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The Quest for an HIV Vaccine Between the laboratory and licensure, successful clinical trials are essential to any new HIV vaccine candidate. Generally, such trials allow investigators to administer new interventions (such as a drug or vaccine) and measure their effects under controlled and monitored conditions. Typically, trials are divided into three discrete phases, each defined by a different purpose and size. The preliminary Phase I trials are usually small, used to test a new drug or vaccine's general safety. If results are favorable, larger Phase II trials are conducted, in which the product must stimulate an immune response. In Phase III, the largest of the pre-approval trials, scientists strive to demonstrate efficacy - that the drug or vaccine actually works in preventing the disease.1 Licensure is dependent on positive results in each phase with respect to both safety and efficacy.2 Both lengthy and complex, clinical trials are often the most costly and time-consuming steps in the development of any new pharmaceutical product. This is particularly true for HIV vaccine research. It has been estimated that even in the most optimistic scenario, six to nine years elapse between the start of a Phase I trial for an HIV candidate vaccine and the reaching of its Phase III results.3 While numerous Phase I studies of HIV vaccine candidates have been conducted, very few have progressed to Phases II and III, and none have produced clearly positive results. Causes of Delay in Clinical Trials For those HIV candidate vaccines currently in development, an array of scientific, logistical, political, and economic factors slow progression through Phase III trials.4 In order to test the efficacy of a vaccine, large populations with high incidences of the disease - primarily located in developing countries - are required. Not only are there shortages of appropriate trial sites, but the areas where trials must take place are often economically and politically unstable.5 Meanwhile, developing countries lack the research facilities and staff necessary for the successful coordination of a trial, meaning that trial staff must come from foreign countries. The Global HIV Vaccine Enterprise states that "the acute shortage of qualified personnel is a major bottleneck to the conduct of clinical trials in developing countries with severe or rapidly emerging HIV epidemics."6 The scarcity of local investigators may be due to a lack of sufficient training and/or expertise to undertake the trials or to their commitments to other research projects.7 Additionally, it is widely acknowledged that strong political and community support is vital to conducting clinical trials successfully. Public awareness of AIDS, HIV, and the transmission of infectious diseases is often limited, justifiably, by communities' greater attention to meeting basic needs for survival. Furthermore, international research often proves extremely burdensome for trial communities and participants. Clinical trials impose inconvenience and uncertainty on research subjects. They face possible threats to their health, stigma, and the risk of exploitation.8 For HIV trials in particular, the most common reasons for refraining from enrollment in a vaccine trial include: a fear of side effects from the vaccine, contracting HIV from the vaccine, difficulties with obtaining insurance, and a general distrust of drug companies, the government, researchers, and clinical research.9 Communities as a whole may suffer if research priorities dominate health services. In poverty-stricken areas, scarce health resources can impede research. Scientists may recruit skilled health personnel from community health centers, but once the trial ends, poorer access to care may result from this disruption to the local infrastructure.10 Furthermore, an ethical problem arises when individuals who want to participate in trials are prevented from doing so by the disapproval of their community.11 In areas where clinical trials have already been held, researchers often have great difficulty convincing civic leaders that their communities should again enroll in clinical trials.12 This is understandable given the possibility that these communities may never benefit from their contribution if a product is eventually developed. Such was the case in the development of the hepatitis B vaccine. As journalist Michael Specter reports, "Africans served as essential participants in trials for the principal vaccine now used against hepatitis B; yet when the vaccine finally arrived they could not afford it."13 The Core Issue Time and resources are not the only constraints in this stage of HIV vaccine development. Clinical trials of HIV vaccines have proven particularly controversial. A deceptively simple, one-line description of the third phase, "Phase III generally involves several thousand healthy volunteers at a relatively high risk of HIV infection," instantly gives rise to a multitude of ethical issues. A tension exists between the investigator's dual obligation, one in ensuring that the study is up to the "gold standard" of scientific research through unbiased design and control, and a second to the protection of the trial subjects.14 In order to establish efficacy, new infections must occur among trial participants if the results are to show a difference in incidence between the control and the treatment group.15 A conflict of interest arises between researchers who need to prove efficacy, and trial participants who naturally desire to protect themselves.16 However, research subjects may also be motivated by altruism, expecting no return or personal benefit from their participation. In this case, physicians have a duty to protect the subjects and prevent them from taking undue or excessive risks. Scientists may understandably also wish to minimize risk to study participants, and it has been shown that HIV can be prevented by reductions in high-risk behaviors. However, if this ethical imperative is followed and counseling and contraceptives provided, the study results could be jeopardized. If there is a decrease in the risk and incidence of HIV infection in the entire community, it can be difficult, costly, and time-consuming to determine whether the trial results were due to public health interventions or the efficacy of the vaccine candidate.17 The reality remains that the effectiveness of any experimental vaccine cannot be fully determined unless it is the only variable being tested and administered in the study. Ethical Issues in Enrolling Women and Adolescents Research can often be hampered by the need to enroll certain groups that are difficult to reach or whose involvement raises unique ethical issues. For example, it has been stated that because the number of HIV-infected women is increasing worldwide, "enrolling women in HIV trials... must be fulfilled in order to conduct ethical, valid, and generalizable trials."18 However, this is difficult in areas where women facing social, cultural, or economic constraints and thus lack the freedom to make autonomous decisions, including regarding participation in medical research. Enrollment in a clinical trial, particularly one related to a sexually-transmitted