In Search of an HIV Vaccine: Meet the Researchers 'Standing On Each Others' Shoulders'

By In the early 1950s, when Jonas Salk produced the first inactivated polio vaccine and Albert Sabin later produced a live, attenuated, oral polio vaccine, the individual researchers' names were permanently linked to the products. But development of an HIV vaccine--a task President Bill Clinton has charged researchers to accomplish by 2007--requires the skills of so many scientists and so many laboratories worldwide that it would be impossible, and perhaps even improper, to link any vaccine to one person's name. "It's a pretty collaborative field these days; it's not as fractious as I heard it used to be," says Robert W. Doms , associate professor in the department of pathology and laboratory medicine at University of Pennsylvania in Philadelphia. Doms and others interviewed for this story describe the research community as very cooperative. "We are all standing on each others' shoulders and supporting each other," states Margaret Liu, vice president of vaccine and gene therapy research at Chiron Corp. in Emeryville, Calif. Larry Arthur Because the field is so complex, researchers come from many academic disciplines--and some even switched from one discipline to another in the course of their vaccine work. They also come from many parts of the world. Yet, no matter what their discipline and what their country of origin, all, as Liu points out, are "incredibly and passionately committed to" the work of finding a successful HIV vaccine. In an attempt to keep the life sciences community abreast of the overall AIDS vaccine research effort, The Scientist interviewed nine prominent researchers and program administrators to find out what leads they are pursuing and how they became involved in HIV vaccine research. The following accounts are organized according to disciplines. Microbiologist/biochemist Larry Arthur has been involved in HIV research from the early years of the epidemic. Arthur is with Scientific Applications International Cooperation (SAIC), the organization that operates the National Cancer Institute's (NCI) Frederick Cancer Research and Development Center in Frederick, Md. Arthur's group, the AIDS Vaccine Program, is developing a DNA vaccine that, when inoculated into a person, will result in the "initial infectious events without the infection" within cells, says Arthur. This vaccine is based on DNA encoding for HIV's nucleocapsid protein. In vivo tests on monkeys that later underwent pathogenic virus challenge showed that three of four control animals developed AIDS two years after being exposed to the virus, while "only one of five of the DNA immunized animals has developed AIDS," according to Arthur. Another promising avenue of research is producing an intact particle virus that maintains "appropriate protein configuration" to maintain its immunogenicity. Using a compound derived from zinc fingers of the nucleocapsid protein, the researchers can deactivate the virus while "proteins on its surface retain structural and functional activity," says Arthur (D.E. Ott et al., Virology, 243:283-92, April 10, 1998). Arthur became involved in HIV research via an indirect route. He was running a viral production facility for NCI, producing large-scale quantities of human T-cell lymphotrophic virus-1 (HTLV-1), when asked to produce HIV-infected cells for companies making the early HIV tests. Because he was producing such large quantities of virus, he became involved in working with the virus, initially testing the gp120 protein. James Bradac is another microbiologist who became involved in HIV vaccine research. Bradac began working on primate retroviruses while in graduate school at the University of Alabama. "Following graduation, I worked several years as a molecular biologist, carrying out gene regulation studies using retroviruses as research tools, then accepted a position in the Vaccine Branch at the Division of AIDS, NIH [National Institutes of Health]. The enormity of the AIDS problem was quite evident in 1990 when I accepted this position, and I was lured by the scientific challenge that researching an AIDS vaccine offered," explains Bradac. He is now an extramural scientist at the Vaccine and Prevention Research Program, Division of AIDS, in the NIH's National Institute of Allergy and Infectious Diseases in Bethesda, Md. Bradac explains that the role of extramural scientists in his program is to "carry out vaccine research, both as research facilitators and as research directors." They may provide "reagents to vaccine companies and basic researchers, organize workshops to discuss topics relevant to the vaccine field, and provide scientific advice to investigators attempting to gain funding for their studies." Bradac's particular interest "involves the variable nature of HIV and how that variation may [affect the] development of a vaccine that is efficacious worldwide against multiple strains of the virus." Thus, he serves as project officer for the Variation Program, several interactive laboratories that work on contract to the NIH, studying the genetic variability of the virus--even within one patient--and its immune effects. Dennis Burton, a professor at Scripps Research Institute in La Jolla, Calif., began his research career as a chemist. He trained in Europe, receiving his undergraduate degree from Oxford University and his Ph.D. in Lund, Sweden. But he began work in biochemistry and now does research in molecular immunology. Burton and his colleagues are studying neutralizing antibodies to HIV. The group is "defining what these antibodies will do and what they won't do against the virus," says Burton. The goal, he continues, is "to use the information from these antibodies to tell us what the qualities of a good vaccine should be." His group became involved in HIV vaccine research through their development of what Burton calls, "a new approach to generating human antibodies, ... a molecular biological approach, which, technically, we refer to as phage display." Because antibody production, and production of cytotoxic T-lymphocytes (CTLs), are essential immune responses to inoculation with a vaccine, the Scripps researchers realized that they could apply their antibody production technology "to