pp. 120-125 in
Bioethics in Asia
Editors: Norio Fujiki and Darryl R. J. Macer, Ph.D.
Eubios Ethics Institute
Copyright 2000, Eubios Ethics Institute
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3.7. AIDS Vaccine Trial and Ethics
Ann Lewis Boyd and Pinit Ratanakul.
Hood College, USA and Mahidol University, Thailand
The World Health Organization (WHO) estimates that 22.7 million persons are infected with Human Immunodeficiency Virus (HIV), which causes the lethal illness, Acquired Immunodeficiency Syndrome (AIDS). Thailand is experiencing a rapidly spreading HIV epidemic with at least 700,000 of its 60 million citizens infected with the virus. In the whole of Southeast Asia, there are an estimated 5 million cases of HIV infection. Educational efforts are now aimed at curbing the spread of the virus through preventive measures and behavioral modifications. These efforts appear to be having some success, but the long-term solution rests in the creation and deployment of a protective vaccine.
Pharmaceutical companies develop vaccines using successful paradigms, then search for an opportunity to conduct human clinical trials to determine the safety and efficacy of the vaccine. The rapid increase in HIV infection in Thailand evokes two immediate responses: the concern by the government to intervene in protective ways, and the opportunity to test developing vaccines. The fact that AIDS is lethal prohibits using a live challenge dose of virus to establish efficacy. Dense populations that are at risk of future exposure to acquired infection are an attractive means to determine the protective potential of new candidate vaccines. There are two questions to answer: What is the scientific merit of the vaccines proposed for clinical trial in Thailand? What is the ethical basis of the decision to proceed with a vaccine trial?
Four factors that contribute to viral epidemics are the time of exposure, demography, mobility, and duration of infection. Each factor is important in the Thailand epidemic. Modernization prompts residents of rural regions to relocate to the major cities to take advantage of educational and economic benefits. The relocation separates them from families and communities which have traditionally helped maintain modes of behavior that potentially reduce the risk of HIV infection (1, 2).
The surveillance program in Thailand is excellent. Three decades of collaboration between the Thai and the United States military has established a monitoring system for any infectious disease in the region. Serum samples are taken from all prospective Thai military recruits and provide a demographic profile and accurate data bank regarding the number of HIV-positive cases. Between 1987 and 1990, there was a significant increase in HIV-positive cases among intravenous drug users (IVDU), from 0.2% to 32%. In the same period, cases among commercial sex workers rose from 1% to 40% (2, 3, 4) .
A new strain of virus was isolated, clade E, in Chiang Mai (4,5). The prevalent clade E is divergent from the clade B, common among AIDS patients in North America. This point is important because the first cases of HIV infection in Bangkok were clade B and the first stages of clinical safety trials used a recombinant DNA vaccine for clade B. The vaccine generates only the outer glycoprotein, gp120, of the virus, without any other viral components. Three doses of vaccine were given over a six month period with subsequent tests for antibody production. Among 36 vaccine recipients, the majority produced antibody to clade B. The candidates were offered education about how to prevent future exposure and placed in the trial after signing an informed consent document, which one virologist described as grequired.h Blood tests of a few volunteers in the vaccinated cohort showed antibody to clade E and subsequent tests revealed that they were infected, not from the vaccine, but from subsequent exposure through either heterosexual intercourse with an infected person or intravenous drug use. These preliminary data indicated that antibody to clade B alone would not offer solid protection to persons exposed to clade E through personal communication. Therefore, it was necessary to defer further scheduled clinical trials while the vaccine producer modified the vaccine to include clade E. Plans to proceed with clinical trials using gp120 B/E are the subject of scientific and ethical debate.
The scientific paradigm of vaccine strategy rests on the ability to mimic the actual virus in order to stimulate an immune response that will protect against future exposure to the infectious agent. The polio vaccine created by Albert Sabin was an attenuated form of the virus that caused a mild infection in order to stimulate a full immune response (6). The earlier vaccine produced by Jonas Salk was a killed virus preparation (7). The Salk and Sabin vaccines are both in current use in WHO efforts to eliminate polio globally by the year 2000 (8).
