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JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology And Social Science

Challenges to Conducting HIV Preventative Vaccine Trials With Adolescents

McClure, Cori A.*; Gray, Glenda MD†; Rybczyk, G. Kyle MSN, FNP*; Wright, Peter F. MD*

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From *Vanderbilt University Department of Pediatrics, Nashville, TN, and †Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa.

Received for publication October 16, 2003; accepted October 31, 2003.

Supported by a student intern award from the Elizabeth Glaser Pediatric AIDS Foundation (to C.M.) and by grants from the NIAID to the HIV Vaccine Trials Network Units at Vanderbilt University (5UO1AI047985) and the University of the Witwatersrand (5UOAI048013).

Presented in part at the 14th International Conference on AIDS, Barcelona, July 7–12, 2002.

Reprints: Cori A. McClure, Vanderbilt University Department of Pediatrics, Nashville, TN (e-mail: cori.mcclure@mcmail.vanderbilt.edu or peter.wright@vanderbilt.edu).

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Abstract

It is estimated that 10.3 million people aged 15–24 are living with HIV infection/AIDS worldwide, with 7000 new infections occurring each day. Many of these infections occur during the adolescent years. These rates of infection make adolescents an important target for research in primary prevention. Currently, preparations are under way by the National Institutes of Health–supported HIV networks—the Adolescent Trials Network, the Pediatric AIDS Clinical Trials Group, and the HIV Vaccines Trials Network—for phase 1/2 HIV vaccine trials involving adolescents in the United States. Identifying the challenges to conducting HIV vaccine trials with this population is a crucial component of these preparations. Challenges to HIV vaccine trials with adolescents were identified by reviewing previous vaccine research for adolescents and HIV infection in adolescents and speaking with experts in HIV/AIDS and adolescent medicine. Adolescents (typically those younger than 18 years of age) are minors and fall under ethical and regulatory safeguards for their participation in clinical research including parental permission. Adolescents may not appropriately perceive personal risk, posing challenges for informed consent as well as prevention counseling during a trial. Safety and immunogenicity studies of adolescents are likely to be required by the US Food and Drug Administration before vaccine approval for this population. Early identification and subsequent follow-up of high-risk adolescents are problematic. Vaccine-induced seropositivity may present potential barriers to military service, employment, marriage, and acquiring health insurance. The age at optimal immunization, particularly for girls in some countries, may be during preadolescence. The successful completion of HIV vaccine trials with adolescents must address these challenges both in the United States and internationally. This report addresses relevant background information, identifies the issues surrounding HIV vaccine trials with adolescents, discusses what progress has been made, and addresses plans and implications for the implementation of these trials.

Since 1988, candidate HIV vaccines have been studied in phase 1/2 trials involving healthy adult volunteers 1 and more recently infants 2 and pregnant women. 3 In contrast, no HIV vaccines have been evaluated with adolescents. Promising new vaccines continue to be developed and enter clinical trials, and it is likely that in the next few years large-scale efficacy evaluations of HIV vaccines will be instituted. In any discussion about the eventual widespread use of an HIV vaccine and the characteristics of the ideal recipient population, it is clear that an effective vaccine must be targeted to the adolescent population, particularly in developing countries. Vaccinating adolescents before the onset of behavior that puts them at risk for HIV infection will be one of the most effective ways to curb the global HIV epidemic. The use of a vaccine for this population requires clinical trials including adolescents to determine the vaccine's safety and immunogenicity, because the US Food and Drug Administration and international licensing agencies will likely only license the vaccine for use in age groups in whom the vaccine has been evaluated. In developing countries, the adolescent group may be a target for efficacy trials as well, because of the rapidly accumulating risk in this age group.

