No Vaccine, No Cure

Editor's Note: This is the second of two articles that looks at the progression of AIDS research over the 20 years since its identification. The first part: M.E. Watanabe, "AIDS, 20 years later," The Scientist, 15[12]:1, June 11, 2001. Despite billions of dollars spent in research funds and a brief reprieve in Western nations after the introduction of multidrug therapy, AIDS continues to win its battle against humankind. First diagnosed 20 years ago, there are still no cures and no vaccines. Prevention remains elusive and worldwide infection numbers are skyrocketing. A vaccine is still a decade or more away. When first diagnosed in the United States, the disease mainly struck gay men, intravenous drug abusers, and those who had received tainted blood or blood products. Today, its targets have changed. AIDS thrives in poverty and among those who are disenfranchised. Increasingly, it is becoming a disease affecting women and children: worldwide, in 2000, 2.2 million of the 4.7 million new HIV infections were in women.1 In the United States, "it continues to disproportionately [strike] communities of color," says Helene Gayle, the outgoing director of the Centers for Disease Control and Prevention National Center for HIV, STD, and TB Prevention. "Almost 70 percent of new HIV infections are among African Americans and Latinos." Moreover, the prevalence of AIDS in gay men in the United States is no longer declining, after years of decreasing. "It's not enough to tell people that this is AIDS and how you get it," says Karungari (Karusa) Kiragu, research writer and associate, Population Reports, Johns Hopkins University Center for Communication Programs. "What do you say to young people, and will they listen?" Today, the disease's epicenter is in Sub-Saharan Africa, where, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS), 25.3 million people are HIV-positive, for a prevalence rate of 8.8 percent of those between 14 and 49 years of age.2 Its spread is abetted by cultural traditions, prostitution, lack of public health infrastructure, governmental indifference, superstition, ignorance and poverty. In some parts of the world, specific "cultural factors...will put women at risk," Kiragu says. Nearly 20 antivirals on the market today have changed AIDS from an absolute death sentence to a potentially chronic disease, but these drugs are very expensive and usually not available in developing countries. "It's a pretty disturbing experience to ...leave your patients here because they're doing great, and walk into a hospital [in South Africa]," states Bruce Walker, director of the Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, who has been treating AIDS patients since the mid-1980s. "You know you have medications here and [if administered] they can get up from their death beds. Instead, they're going to die." Only recently have pharmaceutical firms, under intense pressure from activists and politicians, agreed to provide drugs at a reduced cost or for free to some of the developing nations. A consensus statement, spearheaded by Harvard University economist Jeffrey Sachs, estimates that HIV testing, drug treatment, clinical follow-up, and research on HIV in Africa would cost $1,123 per patient per year.3 But distributing drugs and following up on patients are problems. "Even if you parachute [in] all the drugs that you need for a developing country, you are still going to have great trouble distributing them because the health care infrastructure in these countries is nonexistent or minimal," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). "This might be an opportunity to jump-start interest in developing this health care infrastructure in these developing nations." Harvard's Walker sees more opportunity: "Once you have the clinic with the health care staff that can deal with the HIV infection, they can deal with other infections as well." Even when the drugs get distributed, current pharmaceutical treatment does not cure HIV/AIDS. "We need a new set of drugs," states Gregg Gonsalves, an activist with the Gay Men's Health Crisis in New York and founder of the Treatment Action Group. The drugs in use are highly active antiretroviral therapy (HAART), the multidrug cocktails that keep those infected alive and their viral loads low or negligible. Gonsalves notes, "All our drugs are reverse transcriptase inhibitors and protease inhibitors. We need drugs directed at other viral targets." The HIV virus replicates rapidly and mutates quickly. "Breakthrough" viruses evolve and elude antiretroviral treatment--as well as the immune systems' scavenging effects. Furthermore, these drugs are toxic. "You run out of options and you run into toxicities," remarks Gonsalves. Finding a Cure There is one therapeutic success that is saving lives in developing nations. Susie Zeegen, cofounder of the Elizabeth Glaser Pediatric AIDS Foundation, explains that the drug nevirapine cuts mother-to-child transmission almost in half if given to the mother at delivery and to the child in 72 hours. Zidovudine (AZT) also can prevent vertical transmission from mother to fetus, but the dosing regimen is more complex. Virologist John Moore, of the Joan and Sanford I. Weill Medical College of Cornell University in New York, thinks the future will bring more effective drugs with fewer side effects. Among these are inhibitors that will prevent HIV from attaching to or entering its target cells--T cells or macrophages. Moore and his colleagues are studying these entry inhibitors, which he sees as "moving toward the clinic." Early on, some researchers thought that developing an HIV/AIDS vaccine would not be a unique challenge. AIDS vaccine researcher Margaret Liu, senior adviser in vaccinology for the Bill and Melinda Gates Foundation, says