There are several points derived from the experience with polio vaccines that are worthy of consideration. The vaccine clinical trials established safety and efficacy and 99.9% of those vaccinated are resistant to virulent poliovirus infection. The vaccine strategy satisfied stringent scientific principles when they were first constructed, but these may not satisfy current regulatory reviews (7). The risk-benefit ratio remains in favor of the vaccine (8). However, after thirty to forty years of use, cases of polio still occur throughout the world; total eradication has not been achieved. A better vaccine could be created with modern technology that has less risk of mutation, but it would be expensive to produce and distribute in remote areas (7).
Hypothetically, educating people to sterilize all water prior to use would have drastically reduced the threat of poliomyelitis because the source of most infections was poliovirus consumed in fecal contaminated water. This was not a practical solution. Likewise, preventive education is an intermediate solution to the AIDS epidemic. A large number of people know how HIV is transmitted and how to avoid infection, yet the statistics of the epidemic reveal the difference between knowledge and action. The potential protective scientific merit of the proposed vaccine deserves careful consideration. The presence of antibody to the surface antigen (gp120) alone may be insufficient to protect against future exposure to live virus. The only certain way to know for sure is evaluation in clinical trials. Scientific data show that persons with HIV infection continue to produce virus for years after antibody is present (9). Progression from HIV infection to AIDS is a direct consequence of virus replication within cells of the immune system, with concurrent loss of immune function that makes the person vulnerable to a wide range of opportunistic pathogens causing death. A vaccine that induces antibody to only one of the viral proteins may fail to protect the individual from subsequent infection and progression to AIDS. These concerns formed the basis of the Food and Drug Administrationfs (FDA) refused to extend the human clinical trials to phase III in the United States with the gp120 recombinant vaccine that is being planned in Thailand.
What ethical standard or principle will satisfy the world community that the HIV vaccine OUGHT or OUGHT NOT be used in Thailand? The Respect for Persons ethical standard is based on the philosophical merit ascribed to individual human dignity and equality of persons. The dictum is that no individual can be treated as a means to an end, nor can one person act in a way that all others ought not act. The conversation in bioethics across cultures faces the challenge that these words carry differential weight and meaning in different contexts. The priority of the family unit may be roughly equivalent to the individual in the Thai or American context, respectively. Attempts to evaluate the vaccine test proposed for Thailand by this standard requires a careful consideration of the place of the individual within the society, the values of Thai culture, and the meaning of equality. The principles of autonomy, beneficence, nonmaleficence, and justice have been used to justify actions that are not evident through reasoned analysis of a standard. Perhaps this is an admission that the proposed action is in need for greater reflection.
Autonomy (Greek gselfh + glawh) understands the moral imperative as the moral agentfs own freely and rationally adopted moral policy. According to Kant, persons as moral agents are subject to the moral law, but repudiate maxims which gcannot accord with the willfs own enactment of universal lawh (10). The Respect for Persons moral imperative is based on the centrality of the dignity of each human being. The principle of autonomy is a principle derived from the maxim but diluted significantly in American culture by the value placed on individualism. Autonomous moral maturity crucially involves the recognition of individual choice and freedom to act in accordance with personal resolution and commitment.
What autonomy means in the more pragmatic arena of clinical medicine is radically different. The importance of the informed consent document as a contract between patient and physician is derived from the autonomy principle. Informed consent implies that those individuals who are recruited, educated, and chosen for clinical trials with the putative HIV vaccine understand the risk and potential benefit of the vaccine. It is necessary to discern whether the average Thai citizen is acting autonomously, as free and rational moral agents, or on the belief that prior vaccine approval by doctors, professors, and government officials constitutes a substituted judgment upon which the individual acts. If the recipients of the vaccine act in such a way as to avoid future exposure to the virus, the scientific evaluation of the vaccine would be impossible. Therefore, it is assumed that some percentage of these people will risk future exposure to HIV infection, and it is through this autonomy that the vaccinefs efficacy will be evaluated. Are Thais more likely to respond favorably to medical authorities who offer the vaccine or to reject such an offer? The Buddhist tradition and Thai culture promote society over individualism. Self-determination arises in respect to the responsibility for onefs self and for actions done or left undone that affect future incarnations. Overcoming desires that cause suffering are strong psychological and cognitive influences. Thailanders place a strong emphasis on national and social harmony. These cultural factors make it difficult to evaluate the value of informed consent in the context of autonomy. Socioeconomic, religious, political, and educational factors are instrumental in shaping individual reason (11). How many of these factors will influence the validity of informed consent for vaccine trial participants and the decision of government and health care officials to conduct the clinical trial?
