AIDS Vaccines: The Ethical and Social Issues
A Little History
Perhaps no prediction about vaccines was as optimistic as when Health and Human Services Secretary Margaret Heckler stated in 1984 that an AIDS vaccine should be "ready for testing in two years," hopefully to be on the market a year afterward. [Ed. note: While a candidate was ready for testing two years later, none have yet made it to market.] Seventeen years later, only one potential preventative HIV vaccine has entered efficacy, or Phase III, trials.
That vaccine, VaxGen's AIDSVax, stems from one of the earliest ideas for creating such a vaccine: genetically engineering copies of a piece of HIV's outer layer (envelope), known as glycoprotein gp120. Though many scientists are skeptical that AIDSVax will be effective -- the National Institutes of Health (NIH) refused to fund a Phase III study of an earlier version of the product in 1994 -- the fact that a private company finally managed to mount a large-scale AIDS vaccine trial is considered a milestone.
For many years experts in the field seemed to be treading water, navigating "without a compass," as researcher Dani Bolognesi, Ph.D., commented at the 9th International Conference on AIDS held in Berlin in 1993. A year after President Clinton's 1997 declaration that the U.S. would commit itself to developing an AIDS vaccine within ten years, the AIDS Vaccine Advocacy Coalition (AVAC) -- the only activist group specifically focused on AIDS vaccines -- issued a glum report declaring, "At the current level of effort, we will not have an HIV vaccine in nine years. Unless more is done, the president's challenge will not be met."
Fortunately, more has been done. U.S. government funding for vaccine research has increased. The International AIDS Vaccine Initiative (IAVI), a private charity seeking to accelerate vaccine testing and development, received a $100 million cash infusion from the Bill and Melinda Gates Foundation enabling it to move forward on several fronts. Major pharmaceutical companies that had little or no prior involvement in AIDS vaccine research, including Merck and GlaxoSmithKline, have entered the field on a significant scale.
The scientific news also has improved. Studies of long-term nonprogressors (people infected with HIV but experiencing little immune system damage after ten or more years without drugs) as well as individuals who remain uninfected despite repeated exposure to the virus provide "growing evidence that cellular immune responses can provide at least some protection against HIV -- if not against infection, at least against disease," notes David Gold, IAVI's Vice President for Policy and Public Sector Development. Particularly encouraging have been studies of several vaccine concepts tested against simian immunodeficiency virus (SIV), a virus similar to HIV that infects certain species of monkeys. These vaccine candidates have provided significant protection to monkeys given the vaccine and then challenged with pathogenic (disease-causing) SIV.
University of California at San Francisco (UCSF) researcher Susan Buchbinder, M.D., a local principal investigator and national steering committee member for the NIH's HIV Vaccine Trials Network (HVTN), notes that Phase II data from a "prime-boost" combination vaccine will be released in December 2001. HVTN will then consider whether this two-stage vaccine, using a harmless canarypox virus engineered to express (produce) certain HIV genes followed by a gp120 "boost," should move into Phase III testing.
Decisions about what products deserve efficacy trials can be difficult, as the NIH's public agonizing about the merits of the gp120 trial made clear. Once those decisions are made, the studies themselves open up a huge range of issues connected to the rights and welfare of participants. Of necessity, efficacy trials must be large and international, aimed at creating vaccines that can be used in the developing world as well as in developed countries including the U.S., Europe, Japan, and Australia, i.e., for all HIV clades (strains). Such trials will need to be conducted over many years. It may well be that early vaccines will not prevent infection but will enable the immune system to keep HIV under control, preventing or delaying disease progression in those who become infected -- something that will require a long period of follow-up to prove.
Even the selection of study sites is fraught with complications. There have been cases in which researchers appear to have chosen developing country sites specifically to avoid the ethical constraints and reviews required in more developed countries. Because it is considered unethical to conduct research in a population that will not benefit from that research, information about local HIV strains -- and the current uncertainty about whether protective immunity is possible against different viral strains found around the world -- must be considered, as must economic barriers that could block access to a successful vaccine.
In the wake of grotesque experiments performed by Nazi scientists on concentration camp inmates during World War II, the 1947 Nuremberg Code established "voluntary consent" of human subjects as a bedrock principle of medical research. Over the years (particularly through the example of the infamous Tuskegee syphilis experiment, in which African-American male participants were not told they were being denied treatment that could cure their illness) it has become clear that consent is only meaningful if it is informed. In the words of the Declaration of Helsinki, an important research ethics document drawn up in 1964, informed consent means that "each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study, and the discomfort it may entail."