an important problem"--the generation of human antibodies against HIV. Like Burton, Doms also is "more familiar with the antibody side of things." Doms, who was trained as a cellular biologist at Yale University, and whose initial work was on the influenza virus, then moved to NIH, where he began working with vaccinia virus. He collaborated with other scientists on studying the HIV envelope protein. "It was sort of a wide-open field," he remarks. Six years ago, he moved to the University of Pennsylvania, where he has continued work on the HIV envelope protein. Doms notes that the field moves so rapidly, researchers must be able to "take advantage of new information." His group has. Earlier in the summer, Joseph Sodroski and colleagues at Harvard Medical School published the crystalline structure of the gp120 receptor on the HIV envelope (R. Wyatt, J. Sodroski, Science, 280:1884-8, June 19, 1998). "It's pretty clear that there's a conserved region of the protein that's linked to chemokine receptors," Doms says. He points out that it has been difficult to make antibodies to the site, perhaps because it is "partially occluded or hidden by these variable loops." Doms' group is now "identifying and generating virus gp120 that exists in a partially triggered state." Their next step will be to immunize animals to this site on the virus. Dennis Burton Norman I. Letvin Immunologist Norman Letvin, professor of medicine at Harvard Medical School, explains that he and his colleagues have been studying "the interface between AIDS immunology--that is, what's the normal immune response that contains AIDS virus replication--and vaccine induction of immune responses specific for the AIDS virus." They work on primate models for AIDS. Letvin and colleagues "work in disease pathogenesis [that] has indicated over the years that the CD8+ T-cell response seems to be a crucial component for the immune response necessary for containing the virus," he says. The group also has been working on induction of cytotoxic T-cell response to vaccine. Letvin became involved in HIV research during the earliest phases of the epidemic. "I was doing basic cellular immunogenetics at Harvard Medical School as a junior faculty person. I was asked to help in 1981 to clarify an epidemic in Asian monkeys, a disease characterized by opportunistic infection and death," Letvin recalls. This resulted in isolation of the first simian AIDS virus, and he has been working on AIDS virus-infected monkeys ever since. Yichen Lu, director of the Institute for International Vaccine Development in Cambridge, Mass., worked with Letvin and other Harvard scientists while he was an assistant professor at Harvard. Although Lu is pursuing several major projects in HIV immunology, he began working with animal models at Harvard and continued this work when he left in 1992 to join the Virus Research Institute (VRI), also in Cambridge, where he is still director of the HIV research program. Lu and his colleagues developed a standardized reagent for use in HIV challenge studies in monkeys. Based on the chimeric SHIV--a virus artificially manufactured from simian immunodeficiency virus (SIV), which infects monkeys, and the HIV envelope--the virus is used worldwide in HIV immunology research in monkeys. The group has developed chimeric viruses that can cause disease in monkeys within six months of introduction and can mimic the routes of introduction of HIV in humans; the virus causes disease via intrarectal, intravaginal, or oral introduction. Lu's group is continuing its collaboration with Letvin, working on SHIV subtypes that are similar to HIV subtype C (the strain prevalent in India and Africa) and HIV subtype E (the strain prevalent in Thailand, the Golden Triangle of Southeast Asia, and Yunnan Province in China). Animal models of disease and immunization of these subtypes are necessary to developing human vaccines specific to the strains. Lu also has been working with a new adjuvant, PCPT, which was serendipitously discovered by VRI scientists in a trial on developing a vaccine for microsphere delivery. PCPT was the control solution and proved to be more immunogenic than the test material. The adjuvant has been licensed to pharmaceutical company Pasteur Mérieux Connaught for use in influenza vaccine, Lyme disease vaccine, and several others, including an HIV vaccine. Lu points out that this adjuvant is water soluble and does not inactivate antigens--an important concern in creating an HIV vaccine, where antigens are very sensitive and can be degraded easily. Lu also is involved in setting up an HIV vaccine development project in Thailand. "I'm putting all my energy into it," he says. The plan is to manufacture DNA virus and genetically inactivated virus-particle with PCPT adjuvant vaccines in Thailand, then test, develop, and sell the vaccines in Thailand and developing nations at a low price. The project is supported by the World Health Organization and the Thai government, but it needs additional financial support in order to run. David C. Montefiori, associate research professor of experimental surgery at the Center for AIDS Research, Duke University Medical Center, is a microbiologist and viral immunologist. This dual training is complemented by research in both the antibody field and primate immunology. He jokes about his appointment to a surgery department, especially as he began working on HIV while in the pathology department at Vanderbilt University School of Medicine: "Here I am, a microbiologist who's moved from pathology to surgery!" Montefiori's group runs "the central immunology laboratory for the AIDS Vaccine Evaluation Group (AVEG)," an NIH-supported program. This laboratory, according to Montefiori, does all of the immunological testing and assessment for six centers across the country that test HIV vaccine candidates. The laboratory's role is to measure the neutralizing antibodies from the sera of individuals who receive vaccine candidates in clinical trials. "Basically, we're looking at titers of neutralizing antibodies that the vaccines are generating and how broadly cross-reacting those antibodies are with different strains of the virus," he explains. He also is co-principal investigator with Letvin on an NIH contract that supports a central