Many significant obstacles must be addressed to successfully complete HIV vaccine trials with adolescents. Some of these are specific to the challenge of adolescent HIV vaccine trials, while others are common to all research involving adolescent subjects. Unfortunately, the unique challenges presented by including adolescents as research subjects often lead to their exclusion from clinical research. Treatments and interventions used in this group are usually extrapolated from studies performed with children or adults. 4 Many national committees and panels have recognized the lack of research involving adolescents and have urged that more research be conducted in this age group. This would enable interventions targeted to adolescents to be focused to the particular needs of this group. 4

Many of the special issues regarding HIV and youth have been reported by the Office of National Aids Policy 5 and by Rogers. 6 By speaking with experts in the fields of adolescent medicine and HIV and reviewing efforts to initiate HIV vaccine trials with adolescents, a set of challenges to HIV vaccine trials with adolescents has been identified. Clinical and operational research that identifies how to overcome these challenges will be necessary before beginning adolescent vaccine trials.

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HIV RISK IN ADOLESCENTS

Both within the United States and internationally, the rate of acquisition of HIV infection among adolescents is steadily increasing. This makes adolescents an important target for an array of primary prevention efforts, including, when an effective vaccine is available, vaccination of HIV-seronegative individuals as they enter the risk period for acquisition of HIV infection. HIV infection in young people between the ages of 13 and 24 comprised 16% of all new HIV infections in the United States between July 1999 and June 2000. 7 Another report estimated that ~1 in 4 people who are HIV positive acquired their infection before the age of 22. 5 Moreover, because of the average 10-year period between HIV infection and the onset of AIDS, it can be assumed that many of the AIDS cases in 20- to 29-year-olds result from HIV infection acquired in adolescence. 8 Internationally, the HIV epidemic in adolescents is an even greater problem. Each day, 7000 young people between the ages of 15 and 24 acquire HIV infection worldwide, resulting in 2.6 million new infections per year; 1.7 million of these infections occur in Africa. 9

The risk of HIV infection differs in adolescents depending on their behaviors. The prevalence of intravenous drug use, anal intercourse, and vaginal intercourse varies within adolescent subgroups, but most HIV infections in adolescents are heterosexually acquired. 10 The percentage of American high school students who have ever had sexual intercourse steadily increases from 9th to 12th grade, with 34.4% of 9th graders and 60.5% of 12th grade students having engaged in sexual intercourse. 11 Although risk behavior has decreased somewhat in the last decade, 12 initiation of sexual intercourse is not uncommon before the age of 13, with 4.7% of whites, 7.6% of Hispanics, and 16.3% of blacks reporting such activity. 11 Minority adolescents are at much greater risk for HIV infection. Data from the state of Tennessee show that 82% of identified cases of HIV infection in 13- to 19-year-old females and 76% of identified cases of HIV infection in 13- to 19-year-old males are in blacks (unpublished data, Michael Kinzer, 2002). Because black and Hispanic adolescents are more likely to engage in early sexual activity and because the prevalence of HIV infection is often higher in their social networks, AIDS rates among these adolescents are significantly greater than those found among white adolescents. 11

Sexual encounters in adolescents are frequently unprotected, with 58% of adolescents reporting condom use with their most recent sexual encounter. Pregnancy rates represent a marker of unprotected sex, and 4.7% of high school students report that they have been pregnant or gotten someone pregnant. 11

These problems are not unique to the United States. South Africa has the largest and fastest growing HIV/AIDS epidemic in sub-Saharan Africa. In 2000, it was estimated that 4.7 million South Africans between the ages of 15 and 49 were HIV infected. 13 In South Africa, research shows that although knowledge of HIV/AIDS among adolescents is good, many engage in “high-risk” sexual behavior because they do not perceive themselves to be at risk for acquiring HIV infection. In a study of young urban black youth aged 16–20, it was found that 40% of young women and 60% of young men had had >1 sexual partner in the previous 6 months and that condom use was relatively low. 14 Various studies conducted in South Africa have shown that adolescents commence sexual activity at a young age. 15 In a study conducted in a rural area in the southeastern part of South Africa where the mean ages of girls and boys were 15 and 16 years, respectively, 76% of the girls and 91% of the boys were sexually active. 14,15 Boys were found to initiate sexual activity at an earlier age than girls (13.4 vs. 14.9 years, respectively), to have more partners, and to have nearly twice as many sexually transmitted diseases. 15 Findings from a study in the northern province of South Africa, which conducted interviews with 900 adolescents aged 16–20 and focus group discussions in 9 schools, indicated that many adolescents are sexually active by 15 years of age, with some reporting up to 7 sexual partners. 16

