of treatment, morbidity and mortality, and loss of life. Many companies are involved in HIV-vaccine efforts, including Pasteur-Mérieux Connaught; VaxGen; Apollon Inc. of Malvern, Pa.; Chiron Corp. of Emeryville, Calif.; Merck & Co. Inc. of West Point, Pa.; and Wyeth-Ayerst Laboratories of St. Davids, Pa. But some scientists say there are serious disincentives for companies to become involved in HIV-vaccine research. Among those listed in a report produced by IAVI in December 1995 (The International AIDS Vaccine Initiative: Accelerating the Development of Preventive HIV Vaccines for the World, Financial and Structural Issues) are a small market in developed countries, lack of resources to purchase vaccine in developing countries that need it most, cost and logistics of clinical trials, liability both during the trials and after the vaccine is licensed, and difficulty in conducting clinical trials in developing countries. EARLY MISTAKE: Seth Berkely of IAVI laments the fact that therapy-based research was stressed at the beginning of the AIDS epidemic. IAVI is now concentrating on several efforts to overcome those disincentives. It is working with organizations like the World Bank to set up a fund that will allow developing countries to purchase HIV vaccine for their populaces. IAVI also is studying ways to license intellectual property rights so IAVI can "develop, manufacture, and distribute [these vaccines] to developing countries," says Margaret Johnston, scientific director at IAVI who previously served as acting deputy director of the Division of AIDS at NIH. These strategies not only may convince more companies to engage in research, but also will provide future markets for the vaccines. Industry, however, is not avoiding the issue. Leading AIDS- vaccine researcher Margaret Liu, now vice president for vaccine research at Chiron but previously a researcher at Merck, says, "In general, it's public demand for therapeutics vs. prophylactics." Thus, although Merck, for example, worked on both therapeutics and prophylactics, the industry in general may have stressed therapeutics and interventional methods over vaccines. Liu does not reflect some of the concerns that others have voiced about the lack of a market. "There is just such a great clinical need for an AIDS vaccine, I don't think that [the market] will be a question," Liu states. Assuming there is both industry and government investment in an AIDS vaccine, then what is slowing the process of finding one? Some of the delay is related to both real and perceived scientific problems. "The lack of industry involvement is not the major obstacle. It's the lack of scientific knowledge," states researcher John Moore, a staff investigator at the New York-based Aaron Diamond Research Institute. "The big companies are not that interested at the moment in making an AIDS vaccine because they don't know what to make," he states. Moore points out that nothing tested in Phase I and Phase II trials has worked well. The simple recombinant proteins, he says, were safe, "but completely useless." The vaccine currently going into Phase II trials and touted by the newspapers is "likely to be too weak to be effective from the antibody perspective" since it uses the "same proteins that have done badly in the past," he says. "Whether this vaccine has any chance of working will depend on how good it is at inducing a cellular immune response." Moore believes, however, that the DNA-based vaccines like those that Liu has been working on "can be a very promising concept." In these vaccines, one or more genes that code for particular proteins are put into DNA, which then is inoculated into a muscle or under the skin. This should result in expression of a particular protein. "Probably the concept that is most likely to work," according to Moore, is a live-attenuated virus vaccine. He notes, however, that there are genuine safety concerns about using such a vaccine. Experiments with a live-attenuated simian immunodeficiency virus (SIV) vaccine in monkeys have resulted in animals coming down with AIDS (J. Cohen, Science, 278 :24, 1997). Recently, a furor has broken out in response to recruitment by the International Association of Physicians in AIDS Care (IAPAC) of subjects for trials with such a vaccine (J. Cohen, Science, 277 :1035, 1997). Miramontes from the president's committee has volunteered for such a trial. Some scientists have misgivings about the prospects of success. Says David Baltimore, president of the California Institute of Technology and chairman of NIH's less-than-year-old advisory AIDS Vaccine Committee: "It will be very difficult to prove that it is safe enough to use widely in people, even if there are a few brave people willing to try it." Another difficulty faced by companies is