An AIDS Vaccine by 2007? Not Likely, Say Participants

May 18 marked the one-year anniversary of President Bill Clinton's pledge--some say more politically motivated than realistic--that there will be an AIDS vaccine by the year 2007. READY FOR PHASE III: Donald Francis of VaxGen is ready for Phase III trials of its AIDS vaccine to begin. The field of AIDS vaccine research has been and remains acrimonious. The basic researchers who insist on proof of immune response prior to large clinical trials disagree with the vaccine researchers whose experience tells them that the proof of a vaccine's efficacy comes with those large clinical trials. The latter group maintains that many people don't understand the immune correlates of any vaccines currently in use and an AIDS vaccine is being held to a higher standard. Some of those involved in policy issues question whether the National Institutes of Health, the nation's designated lead organization for direction of AIDS vaccine research, is up to this task or whether oversight should come from another direction--perhaps the White House Office of National AIDS Policy (ONAP). No matter where people stand in these debates, there is one thing on which they all agree: It is not likely that an AIDS vaccine will materialize in nine years. "If you look at what's happened over the last year, there's been some progress, but it's not going to be enough to get us to a vaccine in nine years," states Sam Avrett, executive director of the AIDS Vaccine Advocacy Coalition (AVAC), an HIV vaccine analysis and advocacy group in San Francisco. AVAC published a report in mid-May (9 Years and Counting: Will We Have an HIV Vaccine by 2007? An Agenda for Action for an HIV Vaccine, see accompanying Internet address list) that lays out the reasons they do not expect a vaccine by the president's time limit. AVAC contends that the NIH needs "to overcome bureaucratic constraints" to coordinate HIV vaccine discovery activities within NIH; to rapidly appoint a director of the NIH Vaccine Research Center, which was also announced in the president's statement last May; and to increase industry involvement in AIDS vaccine development. AVAC advocates moving forward with Phase III clinical trials (efficacy trials involving thousands of people) of vaccine candidates. The group also urges increased involvement of Group of 8 (G-8) nations, the world's eight richest countries, in HIV vaccine research and development. Margaret Johnston, scientific director of the International AIDS Vaccine Initiative (IAVI), a New York and Washington, D.C.-based not-for-profit AIDS vaccine advocacy group, says that "the NIH has not taken that goal [vaccine by 2007] seriously; they have focused on basic research ... to the exclusion of empirical research." She adds that international cooperation is necessary for clinical trials to begin. ANOTHER COMMITTEE: Carole Heilman of NIAID sees the need for a "water walkers" advisory group. One of the basic problems some cite is that the NIH is the lead organization for the nation--perhaps even the world--in developing an AIDS vaccine. Some question whether NIH, although a premier basic research establishment, has the staff and skills needed to develop a vaccine and shepherd it through to the point at which a pharmaceutical company can bring it to commercial use. Jonathan Mann, dean of the School of Public Health at Allegheny University in Philadelphia, delivered an address to the Presidential Advisory Council on HIV/AIDS (PACHA), a group of individuals named by the president to advise him on issues related to AIDS, in which he blamed the NIH for "the failure to proceed to field trials." Mann added, "At an institutional level, this failure stems from decisions and recommendations made by NIH and its AIDS vaccine advisory committee [chaired by Nobel Laureate David Baltimore of the California Institute of Technology], both of which are headed by notable scientists who nevertheless lack experience with vaccine development and public health." PACHA recommended to the president that the responsibility for oversight of AIDS vaccine development be handed over to the Office of National AIDS Policy (ONAP) in the White House. Mann's remarks and PACHA's recommendation led to a public furor among AIDS researchers. More than 50 of them signed a letter in Science that stated: "Slow progress is frustrating to all concerned, but attacking NIH and the scientists who are working on the problem serves no useful purpose." (M. Agosto, et al., Science, 280:803, 1998). According to a source who wishes to remain anonymous, scientists who support PACHA's position are using this letter as an opportunity to air their concerns publicly in letters to the editors of several major scientific publications. Others also are not pleased with PACHA's position, including Carole Heilman, deputy director of the National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS, and liaison between the AIDS Vaccine Research Committee (AVRC) and the NIH. She also is acting associate director for the vaccines and prevention research program at NIAID. Heilman asserts that the PACHA recommendations were based on old information. "My understanding is, from the time that they began their discussion to the time they issued a report was a very long time frame. This field changes every minute ... . It's old. I'm surprised it has taken so long. I would have hoped there would have been a little more updated report from them." Heilman adds that no one on PACHA has ever spoken with her. "I'd like to talk to them ... . I was surprised that there were some concerns that we could have answered," she remarks. Helen Miramontes, a PACHA member who is associate clinical professor of nursing at the University of California, San Francisco, although explaining that the people at NIH mean well, complains, "I just don't know what it's going to take to move these people [NIH] along." She opines that part of the problem deals with individuals and their egos. "It ends up being politics. NIH is a big, 800-pound gorilla, and they're used to getting their way." William Snow, a board member and founder of AVAC, who also is