In South Africa, despite the greater prevalence of early sexual activity by males, women are more likely to be infected with HIV at a younger age than men are. It is estimated that by 2010 50% of all infections in women will have occurred before the age of 20 (Fig. 1). This has been attributed to transgenerational sex with young girls who engage in transactional sex. The exchange of sex can occur as a means of daily survival or for cell phones and fashionable clothes between “sugar daddies” or older men and schoolgirls. 17

Figure 1
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Moreover, adolescent girls in South Africa commonly experience rape, violence, and assault. 18 Even within relationships, girls are often forced to have sex against their will 19 and feel unable to refuse sex or to discuss safe sex, including contraception or condom use, because of fear of violence. Young men in South Africa feel justified in committing rape because of the perception that young girls have sex with older men for material gain. 20

The risk of HIV acquisition with each unprotected sexual encounter increases with a population's overall seroprevalence in both developed and developing countries. However, the dynamics of acquisition of HIV infection described above for adolescent women in some developing countries demonstrate girls must be special targets for prevention.

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LEARNING FROM ROUTINE ADOLESCENT IMMUNIZATION

The literature on vaccine research conducted with adolescents was reviewed with a focus on the prior targeting of rubella virus and hepatitis B vaccines for adolescents. In the United Kingdom, selective rubella vaccination of 11- to 14-year-old girls was introduced in 1970. Overall, 90% of schoolgirls were vaccinated, and although the circulation of rubella was not interrupted, the incidence of congenital rubella syndrome decreased by 75%. 21 Significantly, however, ~15% of children refused vaccination. 22 Eventually, an early childhood vaccination program for all children was adopted in the United Kingdom.

Hepatitis B vaccination is currently strongly recommended for all US adolescents and in some states is required for 7th grade entry. 23 Risk factors for not initiating or completing vaccination schedules are predictably some of the same risk factors that increase HIV exposure, and adolescents are currently a group with low coverage of hepatitis B immunization. 24 However, with intensive follow-up, hepatitis B immunization can be successfully completed in a high-risk cohort. 25

Immunologic maturation is complete by adolescence; therefore, adolescent responses to vaccines would be expected to be equal or superior to those of older adults. 26 In fact, studies that have looked at developmental differences in immune responses suggest that in a few instances adolescents may respond better to vaccination than children or adults. For example, the immunogenicity of hepatitis B vaccine has been extensively evaluated in adolescents, with the conclusion that in this age group 2 doses of some vaccine preparations will achieve a protective titer when compared with the traditional 3 doses. 27

Clinical vaccine safety may differ by age. For example, studies of side effects of rubella vaccination found much higher rates of arthropathy and arthritis among older children and adults than among young children. 28 A number of clinical infections (eg, varicella and measles) are more severe in older children and adults than in early childhood. Thus, adolescent phase 1/2 trials can play an important role in illustrating whether responses will differ from the adult experience for candidate HIV vaccines.

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LEGAL ISSUES IN CONDUCTING RESEARCH WITH ADOLESCENT SUBJECTS

Adolescents are minors under the law and therefore fall under special regulatory safeguards that govern the approval of research with minors by institutional review boards. 29 As stated in the Code of Federal Regulations, “‘children’ are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.” 30 It is likely that institutional review boards will place adolescent HIV trials in Category II of the US Department of Health and Human Services 45 CFR 46, Subpart D (46.405), which describes “research involving greater than minimal risk, but presenting the prospect of a direct benefit to an individual subject.” 29 Parental permission must be obtained for research in this category. In addition, the assent of the child or minor if older than 7 years of age is also required, provided the child is capable of assenting. Adolescents without parents or guardians present in their lives will likely be ineligible for the studies, which may prevent access to certain high-risk populations, such as homeless teenagers. Some states have laws that allow adolescents to obtain legal status as mature or emancipated minors based on their social situations. For example, in certain states, girls younger than 18 years of age who have their own children are considered mature minors and are able to provide their own consent (personal communication, J. Lynn Randle, Institutional Review Board Compliance Officer, Vanderbilt University Medical Center, 2001).