The AIDS epidemic has motivated federal agencies such as the FDA to relax guidelines in order to hasten development and access to drugs and vaccines. These changes in policy represent a radical departure from the guardian standards of the past and raise concerns about whether these relaxed standards will result in excessive risks regarding safety and futile remedies being marketed to the desperate. The risk is justified on the theory that any drug or therapy, whatever the risk, is better than no treatment option at all. A balance is needed between vigilance for safety and promotion of patientsf welfare and rights (12).
The Hippocratic Oath essentially assumes that both the doctor and the patient are committed to a desire for wellness, that the doctor will act in the best interest of the patient on the maxim of gdo no harm.h The Nuremberg Code extends the command to consider a relationship between the doctor and patient that is based on mutual competence and consent. The doctor and patient form a partnership in which it is assumed that each partner is competent, the doctor in the practice of medicine that promotes the health and well-being of the patient, and the patient who is free and competent to decide whether or not the proposed treatment is acceptable to him or her. It is here that the argument becomes complex and often flawed. The facts about HIV and AIDS relevant to the proposed vaccine are complicated and masked in scientific and medical jargon. A person who does not understand the procedures and risks proposed is not informed sufficiently to be truly autonomous. In such conditions, the document of informed consent asserts a freedom that may not be valid.
The AIDS pandemic is large, frightening, and expensive. The resources necessary to care for HIV-infected persons as they progress into the terminal stages of AIDS are limited. Anti-viral drugs that reduce the vertical transmission of virus from mother to newborn are costly. Thailand, as a case study, can anticipate 100,000 deaths each year beginning in the year 2000 if the progression of HIV infection to AIDS continues on the present trajectory. Economically these facts predict a 10% loss in workforce annually (1-4). What action should the government and the Ministry of Public Health (MOPH) take on behalf of the country?
It has been said that the principles of justice and autonomy conflict when the will and rights of individuals are contrasted with those of the society. The competition becomes evident when individuals demand and receive expensive treatments that consume resources that could be allocated differently. It is easy to assert that helping those who can purchase expensive medicines is an exercise of freedom. Distributive justice, according to Rawls prescribes a way to determine which recipients get specific benefits and/or burdens. Justice would prescribe a minimal level of care for all persons and allow the fortunate, individually, to elect to purchase more (13). Justice, in the most practical sense, means availability of resources to develop new cures and treatments, health care access that is fair and equitable. The position of health care within the context of social justice is one that requires wisdom about which choices are offered among all the potential choices that exist (14). Recent scholarship about futile treatments is an important example. Can a futile treatment be an individual right? Can it be demanded by a patient or denied by a doctor? Is it a form of false hope to the patient to offer a treatment that has little or no proven scientific merit? The principle of justice would invite wider public debate about the limits of costworthy care (15).
The values of a culture ought to be factored into a justice formula for a decision like the vaccine trial in Bangkok. The truth is simple: one cannot choose what does not exist. Individuals who agree to participate in a vaccine trial can only be free to do so if the trial exists. Whether national resources ought to be invested in purchasing the vaccine and offering such a choice should rest on the principle of justice applied to the allocation of resources. It will be necessary to decide if the distribution should be to each person according to an equal share, need, effort, merit, contribution, or some other criterion. The presumption lies in favor of treating persons equally in distributive matters, unless some relevant difference can be specified to distinguish persons treated unequally, but there is no universal criterion for ascribing equality. Constructing a justification to conduct the AIDS vaccine trial will require a carefully weighted argument that considers potential risks and benefits, cost of the vaccine in contrast to anti-viral drugs, and/or creation of more AIDS terminal care facilities as competing and compelling claims on national resources.