a member of AVRC, points out that although there are "some elements of truth in what [PACHA is] saying," they are "ill-informed," and "need to establish better lines of communication with the NIH." Snow believes there is "some kind of power thing going on," between PACHA and NIH. He continues that although there may be some things that NIH is not going to be the best at doing, coordination of AIDS vaccine research should remain at NIH. Snow points out that the NIH's Office of AIDS Research (OAR), is charged with coordinating AIDS research with other federal agencies. On May 15, NIH Director Harold Varmus announced that Neal Nathanson, who has a broad background in virology, epidemiology, and public health, has been named OAR director. Nathanson comes from the University of Pennsylvania Medical Center, where he was vice dean for research and research training. Not only is there the contentious policy issue related to which group should lead the AIDS vaccine research effort. The research, too, is contentious, according to several sources involved. There is an ongoing feud between Donald Francis, president of VaxGen, a vaccine-producing spinoff of Genentech, South San Francisco, Calif., and John Moore, staff investigator at the Aaron Diamond AIDS Research Center at Rockefeller University in New York, along with his colleagues at Aaron Diamond, including David Ho, Diamond's director. VaxGen plans to institute Phase III clinical trials--the first Phase III trial of any AIDS vaccine candidate--of its bivalent gp120 vaccine candidate in Thailand and the United States some time this year. Francis has evidence that Ho coauthored a letter to Thai officials voicing concern about the efficacy of the gp120 subunit vaccines. In a letter to Kachit Choopanya, deputy governor of Bangkok, Thailand, Francis and Phillip W. Berman, VaxGen's vice president for research, point out that the gp120 vaccine raised "antibodies capable of killing HIV-1" in 100 percent of all humans and all chimpanzees that received the formulation. Francis has been concerned that Ho has intervened with the Thai government, questioning VaxGen's Thailand Phase III trials before they even start. An article in The Bangkok Post, (A. Bhatiasevi, May 17, 1997, page 3) states that Ho suggested Thailand "should carefully consider approving trials of a vaccine made synthetically from the outer cover of the AIDS virus." According to the article, Ho explained that gp120 was not likely to have a significant effect in countering infection. Moore's criticisms of Francis, although often couched in professional language, have, according to some, tended to extremes. Francis and others who wish not to be identified, explain that Moore sends researchers E-mail and letters that many consider to be unprofessional, if not inflammatory. Francis believes that the animosity between Moore and him began at a World Health Organization committee meeting several years ago, at which Moore announced that the gp120 vaccine was not likely to be effective. Francis claims that Moore had changed his position on the vaccine, which he previously supported. Francis points out that Moore and Ho are criticizing the first-generation gp120 vaccine, which has since been reformulated and contains antigens that induce relevant neutralizing antibodies. "Despite being invited, they have not even seen our latest data [on these vaccines]," notes Francis. A spokesperson at the Aaron Diamond Center told The Scientist that Moore was unavailable for an interview. Snow points out that the problem is not necessarily the differences in scientific opinions, but because "they [both Moore and Francis] believe passionately in what they're saying." Despite the scientific concerns that Phase III trials not begin before correlates of immunity are understood, there is broad-based support for beginning Phase IIIs. Heilman of NIAID explains that NIH is planning an advisory committee-- "water walkers," as she calls them--to advise the institute on HIV-vaccine Phase IIIs. This committee would differ from the existing AVRC headed by Baltimore. It would consist of "people that are really above everything," according to Heilman, "who have no vested interest ... who can listen to the sets of arguments ... act as true advisors." Johnston, of the International AIDS Vaccine Initiative, in commenting on the Science letter, opines, "I wish I had the crystal ball that these fellows [have]. I think they have too much faith in the significance of their lab assays to what happens in humans." She points out that vaccinology has relied heavily on empirical data, which, she adds, is needed. AVAC's Snow looks upon Phase III clinical trials with an AIDS vaccine as an experiment that needs to be accomplished. "I don't think there's any harm in running the experiment," he says. Although the lack of any viable candidates and time are limiting factors in the quest for a vaccine by 2007, veteran vaccine developer Maurice R. Hilleman, director of the Merck Institute for Therapeutic Research, in West Point, Pa., points out that there are yet-unresolved scientific problems for developing a vaccine. The AIDS virus "destroys the very immune system that is intended to destroy the virus; it ... has the power for rapid antigenic change, at least with respect to its external antigens, and it integrates into human cells." Even once these scientific difficulties are met and conquered, Hilleman points out that the basic research, carried out in academia and government laboratories, must find its way into industry. "Of greatest importance is the area that lies between traditional academia and traditional industry, in which targeted basic and developmental basic research data are needed to breach the gaps and potholes in knowledge that must be achieved," Hilleman recently wrote in a paper (M.R. Hilleman, Vaccine, 16:778, 1998). He continued, "Traditionally, this may have both academic and industrial participation, but is an area that is not being successfully fulfilled by either at the present time." Hilleman points out to The Scientist that there is "a need for targeted research" to establish feasibility--for development