that researchers used the hepatitis B vaccine as a paradigm for a putative HIV vaccine "and they started off making a vaccine before they knew the pathophysiology of the virus. Then it became clear that it was a different ball game, a different challenge." Robert Gallo, then at the National Cancer Institute and now director of the University of Maryland Institute of Human Virology in Baltimore, notes, "there was no antiviral success.... I thought it would be exceedingly difficult to get new therapy against HIV; [I] thought [it would be easier] to get a vaccine." He admits he was wrong. Another reason there is no vaccine is that, for many years, vaccines were a stepchild of AIDS research and were considered secondary to pharmaceutical development: Jon Cohen, Science's HIV/AIDS correspondent, posits in his recent book that a lack of organization and leadership has hindered the vaccine effort.4,5 Liu says that the vaccine industry had an early interest in developing AIDS vaccines. "If you go back and look in the '80s and early '90s, there were companies that invested quite heavily." Among these were Genentech and its spinoff, VaxGen; Pasteur-Mérieux Connaught [now Aventis]; Chiron; and Merck & Co. Liu worked on HIV vaccines for Merck and then Chiron. In the mid-1980s, says Liu, efforts to produce a vaccine started dropping off. Part of this was due to the science. "There were still many people who clung to the paradigm of making an antibody-based vaccine hoping to generate sterilizing immunity as the only way to make a vaccine," she recalls. Without sterilizing immunity, Liu says, an individual could suffer from a lifelong infection or an infection that would be difficult to annihilate. But Liu reasoned that an HIV vaccine that would result in a cellular response (production of cytotoxic T lymphocytes (CTLs) rather than an antibody response) "could target more conserved proteins, could have a vaccine that was more widely effective." She recalls, "I found a lot of resistance [from other researchers] when I started making an HIV vaccine that would either be based on or [cause] a cellular response." Sterilizing immunity may be desirable, but it may not be essential for a useful vaccine. Only one vaccine is in large Phase III clinical trials: VaxGen's gp120 vaccine, which contains a piece of the HIV protein envelope to stimulate antibody production. Some researchers expect the vaccine will be ineffective in protecting against HIV infection.6 At least a dozen vaccine candidates are now in early clinical trials, and many more in preclinical development.7 Among these are a series of DNA-based vaccines used in monkey tests by Merck scientists. Two of these constructs have protected the monkeys, challenged with a potent simian-HIV (SHIV) pathogen--a hybrid between HIV and SIV--from high viral loads.8 Another is in monkey trials at Yerkes Regional Primate Research Center at Emory University in Atlanta. The construct, according to lead researcher Harriet Robinson, contains DNA plus a recombinant modified vaccinia Ankara (rMVA) booster. The researchers allowed seven months to elapse after vaccination with a rMVA booster, to allow long-term immune responses to develop and then gave the monkeys a mucosal challenge with a very pathogenic SHIV construct.9 When The Scientist spoke with Robinson, the experiment was at 42 weeks post-challenge. All of the controls died, but 23 of 24 vaccinated animals "are doing incredibly well," says Robinson. "We're going ahead now to develop the components that we think will develop a worldwide vaccine." If this trial remains successful, the group plans to go into a Phase I clinical trial in humans in 2002. Courtesy of International AIDS Vaccine InitiativeSeth Berkley These vaccines will not prevent infection, but they will stimulate immune responses once infection has occurred, allowing the affected individual to ward off full-blown AIDS, and perhaps even allowing them to clear the virus from their bodies. Seth Berkley, president of the New York-based International AIDS Vaccine Initiative (IAVI), a nonprofit organization that is working to bring HIV vaccines to less-developed countries, says that it's a long road to a vaccine. "We've only got one vaccine in Phase III trials. At best, by 2003, we can have a second candidate enter." The next two candidates would not be ready for clinical trials until 2005 or 2006. "Right now, there's no evidence of any vaccine that will be effective in a human population," says Ronald Desrosiers, of the New England Regional Primate Research Center, Harvard Medical School. Prevention, Prevention, Prevention Until a vaccine or complete cure becomes available, the best investments will be in continued research and in prevention. Fauci notes that NIH's AIDS research budget for 2002 is $2.5 billion--more than NIH has budgeted for any other disease. Prevention encompasses education, condom distribution, needle distribution (for intravenous drug users), and development of vaginal or rectal microbicides. But education must take culture into account. Wife inheritance is prevalent in Eastern and Southern Africa, where a brother-in-law inherits his brother's widow as his wife. "The problem is, if the new husband has HIV, the woman may not know and may not have a choice anyway," says Johns Hopkins' Kiragu. Another is male sexual expectations. "Men are socialized to expect sex from women.... Women are socialized to give in," she notes. Nor do males necessarily see condom use as their responsibility: "If women demand condoms to be used, [it] means they must have been running around." Phyllis Piotrow, director of the Center for Communication Programs, Johns Hopkins University Bloomberg School of Public Health, suggests that education cannot be directed just at the individual. "It's also necessary to educate the community about the ways in which community...norms can be changed in order to support individuals who are trying to change their behavior." She continues, "There can be a lot more emphasis on income-producing activities for girls so that they don't engage in survival sex to earn money .... We need to put more focus on male behavior and to identify what is unacceptable male behavior." Says IAVI's Berkley: "[AIDS] is the greatest public health challenge of our time, of the century, and we are not approaching it with the seriousness that it needs." Myrna E. Watanabe is a freelance writer in Patterson, New York. References 1. UNAIDS/WHO, "AIDS epidemic update: December 2000," December 2000. 