determining the type of vaccines on which to concentrate their efforts. HIV- vaccine research began in the U.S. and Europe and concentrated on the virus subtype most prevalent in these areas, subtype B. In a recent paper, Heyward and colleagues illustrate that although subtype B is prevalent in the Americas, Western Europe, and Australia, subtype E is causing disease in Southeast Asia; C in India; F in Eastern Europe; and A, AD, C, F, HJ, G, and O in Africa (W.L. Heyward et al., Journal of the International Association of Physicians in AIDS Care, August 1997, page 28). Heyward explains, "For the first trial, there needs to be a match [of subtypes] to prove vaccine efficacy." Moore makes it clear that, as yet, scientists can't produce a vaccine to even one subtype, let alone the entire group. He believes, however, that once a successful vaccine formula is discovered, scientists will be "able to adapt it to deal with the variation issue. It's not out of the question that a single [subtype] vaccine will give broad protection." VOLUNTEER: UC-San Francisco's Helen Miramontes would sign up as a subject for an HIV vaccine trial. Some researchers, like Moore, believe the lack of scientific knowledge is the holdup in the vaccine discovery process. Others say scientists have more knowledge already than they have had about other pathogens for which successful vaccines now exist. Heyward, who witnessed the AIDS epidemic in Africa firsthand while directing Project SIDA in Kinshasa, Zaire (now Congo), maintains, "Science generates science, and answering scientific questions generates more questions and further studies to do." He states, "We have to move from basic research to practical public health application. And that is what we have not done." Berkley sees that a mistake was made early on when therapy- based research was pushed almost exclusively: "We should have continued a full effort on the vaccine." But vaccines, Berkley says, were not a priority. Those who have faced the AIDS epidemic, as Heyward has, want to see some action. "The best way, I think, we should proceed is to take some of our advanced existing candidate vaccines and put them into large-scale trials, and do these trials to learn how best to proceed," Heyward maintains. Public complacency also hinders action, Berkley contends. "People kind of say, 'Well, the AIDS epidemic is now peaking out. We have these powerful drugs.'" What people do not understand, he reports, is that the drugs "don't work for everybody. . . . There is going to be viral resistance. . . and we're already seeing that." The rest of the world can't afford the drugs, which may run in the tens of thousands of dollars per year per patient. "If we, in this country, sensed the global epidemic, I think that we'd be proceeding differently," states Heyward. The infusion of new federal money will likely increase industry involvement, predicts Fauci. "I can't imagine our making a vaccine without a very close partnership with industry," he adds. SAFETY CONCERNS : AIDS Vaccine Committee chairman David Baltimore notes the difficulty in proving that an HIV vaccine is fit for widespread use in people. It's "a long-term hope that vaccine candidates will emerge that will attract support from industry after early testing through NIH," states Baltimore. Francis, who left CDC to pursue vaccine research in the private sector, states that the problem of creating an HIV vaccine "certainly will not be solved by giving money to NIH." He says that the government, in general, does not have the personnel with experience in actually developing and manufacturing vaccines. Berkley explains that the government is not used to working in what is now needed: "a directed research approach." He continues, "It is very hard to do vaccine development through an R01 [investigator-initiated grant, the standard NIH granting method]." As far as government investment in corporate research, VaxGen's Francis states, "If the government would like to come in and help any time, they are welcome. But, to date, the government has not proved themselves to be a very reliable partner." International AIDS Vaccine Initiative http://www.iavi.org National Institute of Allergy and Infectious Diseases Division of Acquired Immunodeficiency Syndrome http://www.niaid.nih.gov/research/Daids.html Office of AIDS Research http://www.nih.gov/od/oar/ President's Advisory Council on HIV and AIDS documents http://www.hsph.harvard.edu/Organizations/hai/vaccines/preamble.html Myrna E. Watanabe is a science writer based in Yonkers, N.Y.

Science, Policy Issues Put AIDS Vaccine On Slow Track

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Myrna Watanabe

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November 1997

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