immunology laboratory for primate AIDS vaccine studies. For the past five years, his laboratory has done "all the humoral immunology assessments in primate studies and other animal studies of candidate AIDS vaccines," he says, while Letvin's lab does the cellular immunology assessments. Their contract was recently renewed for an additional five years. Because the immunology work for all the major HIV vaccine studies--they have had a role in more than 70 studies in the last five years--is done in one central location, Montefiori notes, "You can make comparisons from one study to the next, from one virus strain to the next, as it's all done in similar assays in the same laboratory." Montefiori, according to John P. Moore of the Aaron Diamond AIDS Research Center at Rockefeller University, is "a scientist's scientist," who "rarely gets the attention he deserves." His resume lists more than 110 original research publications and review articles and more than 150 published abstracts. His coauthors include many of the individuals interviewed for this story. Chiron's Liu began her research on HIV as a young clinician at Harvard "in the early years when the first cases of AIDS were seen." She remembers, "There was a sense of urgency and kind of a charged atmosphere: here was a disease that hadn't been known and was just being understood and parameters were being described." She began work on cancer, trying to activate cytotoxic T-lymphocytes, "because it was an area that seemed approachable at the time." Once it became evident that there were many strains of HIV, Liu says, "It seemed like approaching HIV by really focusing on the cellular immune side could have more possibilities than the antibody side of things." Liu moved to Merck & Co. in West Point, Pa., where her work involves "setting up the immunology effort related to vaccines." She has been at Chiron for more than a year. She explains that the company has a broad-based program to explore a wide variety of approaches to an HIV vaccine. Among these are DNA vaccines, protein approaches using envelope protein, adjuvants, and new delivery systems including oral and intranasal vaccine delivery routes. Liu sees her involvement in HIV vaccine research as a result of timing, along with her background in immunology and as a clinician. It was, she says, a "meshing of interests and background with a need." Diamond's Moore refuses to be pigeonholed. "The immunologists call me a virologist; virologists call me an immunologist. I'm really an AIDS researcher," he states. But Moore, who is known among the research community for his long E-mail recipient list, his pithy E-mails, and his large collection of humorous sweatshirts, runs a laboratory that is studying HIV envelope blanket proteins. The researchers have used antibody mapping to look at the topology of the envelope, have looked at responses to the envelope proteins, and are studying everything they can about these proteins. "We want to know everything they do," Moore says. "Everything" includes how the HIV enters the cell, "how immune responses to HIV are affected by antiviral therapy," and how to inhibit HIV entry into the cell. "All of it is to help understand vaccine development," he explains. Moore did not start out to be an HIV researcher. "In the late 1980s, the British government started putting money willy-nilly into AIDS research. They started throwing around a lot of money, which means that you start recruiting people from outside the field." One of the people recruited was Moore, whose friend had a laboratory in Scotland. Before then, he says, "I wasn't working on any virology; I'd hardly even heard of a virus." That was more than a decade ago, when Moore was hired "to make the British AIDS vaccine," and that was where he began to work on HIV envelope protein. Four years later, Moore was recruited by David Ho , director of the Aaron Diamond Center. Scientists point out that more is known about the AIDS virus than any other microorganism against which there is a vaccine. Yet, there is no vaccine to date for AIDS, despite nearly 20 years of research. The researchers interviewed were quite positive about the prospects for a vaccine. "Given what we've learned and the power of molecular biology and immunology, we do have the tools to start to think about designing quite new vaccines," states Scripps' Burton. "We have realized in the last two or three years that we now have vaccines that will generate a cellular immune response that looks hopeful," says Duke's Montefiori. "But, of course we're not going to know how hopeful it is until the vaccines are tested in large-scale Phase III trials, which are either planned or are just under way." Montefiori points out that VaxGen's Phase III trials, just beginning in Thailand and the United States, are of a vaccine "that doesn't raise cellular immunity; that one is a vaccine that mostly generates neutralizing antibodies." (M. Watanabe, The Scientist, 12[12]:1, June 8, 1998, and 12[13]:5, June 22, 1998.] Moore believes very strongly that, "You're not going to make an AIDS vaccine without understanding the science that underlies it." Montefiori points out that, "More work, obviously, needs to be done. ... It's still not clear what immune responses will ultimately be needed for a vaccine to be effective." Burton adds that although the virus is "tricky, ... we shouldn't be overawed." He continues, "We will be able to make a vaccine ... but we'll have to be much cleverer than we've been in the past with previous viruses." When that vaccine is developed, says Liu, "It is probably going to be a summation and integration of all of the insights and advances." No matter how difficult the task is, probably all of the researchers would agree with Letvin's summation of why he is engaged in HIV vaccine research: "I really do, in my heart of hearts, believe that both as a public health issue and as a scientific issue, the development of an HIV vaccine is the most compelling question that I can conceive of working on. There's nothing I'd rather be working on at this time." Myrna E. Watanabe is a freelance writer based in Patterson, N.Y.

In Search of an HIV Vaccine: Meet the Researchers 'Standing On Each Others' Shoulders'

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