Although adolescents often may seek contraception and treatment of sexually transmitted diseases without parental permission, these laws typically do not allow teens to consent independently to research in this area. Thus, although many studies have illustrated the ability of minors to make decisions similar to adults in both process and consequence, it is still unlikely that adolescents will be allowed to participate in HIV vaccine trials without parental permission. 31

In South Africa, research can only occur with children and adolescents if the research does not place them at greater than minimal risk. If the research involves more than minimal risk, it should provide direct benefit for the child or adolescent or should provide “generalizable knowledge about the subject's disorder or condition.” In all cases of research with children and adolescents, the South African guidelines state that both parents need to be involved in the informed consent process if the research involves greater than minimal risks.

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ETHICS OF CONDUCTING RESEARCH WITH ADOLESCENT SUBJECTS

Informed consent is intrinsically tied to the understanding of research. Although it has been demonstrated that both adolescents and adults commonly fail to comprehend all the implications of participating in research, 32,33 adolescents pose a particular problem because of the unique guardian–child decision-making dynamic. An adolescent's right to autonomy in decision making must be respected unless the situation warrants the extra protection afforded by their guardians. As an example, the Vanderbilt Committee for the Protection of Human Subjects believed it was necessary that parents of 16- to 17-year-old females be informed that their daughter's participation in a vaccine trial of a human papillomavirus vaccine was predicated on her being sexually active.

Postconsent testing may provide verification of an adolescent participant's understanding of a study. One study completed postconsent testing of children and adolescents participating in research and found that they best understand concrete elements of research, such as duration of the study and benefits to themselves. 32 However, the children and adolescents tested had difficulty understanding abstract issues, including purpose of the study, benefit to others, and alternative treatments. This may stem from an inability to place their participation in context because of a lack of life experience.

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OPERATIONAL ISSUES IN CONDUCTING RESEARCH WITH ADOLESCENT SUBJECTS

Common to all adolescent research are the joint barriers of recruitment and retention of adolescent subjects. Developing research and clinic sites that are friendly, attractive, and accessible to adolescents can be crucial in overcoming the challenges of recruiting and retaining adolescent subjects. The key components of such sites have been described for adolescent HIV testing and counseling services. 34 The site must be comfortable, and adolescents must be able to feel at ease during their visits. The site location must be accessible for adolescents, and concerns such as public transportation and hours of operation must be addressed. In addition, the degree of privacy and the ability of the site to maintain confidentiality will be crucial to retention of adolescent subjects. Finally, counseling must be appropriate for adolescent social and emotional development.

Recruitment of adolescent subjects may also be enhanced by working with adolescent consultants to devise strategies for targeting adolescents for enrollment in clinical research. In a study on accessing adolescents and their families for research, peer adolescent consultants advised the investigators on how best to focus recruitment materials to the adolescent population. 35 The consultants were a key resource in the elaboration of presentation and advertising strategies to increase the willingness of targeted adolescents to participate. Peer review also aided in adapting wording of assent documents to adolescents' comprehension levels.

Recruitment and retention may also suffer from the reluctance of adolescents to undergo physical pain during a research study. A survey assessing the attitudes of female adolescents toward human papillomavirus vaccination found that <30% of girls interviewed would participate in a vaccine trial that required 3 vaccinations and 6 pelvic examinations over 3 years. 36 The vaccinations and the examinations were cited as equal deterrents to participation.