In most U.S. studies, research participants must read and sign an informed consent document outlining this information, with a study nurse taking time to explain the form and answer questions. But the informed consent process arguably begins with the first attempts to publicize a trial and attract volunteers. Advertising for AIDS vaccine trials must not mislead participants into assuming they will be protected from HIV, since an experimental vaccine is by definition unproven and some volunteers may receive a placebo. Also, it is unlikely but theoretically possible that an AIDS vaccine could cause HIV infection.
Publicity must therefore encourage people to participate -- effectively enough to bring in thousands of volunteers for Phase III trials -- without giving them a false sense of security that might encourage risky behavior. The goal, says Dr. Buchbinder, is to "try to give as balanced a view as possible. . . . It's hard to do." Sometimes the press complicates the process. While there have been few complaints about VaxGen's efforts to recruit volunteers, some early media coverage of the study was problematic. A December 21, 1999 New York Times story, for example, followed publisher Troy Masters as he signed up for the trial and announced, "This is like signing for permission to end the AIDS crisis." Masters' own paper, LGNY (a biweekly, freely distributed newspaper for lesbian and gay New Yorkers), headlined a story about the trial called "AIDS End Game." Researchers cannot control the press, but they do have an obligation to make sure journalists understand all the risks and uncertainties involved in research. Part of the informed consent process may entail addressing the misunderstandings created in volunteers' minds by exaggerated or oversimplified press accounts.
To demonstrate the benefit of any vaccine, efficacy trials will need to recruit participants at high risk for HIV infection including poor, illiterate villagers in rural parts of Africa and Asia. This requirement brings up issues that rarely arise in U.S. or European AIDS treatment trials. For example, how do you explain the intricacies of research to people who have no experience with the process or whose language does not even have a word for "placebo" (an inactive substance)? How do you discuss viral load or disease progression with people who have no experience with Western biomedical concepts of disease?
In such circumstances the inherent power imbalance between educated, relatively wealthy researchers and their poorer, socioeconomically disadvantaged potential volunteers becomes a barrier and -- combined with cultural differences -- can undermine the informed consent process. In a 1998 South African Medical Journal article, a trio of South African researchers discussed what they termed "social desirability . . . the tendency for research participants to behave and respond in accordance with what they surmise to be the expectations for the situation, including trying to create a favorable impression for the researchers. . . . For example, it is possible that participants, especially those from poor and historically disempowered communities, may say that they understand and are satisfied with the research procedures and feel free to withdraw from the research at any time, and yet not genuinely feel or believe any of these."
Researchers must therefore deal with different cultural norms in consent and decision-making. Western cultures tend to emphasize the individual, but in some tribal societies the norm is group decision-making, or for a tribal council or chief to make decisions for the group. "It has been suggested," the South Africans noted, "that in these contexts, researchers obtaining only the consent of the individual participant are in violation of some fundamental norms of the community, and that the consent of other members of the community (marital partners, family, chiefs, et al.) needs to be obtained for the research to be both ethical and culturally informed. On the other hand, it has been argued that the principle of first-person consent, based on respect for individuals, should be universally applied in medical research, even if this should be supplemented with consent from other people from the community."
Clearly, researchers have a tremendous responsibility. They must not take advantage of the poverty, lack of education, or social vulnerability of potential research participants. When dealing with unfamiliar communities and cultures -- whether in their own country or in another -- those conducting clinical trials need to work closely with local researchers and community members to bridge gaps in understanding, making those local communities informed and active participants.
Former UCSF researcher Peter Lurie, M.D., M.P.H., now with Public Citizen's Health Research Group, goes farther, suggesting, "There needs to be some effort to actually confirm the efficacy of informed consent." Dr. Lurie wants researchers to test at least a sample of participants to make sure they truly understand fundamental concepts in the research they have agreed to join. "When we say someone is informed and consenting, we should take that at least as seriously and as subject to confirmation as [saying] that the blood potassium level is 3.9," he argues.
Linked to the issue of informed consent is the question of testing on adolescents. AVAC executive director Rose McCullough, Ph.D., calls testing on teenagers, many of whom are just becoming sexually active, "a necessity," noting that the Food and Drug Administration (FDA) might not license a vaccine for adolescent use if it has not been studied in teenagers.
Dr. Buchbinder agrees, but adds that it is "tricky," both because it is generally agreed that researchers should be particularly cautious about exposing young people to potential harm and because of the maze of legal and social issues involved. For example, parental consent is often required for underage youths to participate in research, but the young people most at risk for HIV may not discuss with their parents the sex- or drug-related behaviors that put them at risk. The fact that researchers will need to gather information on volunteers' risk behaviors adds another layer of complexity, Dr. Buchbinder explains. "If they report that they've had sexual activity with an older person, then we're required by law to report that they've suffered sexual abuse. It gets very complicated."