disease, exposes women to a number of social stresses. For example, women may encounter discrimination from their families and from their communities if they are thought--accurately or not--to be infected with HIV. Researchers find other potential barriers to trial participation, including women's fears of contracting HIV from the vaccine, testing positive for antibodies to HIV, the effects of the vaccine on future pregnancies, experiencing difficulty with immigration if they test positive for HIV, and the possibility of receiving a placebo.19 Trial participation may have other negative effects on a woman's social and cultural standing. Trials that require women to refrain from breast-feeding or becoming pregnant are problematic in cultures in which women's fertility has a high social value. In addition, trials may recommend condom usage, perceived in some communities as promoting promiscuity. Lastly, some logistical barriers include time taken away from household duties and childrearing, inconvenient clinic hours for mothers and sex workers, potential job loss, and lack of transportation to the trial site.20 All of these factors may have a significant impact on trial participation, and researchers must weigh the ethical imperatives of enrolling women in trials against exposing them to the varied risks from their partners, families, communities, and the vaccine itself. Another elusive target group for clinical trials is adolescents. As demonstrated by the current experiences with the human papillomavirus (HPV) vaccine, future vaccination strategies for HIV may need to reach adolescents prior to initial sexual activity. As a result, scientists need information on immune responses and disease progression in African adolescents to develop safe and effective vaccines. However, adolescent participation in clinical trials is complicated by the need to obtain parental consent. Researchers have found it difficult and often impossible to obtain parental consent in sub-Saharan Africa. In addition, studies that examine adolescent beliefs and behavior regarding sexuality and recreational drug use may place adolescents at risk from their parents.21 Given that many children now serve as the heads of their households in regions where the epidemic has been particularly devastating, the typical age requirements for parental consent may not be applicable in all parts of the world. Researchers must therefore decide whether it is ethically justifiable to enroll adolescents in HIV research without seeking parental consent.22 International Conflicts A disconnect between foreign and local priorities can lead to accusations of paternalism or exploitation. Ethical dilemmas begin long before the start of clinical trials, when the specific HIV subtypes for vaccine candidates are selected. Developed and developing countries have different priorities for a vaccine depending on which strains are most prevalent in their regions. Since vaccines against certain subtypes may not prevent infection by other subtypes, it makes sense for the strains included in candidate vaccines to be those which are most predominant in the trial population. However, this may prove problematic in some African countries where circulating recombinant forms (CRFs) exist.23 CRFs develop when different subtypes of the HIV virus recombine to create new, infectious hybrid viruses.24 When a developed country enters a developing country to conduct a clinical trial, its actions are closely scrutinized because of the disparities which exist between the home nation of the researchers and the local trial population. If regulatory authorities and institutional review boards (IRBs) are not well developed in host countries, political and economic interests can influence which vaccines proceed in clinical trials. For example, after failing to secure the support of local AIDS researchers, a U.S.-based company offered the former president of South Africa a free license to test its vaccine.25 It is clear that developing countries may be averse to trusting pharmaceutical companies and researchers from sponsoring countries as well as their governments. Lawrence Corey, the principal investigator of the HIV Vaccine Trials Network, has identified another dimension to the situation: "We are asking the Third World to take risks that we have actually never taken ourselves. Every other time that we have gone in with a vaccine - whether polio, measles, mumps - we have been able to say, 'It works on our people.' With AIDS, we can't say that."26 Other sources of concern include differing ethical standards for holding clinical trials. The CIOMS Guidelines (formally the International Ethical Guidelines for Biomedical Research Involving Human Subjects) identify a set of ethical principles for human experimentation. The guidelines state that when research is externally sponsored, it must be reviewed by both the sponsoring and host country.27 This leads to the following question: if the ethical norms and standards of care differ between countries, whose rules prevail - those of the country which has developed the vaccine and is holding the clinical trial, or those of the host country?28 Researchers differ on how to resolve a situation in which the review board of the host country permits the research but the sponsoring nation fails to approve it.29 Despite well-meaning intentions to prevent the exploitation of host countries, the CIOMS Guidelines have at times caused confusion and conflict in the international arena. For example, Guideline 8 recommends that Phase I and II trials should only be conducted in developed communities of the sponsor country. While this specification aims to protect developing countries, recruitment for Phase I and II trials is a time-consuming process and may take over a year to complete, causing frustration among researchers. In their eyes, these ethical standards can be seen as paternalistic and detrimental to the search for an HIV vaccine.30 Conclusion All parties involved in the development and testing of candidate HIV vaccines encounter logistical and ethical challenges during their work. These include resource shortages, barriers to individual and community trial participation, enrolling women and adolescents, proving vaccine efficacy, and upholding ethical standards. The challenges facing researchers and sponsors may seem difficult, if not impossible - accelerating vaccine development while safeguarding the rights and welfare of communities and individuals participating in clinical trials.31 However, researchers in individual countries and international collaborations, such as the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization Initiative for Vaccine Research (WHO/IVR) are already examining these and other important issues.32, 33 Their research and recommendations have the potential to enhance and accelerate the development of an HIV vaccine in a manner sensitive to ethical concerns of subjects and their communities. -- By Jessica Ho, University of Pennsylvania (yjho@sas.upenn.edu); Updated July 2010. Continue to III. HIV Vaccine Clinical Trials: The Standard of Care Debate
1 Specter, Michael. "The Vaccine." The New Yorker 78.45(2003):57. |
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