by industry in an area that academic laboratories are presently not equipped to fill. "Who's going to fill the gap?" he asks. The AVAC report may be downloaded from: www.vaccineadvocates.org/avacsite/ (It lists most of the Web sites below.) NIAID's AIDS Vaccine Research page is at: http://www.niaid.nih.gov/daids/vaccine (click on Vaccine Bulletin Board for interactive discussions). Transcripts of PACHA meetings and other related information are at: http://www.hsph.harvard.edu/Organizations/hai/. IAVI Web page is http://www.iavi.org. Other AIDS vaccine-related sites include: ACTIS http://www.actis.org AmFAR http://amfar.org The U.S. Food and Drug Administration http://www.fda.gov. The National Library of Medicine http://www.nlm.nih.gov UNAIDS http://www.unaids.org VactUp http://www.vactup.org Walter Reed Army Institute of Research http://wrair-www.army.mil ASD Online http://www.who.ch/asd/ Despite complaints that little has been accomplished in progressing toward a vaccine during the past year, some tiny steps forward have been taken. NIH's Heilman is trying to get together the "water walkers" advisory committee, VaxGen's gp120 vaccine is proceeding to Phase III trials, the Viral Genetics/Pasteur Mérieux Connaught ALVAC canarypox vector vaccine will be entering trials preliminary to Phase III to select the best vector, and NIH's vaccine research committee has been awarding innovation grants that are beginning to yield unique vaccine concepts. Furthermore, Heilman explains, the Department of Health and Human Services (HHS) is responding rapidly to the needs of the vaccine community. "We're also putting into place essentially a small, but very valuable, infrastructure that will allow both companies as well as academics ...[to] help them transition between a laboratory to a clinical trial." NIH has begun a dialogue on the Internet "to essentially give out a lot of money to a consortium of people." By using the Web, "we think we may have indeed reached another group of people who were not interested in the types of other programs we have in place," explains Heilman. But much more needs to be done. AVAC's Avrett points out that although the Vaccine Research proposed by Clinton last May has been established, "that center does not have a director yet." The position, he explains "is not attractive enough to potential candidates for the job," leaving open questions about the prospective director's position in NIH's hierarchy, and his or her control of the center's budget. Although Clinton called for a G-8 nation effort to combat the disease, only two of the G-8 countries--the U.S. and France--spend any significant amounts for HIV research, Avrett says. Japan, Great Britain, and the Netherlands also invest small amounts of money. "All of the G-8 countries should really increase their investment," Avrett adds. Avrett continues that Clinton's third pledge "was the challenge to the pharmaceutical industry." Although he points out that there certainly is industry involvement in AIDS vaccine development, some major vaccine companies, such as SmithKline Beecham, are not represented. AVAC lists an "Agenda for Action" that includes 19 points. Among these are funding of basic and targeted research along with movement of candidates into Phase I trials and beyond, initiation of more clinical trials, leadership from the NIH, and more funding for Walter Reed Army Institute of Research (WRAIR), a major U.S. government entity engaged in AIDS vaccine research. AVAC also suggests that NIH Director Varmus fill the vacant slot--VRC director--and make the position more attractive. AVAC would like to see more support for innovative research and more pharmaceutical company involvement, more public advocacy for HIV vaccines, and establishment of a fund that will allow poorer countries to purchase HIV vaccines once they are developed. Hilleman believes that the effort needs more organizational procedure and structure so that a vaccine candidate can proceed smoothly from research laboratory to industry involvement. "I think we have a tremendous pharmaceutical industry; we have very good government laboratories; we have very good academic laboratories. It's figuring out ways to engage them optimally for the common good," he states. VaxGen's Francis believes that the next step is to get on with Phase III clinical trials to "go out and test the hypothesis." He hopes that Heilman's "water walkers" are not another potential impediment. "All of these panels ... can build more bureaucracy and slow the progress down." Perhaps part of the problem is that the President's goal is unrealistic. As Hilleman wrote in the Vaccine paper, "There has been great diversity in the judgments of the scientific and nonscientific communities as to whether and when there might be an AIDS vaccine. Projections have been made ranging from 2 to 10 years or maybe never. Such predictions have no substance in the absence of the technical base needed to provide solid evidence necessary to justify entry into a meaningful program for vaccine development." However, what is clear to Hilleman is that there is no room for these nonproductive exchanges in the vaccine development process. He believes the time for inefficient and ineffective organizational structure has "passed by," and that it's time to build a coordinated mission to accomplish the goal of establishing the technical feasibility needed before industrial development of a vaccine can proceed. As researchers debate the theoretical arguments, Francis points out that each day 16,000 people worldwide are infected with HIV. IAVI's Johnston wants to see some empirical data on the vaccine candidates that exist now. The U.S., she explains, has time to wait for a vaccine, but the rest of the world, where infection rates are much higher, cannot wait. "If 60 percent of the people respond and are protected [with a candidate vaccine], that's great. I'll take that for starters," she says. "Let's not guess it. Let's find out." Myrna E. Watanabe is a science writer based in Yonkers, N.Y.

An AIDS Vaccine by 2007? Not Likely, Say Participants

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