In much medical research the potential risk to participants is limited to the direct effects of the study, such as drug side effects. But HIV vaccine researchers must anticipate -- and try as much as possible to head off -- an array of social harms that could befall volunteers.
Many of those most at risk for HIV infection -- sex workers, men who have sex with men (MSM), and injection drug users (IDUs), among others -- face social or legal threats because of the behaviors that put them at risk. Thus, as a research team from UCSF noted, "mere participation in the trial might stigmatize volunteers as being members of such risk groups. One group of researchers in the United States reports that 'AIDS vaccinees in our [Phase I and II] trials have . . . been shunned by coworkers and acquaintances who learn of their participation.'"
In some cases the legal and social stigma may be so severe as to make certain research impossible -- for example, in countries where laws against homosexual behavior are so strict and actively enforced that MSM can never safely come forward. Even in less oppressive environments, researchers must take into account the vulnerability of populations they study and make every effort to minimize harm.
Dr. Buchbinder, who is working on the AIDSVax trial as well as a Centers for Disease Control and Prevention (CDC) collaboration with VaxGen examining social and behavioral issues related to vaccine efficacy studies, has been dealing directly with many of these concerns. A CDC press release aimed at recruiting study participants that referred to "very high risk individuals" concerned her. "There is stigma, I think, associated with participating," she explains, and use of such language in official statements and documents could dissuade people from enrolling in studies.
Every six months, Dr. Buchbinder and colleagues ask the volunteers a detailed set of questions about possible social harms, including stigmatization and related difficulties involving work and family. The data are still being gathered, but Dr. Buchbinder says that even in San Francisco -- a city widely regarded as liberal and highly knowledgeable about AIDS -- some individuals clearly have difficulties. "People hear that you're in a vaccine trial and don't understand what that means. They assume that you're positive or they assume that you're at very high risk or sometimes they think that you're getting injected with live HIV. There are all kinds of misconceptions."
One critical issue is the possibility that uninfected vaccinees will test positive on HIV antibody tests due to antibodies stimulated by the vaccine. This can cause problems in a variety of areas, from insurance policies to immigration issues. "We warn everybody" about this possibility, Dr. Buchbinder says. "We go through a very extensive education piece before we enroll anybody. . . . We ask them about the potential for their needing to be tested in a variety of different kinds of settings in the future and whether or not this could have a negative impact."
Since false-positive antibody tests are a predictable and extremely serious consequence of participation in a vaccine trial, it is accepted that researchers must not only warn participants of the issue but actively assist them in dealing with its ramifications. "What we suggest to them is . . . to alert us up front so we can help them proactively rather than after a problem has happened," Dr. Buchbinder says. Depending on the circumstances, researchers may provide volunteers with a letter explaining their false-positive test or speak with whoever needs an explanation.
Immigration issues are a particular worry, since a positive HIV antibody test can threaten a person's ability to remain in the U.S. "We have a little more ability at times with insurance companies and jobs, [but] the Immigration and Naturalization Service (INS) is sort of an entity unto itself," Dr. Buchbinder explains. "They are the most unreasonable people. . . . Their constituency is a completely powerless group. Even our colleagues at NIH have said, 'We'll do everything in our power, but there are certain things that we just don't really have control over.'"
Fortunately, gp120 vaccines such as AIDSVax produce a fairly distinctive signature on standard antibody tests, one that is usually easy to distinguish from genuine HIV infection. That may not be the case for future vaccines. Dr. Buchbinder says, "We're trying to work on it from a laboratory standpoint, to try to figure out how we can have available assays that can easily differentiate between vaccine-induced immune responses and real infection with HIV." Still, she worries that this "is going to be a real problem."
Counseling and Treatment
Every volunteer in a preventive vaccine trial will need to receive counseling about how to avoid HIV infection. There is widespread agreement that participants should receive what Dr. McCullough calls "state-of-the-art prevention," including counseling, access to condoms and, to the degree legally possible, clean needles.
Nevertheless, a vaccine's ability to prevent infection will be measured by comparing seroconversion rates among those receiving the vaccine with those taking a placebo, creating a dilemma: the more effectively counseling discourages risky behavior, the harder it will be to measure a vaccine's effect. In the view of many, including Dr. Lurie, this creates an inherent conflict of interest that can only be avoided by having the prevention activities handled by people other than the research team who have no vested interest in the results.
Dr. Buchbinder sees it differently, saying, "I think our counselors feel an extra measure of responsibility because these are people who are putting themselves on the line by getting an HIV vaccine. . . . I feel [the researchers] give it an extra boost to be sure that they're getting the very best counseling they can get." She acknowledges, though, that when the prevention counselors are part of the research team, their work must be independently monitored -- an approach Dr. Lurie reluctantly accepts as a second-best option.