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CONDUCTING HIV VACCINE RESEARCH WITH ADOLESCENT SUBJECTS—PHASE 1/2 TRIALS

Although the issues involved with adolescent research are significant, the obstacles specific to adolescent HIV vaccine trials present even greater challenges. Often the very circumstances that make adolescents at risk for contracting HIV infection also make it difficult to contact them. These include social factors such as homelessness, incarceration, sexual and physical abuse, and drug use. 6 A study of difficult life circumstances in HIV-positive youth found that these adolescents experienced much higher rates of these social problems than HIV-negative controls. 37 As with adults, those with the greatest need for the vaccine are often the hardest to include in trials. In addition, vaccine trials by nature require lengthy follow-up, but adolescents are a mobile population, many of whom will be leaving their childhood homes.

Minority adolescents present an additional set of challenges. A high level of distrust in governmentally or pharmaceutically sponsored activities often accompanies research in minority communities. The acceptance of and community support for HIV vaccine trials demand full involvement of local community leaders. This will be even more essential in adolescent trials. The infrastructure and procedures developed for these trials will be used for other prevention interventions; therefore, the process of preparing for and conducting adolescent HIV vaccine trials is an investment in the future.

It is important to address adolescent and parental concerns about the social implications of participating in a vaccine trial as well as potential poststudy vaccine-induced seropositivity. These implications may be viewed negatively and will likely be deterrents to participation. Parental concerns will differ from those of their children in some respects. As guardians, they can be expected to wonder about the future risk behavior of their children and whether they should rely on a possible protective effect of participation. The presence of antibodies to HIV has implications in settings where such screening is done. Vaccine-induced seropositivity may be even more of a problem in adolescents, because they are unlikely to have health insurance of their own at this age and HIV testing frequently accompanies insurance applications. In addition, in a few years, they may seek employment or enter the military, and vaccine-induced seropositivity may hinder those opportunities. A lack of a universally available specific test to verify vaccine-induced seropositivity short of detection of viral genome by molecular mechanisms will be a concern to all trial participants, not just adolescents and their parents. Such a test will also be needed should later high-risk behavior result in true infection.

In addition, HIV vaccine trials, as with any new vaccine, will use unlicensed US Food and Drug Administration–reviewed products with incompletely defined side effects and will be placebo controlled. This will be a probable source of parental and volunteer concern. The combination of a new vaccine candidate with the stigma and fear that often accompanies any mention of HIV/AIDS may be a strong disincentive to trial participation and will need to be addressed through education before, during, and after the trials.

Moreover, the problem of identifying and enrolling high-risk adolescents in HIV vaccine trials will be significant. In phase 1/2 studies designed to test safety and immunogenicity, it is likely that both low-risk and high-risk adolescents would be invited to participate. There would be exclusion criteria that would render some willing subjects ineligible for participation, but low-risk and high-risk behaviors would not need to be revealed for the studies to be valid.

Although all of these concerns may complicate recruitment and retention of adolescents, the results of several recent studies show that HIV infection and/or AIDS is a leading concern among teenage girls and that high levels of retention in adolescent studies involving extended, invasive procedures are possible. The human papillomavirus vaccine study noted that most female adolescents interviewed (87%) feared AIDS most of 5 potentially adverse outcomes to sexual activity. 36 The REACH (Reaching for Excellence in Adolescent Care and Health) Project 38 enrolled 496 adolescents, including HIV-positive and HIV-negative adolescents, between the ages of 12 and 18. This study, designed as an observational investigation to provide a better understanding of HIV disease progression in adolescents, required quarterly blood sampling and physical examinations, biannual gynecologic and urogenital examinations, annual anal examinations for males and females, computer-assisted interviews, and nurse interviews and had an average annual retention rate of 90%. Encouragingly, many of these adolescent volunteers indicated interest in participating in an HIV vaccine trial. 6

In January 2001, National Institutes of Health researchers of vaccines and HIV infection in adolescents met with members of community organizations and researchers from other institutions to explore the potential involvement of adolescents in HIV vaccine trials. 6 This group identified important barriers to conducting vaccine trials with the adolescent population and discussed the characteristics of a successful HIV vaccine trial. Particular emphasis was placed on partnership building and collaboration with minority communities in these efforts. The barriers discussed included the realities faced by at-risk youth and the obstacles those circumstances present to participation in vaccine studies, the legal status of adolescents as minors and the need for parental permission for vaccine trial participation, the developmental state of adolescent cognition and emotion, and the lack of necessary infrastructure. The group then identified some broad methods for overcoming these barriers.