2. S.G. Stolberg, "In AIDS war, new weapons and new victims," The New York Times, June 3, 2001:1. 3. The Harvard Consensus Statement on Anti-Retroviral Treatment for AIDS in Poor Countries is available at www.aids.harvard.edu/overview/news_events/events/ consensus.html 4. M. Watanabe, "Science, policy issues put AIDS vaccine on slow track," The Scientist, 11[22]:1, Nov. 10, 1997. 5. J. Cohen, Shots in the Dark: The Wayward Search for an AIDS Vaccine, New York: W.W. Norton & Co., 2001. 6. R.A. Weiss, "Gulliver's travels in HIVland," Nature, 410:963-7, April 19, 2001. 7. AIDS Vaccine Advocacy Coalition, 6 Years and Counting: Can a Shifting Landscape Accelerate an AIDS Vaccine? Washington, DC: AVAC, 2001. 8. J. Cohen, "Merck reemerges with a bold AIDS vaccine effort," Science, 292:24-5, April 6, 2001. 9. R.R. Amara et al., "Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine," Science, 292:69-74, April 6, 2001. Collateral Knowledge from AIDS Research Courtesy of Cetners for Disease Control and PreventionHelene Gayle Nothing has stopped the AIDS epidemic, but in these 20 years, society has learned more about other diseases and more about dealing with public health issues and with affected populations. "In two short decades, I think we have witnessed the evolution of a disease that, in many ways, will define how we do public health and has changed the way we conceive of issues beyond public health," says Helene Gayle, outgoing director of the Centers for Disease Control and Prevention National Center for HIV, STD, and TB Prevention. Early involvement by activist groups shaped not only the research tenor--with pressure for drugs to cure the sick rather than vaccines to prevent transmission--but also molded how society views drug development. "I think that without the HIV epidemic and the involvement of the activists, we would not be where we are in drug development in general," remarks Arthur Ammann, founder of Global Strategies for HIV Prevention in San Rafael, Calif. "The activists got involved and asked, 'Why can't we do research faster? Why does it take so long to get drugs to the public?' [The movement] said that the consumer has the right to demand accountability in every aspect of their health." Robert Gallo, director, University of Maryland Institute of Human Virology in Baltimore, admits that during the epidemic's early days, after great scientific advances developed rapidly, he didn't quite understand what the AIDS patients, primarily homosexuals, wanted. He does now. "I would say, number one, there's a lot more understanding between scientists, health care workers, and patients in the so-called risk groups than there was by orders of magnitude [in] the early days. I didn't understand what it meant to be surrounded by your friends who were dying [who felt]: 'Why wasn't there something that gave one iota of help to me and my friends?'" Working together--governments, nongovernmental organizations, foundations--is a new paradigm in treating a disease. "Private, nongovernmental organizations have played an ever-larger role, and I think it has nourished and strengthened the environment in which the private sector has been much stronger, much more active, than they were before; and in many cases, they are leading the government, showing the way," says Phyllis Piotrow, professor and director, Center for Communication Programs, Johns Hopkins University, Bloomberg School of Public Health. Bruce Walker, director of Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, sees the lessons learned over the past 20 years as a means of moving medical care in the developing world to a higher standard. "Clearly, what we're going to see over the next five years is finally an attempt to address some of the global inequalities in health care delivery. My hope is that we'll use some of the opportunities afforded by the need to treat the HIV epidemic as a means to treat other diseases as well." Seth Berkley, president of the International AIDS Vaccine Initiative in New York, sees a way to develop a distribution network for vaccines. "For example, let's take hepatitis B vaccine and create a campaign to reach adolescents and high-risk people, who we currently have no mechanism to target .... Using hepatitis B, we can figure out the mechanisms, efficiency, and cost-effectiveness of different modes of delivery." Bringing young scientists to the HIV/AIDS research field has also been an important goal. By giving grants to researchers, especially those in the early stages of work in immunology, virology, or clinical research, the Elizabeth Glazer Pediatric AIDS Foundation says it has "done a lot to try to bring new interest in this area," remarks co-founder Susie Zeegen. "And I think we've been successful." And there are the scientific gains. "New fundamental mechanisms in molecular biology have come out of basic HIV/AIDS research," notes Gallo. Says Walker: "The payoff is not only understanding HIV, but ... other viruses and cancer." --Myrna Watanabe

No Vaccine, No Cure

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