Perhaps the most hotly debated question in HIV vaccine research has been whether study sponsors have an obligation to provide antiretroviral treatment for volunteers who become infected during the trial. Again, the gap between developed and developing nations looms large (see "Affordable Drug Access for Developing Countries" in this issue). In most states in the U.S., a variety of programs makes access to anti-HIV treatment nearly universal, but what about countries where almost no one has access to or can afford highly active antiretroviral therapy (HAART)?
The question seemed particularly urgent a few years ago, when official guidelines leaned toward early treatment. The Declaration of Helsinki stated flatly, "In any medical study, every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic method." To advocates like Dr. Lurie, that was an unambiguous command: if HAART is the standard of care, it must be available to any vaccinees who become infected, however poor, and wherever they live.
Others disagreed just as vehemently. Some wondered if -- since trials will need to look for any effect of vaccine-induced immunity on disease progression in those who became infected -- providing HAART would make it impossible to gather accurate data. Others argued that it would be immoral to delay vaccine trials that might save millions of lives while negotiating access to treatment (and the associated viral load testing, etc.) in places with no infrastructure for such medical care. Also, who would pay for the cost? And might not provision of medical care that is otherwise unavailable constitute an undue inducement to poor people to put themselves at risk with an experimental vaccine, thus violating another established ethical standard?
The Joint United Nations Programme on HIV/AIDS (UNAIDS) held meetings in Switzerland, Brazil, Thailand, and Uganda in an effort to forge an international consensus. What emerged were such sharp disagreements that the UN eventually compromised, suggesting in its official guidance document that the issue of treatment access should be decided locally rather than through an international standard. The dispute has softened lately, thanks to the recent shift in treatment guidelines away from early therapy (i.e., not to treat asymptomatic persons with CD4 cell counts above 350 cells/mm3). However, if the medical consensus moves back toward "hit [HIV] early and hard" due to new data or improved drugs, the controversy may erupt again. All sides agree that the best answer is to make antiretroviral treatment available to all who need it, regardless of income or geography. Recent policies from pharmaceutical companies (including the Indian firm, Cipla, which produces generic drugs) with markedly reduced prices for anti-HIV therapy in developing countries represent a step that might make access a possibility in those locations.
Approval and Access
Eventually an HIV vaccine will likely demonstrate at least some protection against infection with the virus, but almost no one expects the first successful candidate to be anywhere near 100% effective. So what level of efficacy should be required for approval?
VaxGen has suggested that it will seek FDA licensing if AIDSVax proves 30% effective. Yet some researchers, using mathematical models, have suggested that adoption of a weakly effective vaccine, if accompanied by relatively mild increases in high-risk behavior because vaccinees feel protected, could lead to more HIV transmission rather than less. Data linking optimism about HAART to increased risk behavior make such a scenario seem plausible.
What about a vaccine that does not prevent infection but rather helps the immune system ward off disease, as in the case of long-term nonprogressors? A product that allowed most vaccinees to live a normal lifetime without clinical illness would surely be approved. But what about a vaccine that increased the average time from HIV infection to AIDS from ten years to 20 years? Or even 15 years?
Dr. Buchbinder notes that a partially effective vaccine may be useful for some populations and circumstances and not for others. This presents another dilemma: how does one balance the benefit a partially effective vaccine will offer some people against the harm caused by giving others a false sense of security? "I think it's going to be very dicey," she reflects. "I'm not a big believer in the mathematical modeling approach, but I do think you have to look a little bit at that to try to figure out from a public health standpoint what's the break-even point [where there is a balance between the benefit and harm done].
Even a completely effective vaccine provides no protection to communities that never receive it. In a recent white (policy) paper, IAVI noted that vaccines have typically reached developing countries an average of 20 years after being licensed in developed nations. The issue needs urgent attention now, IAVI wrote: "Waiting to address access issues until after AIDS vaccines are licensed will sentence millions to preventable illness and death."
There is also a practical side to dealing with access now. "If those issues are not addressed up front," Dr. Buchbinder notes, "then communities and whole countries are not going to be willing to participate" in vaccine trials. From their point of view, Dr. Lurie explains, "the only conceivable bargaining power a developing country has is its own people. . . . We will be powerless to negotiate [access] if we don't do it from the beginning."
IAVI has addressed this issue. When it funds vaccine trials, IAVI requires the product's developers to agree in writing to affordable pricing in developing countries -- and to give IAVI the right to seek other manufacturers if affordability criteria are not met. The group has proposed a variety of other access initiatives, including tiered pricing (in which developing countries would pay less than developed ones) and a global purchase fund for AIDS vaccines.
Many of IAVI's ideas are supported by AVAC and other advocacy groups. Whether governments and industry will act expeditiously remains to be seen.
Bruce Mirken is a freelance writer based in San Francisco.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.