Respect for individual human dignity is central to the thesis of what is good in the action proposed. Helping a person because they are human is the objective. Beneficence stresses the importance of preventing and eliminating harm. However, help that is forced, coerced, or conditional constitutes harm from the perspective of human dignity. Further, it is the human being who is the recipient of the good, the direct or indirect benefactor. Therefore, informed consent and the availability of a vaccine trial in Thailand ought to be weighed according to how reasonable the expectation is that harm will be eliminated and those at risk of HIV infection helped. The scientific merit is important to this point. If the production of antibody to gp120 is insufficient to produce protective immunity, then the recipients may be deceived in how they understand the value of the gvaccine.h Furthermore, if the risk behavior is assumed as a part of the vaccine evaluation strategy, it is essential that the most efficacious product be used. Otherwise, the beneficent principle that asserts an obligation to help others, confer benefits, and prevent and remove harm would be negated. This principle stresses the importance of considering the probable chance of success of the proposed vaccine trial and then balancing the potential benefits against its probable costs and risks. The proportionality between the benefit and harm is unchallenged in biomedicine, as promotion of the welfare of patients is the goal of medicine and therapeutic research. Progress in medicine requires risks when therapies are experimental and uncertain. Peter Singer contends that gif it is in our power to prevent something bad from happening, without thereby sacrificing anything of comparable moral importance, we ought, morally to do ith (16). The argument could be made that creation of an effective HIV vaccine would prevent harm and promote what is good. The Hippocratic Oath presents the principle of beneficence as the core value in medicine: gAs to disease, make a habit of two things - to help, or at least to do no harmh (17). The primacy of beneficence, usually understood to include nonmaleficence, in medical ethics may tempt some physicians to adopt a paternalistic stance in advising patients about treatments and opportunities to participate in experimental therapies. The physician may have the advantage in understanding the scientific merits of the proposed treatment and ought to carefully communicate the risks and benefits to the patient, who should ultimately decide.
The Buddhist emphasis on compassion has inspired the development of hospice facilities that provide traditional and nontraditional medicine for those in the terminal stages of AIDS. Likewise, many non-governmental-organizations (NGOs), provide anti-viral drugs and care for those dying of the disease. Both are clear illustrations of beneficence. The scientific level of confidence that this particular vaccine will provide protection against future virus exposure is limited. If, however, the recipients develop a false sense of security because they think they are protected with a vaccine and thereby increase their risk of HIV infection, it would be harmful to offer the trial to them. Likewise, it would be harmful to exclude persons on the basis that they might risk future exposure. The selection of candidates for the clinical trial is based on the assumption that some of those vaccinated will risk future exposure to the virus. The knowledge needed to avoid exposure is offered to all participants. If everyone followed these safety precautions, they would not contract HIV, nor would scientists be able to determine whether or not the vaccine is effective. However, the good intended in offering the vaccine is the potential protection of the recipients against future infection and it is possible that the epidemic is so serious that any effort to help is better than doing nothing. It may be that government officials will decide that they must offer the vaccine even if only a few people are protected. There are other options of beneficent action the government might consider, such as increasing funding to achieve wider preventive education, purchasing more anti-viral drugs for pregnant women to reduce HIV transmission to newborns, and building additional AIDS hospice facilities for those who need them. The question is: will the principles of justice, autonomy, and beneficence be supported most by proceeding with the recombinant DNA gp120 vaccine or by waiting for future developments from the scientific community?
The evaluation of the risks and benefits of the proposed vaccine trial creates a vivid example for evaluating the four ethical principles of nonmaleficence, beneficence, autonomy, and justice as supporting principles but also shows how carefully the merits of the proposed action ought to be debated (18). There is uncertainty and much debate about the usefulness of a principle-based ethical assessment of cases such as the AIDS epidemic in Thailand. The authors of this paper consider it more risky to abandon them without a morally preferable alternative. Further analysis is required to eradicate the difficulties of putting abstract principles into practice in particular cases or reducing the conflicts between and among the lexical order of principles. Until a universal, pluralistic moral imperative is constructed, the reflective lens of justice, beneficence, and autonomy offers ethical criteria for the formulation of public policies. A person simply ought not be used as a means to an end, yet only by trial in human populations can the true merit of a new vaccine be determined. Whereas the scientific merit in support of this vaccine would be enhanced by a strategy that induced both humoral and cell-mediated immunity (sterile immunity), there is no reason to reject the proposed clinical trial in hopes of achieving partial protection through antibody mediation. The ethical assessment represents a few conceptual issues that confront all who search for the good action in the midst of human tragedy.
Ann Boyd gratefully acknowledges Hood College Beneficial Hodson Trust for a Sabbatical Fellowship, the United Church Board for Christian Education in Southeast Asia, and the administration and faculty at Mahidol University, Bangkok, Thailand.
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