The characteristics of a successful adolescent HIV vaccine trial identified by this group included the use of youth language and peer education, the restoration of faith in the medical community, and the establishment of mechanisms for the protection of youth trial participants. According to this group, American youth, particularly ethnic minority youth, are underserved when it comes to health care. Adolescents are often concerned with the lack of respect and disregard of privacy that they find in the health care system. Addressing these obstacles through education, outreach, and infrastructure development will make adolescents more likely to trust researchers and to be willing to participate in HIV vaccine trials.

Parental attitudes will need to be assessed and their fears allayed by these programs. Parents often feel as if they have no control over their children's lives and alienated from youth culture. Because parental permission will be required for adolescents to participate in HIV vaccine trials, attitudes of parents toward their child's risk and toward the research itself need to be addressed. 6

Some discussion of minority communities elicited important obstacles to including those communities in the vaccine trials. The group emphasized educating minority groups about research and protection for volunteers, as well as investing in community-based organizations and representative minority investigators. Many of these communities are already wary of researchers and of health care institutions. A comprehensive community education program is necessary to address the mistrust minority groups have regarding research. 6

Finally, for the efforts to succeed, the group agreed that attention must be given to coordinating the creation of the community infrastructure necessary to support large-scale vaccine trials. Efforts to distribute information to communities will be difficult without the necessary means of contacting those at risk and those who would be willing to participate. The Adolescent Trials Network is one organization that has begun to lay the groundwork for HIV vaccine trials in selected cities building on the experiences of the REACH Project. A starting place will be the conduct of hepatitis B vaccine trials in high-risk groups.

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CONDUCTING HIV VACCINE RESEARCH WITH ADOLESCENTS—PHASE 3 TRIALS IN THE UNITED STATES

If phase 3 trials (efficacy trials) are attempted with adolescents, high-risk adolescents must be identified and their risk must be defined. Such a study is powered on the acquisition of HIV infection in spite of optimal counseling. It is probable that an adolescent group would not be sufficiently powered to provide a unique measure of efficacy in this age range but that enrollment would be permissive and attempt to include sufficient subjects to provide a solid safety and immunologic profile from which to bridge to the study as a whole. Strategies must be incorporated that address the issues of admitting to individual high-risk behavior, because such admissions may handicap the adolescent's willingness to enroll. Parental reactions to such admissions may be more complex. Some parents, informed of the factors that have made their children eligible for the trials, may be unwilling to permit their children's participation. Others, fully aware of the situation, may embrace the trial as a means to decrease the risk to their child. Parental concern over the high-risk behaviors of their children and adolescent concerns about privacy will be important issues to address.

An alternative to a classic efficacy trial in which individuals are enrolled based on risk behavior is the identification of high-risk cohorts defined demographically for study participation. Although costly, this may decrease parental concern and the political and ethical barriers to trials, because individual behaviors would no longer be the focus of inclusion or exclusion. Yet, a third possibility is to forego efficacy trials with adolescents in the United States and conduct only phase 1/2 trials with this population.

The response of communities, parents, and adolescents to phase 1/2 trials will determine the feasibility of phase 3 HIV vaccine studies of adolescents in the United States and give strong clues to the success of an HIV vaccine strategy aimed at this age group. There are currently 2 possible avenues for US Food and Drug Administration approval of an HIV vaccine for adolescents. The vaccine may have to be fully tested with phase 1, 2, and 3 trials including adolescents to obtain US Food and Drug Administration approval. Alternatively, it is suggested that a good comparison of immunity and safety between adults and adolescents, ideally with a correlate of immunity that is comparable, would obviate the need for phase 3 trials to include this difficult-to-reach population, thus making a large phase 2 trial a bridge to licensure for adolescents. It is unknown at this time whether the US Food and Drug Administration would license the vaccine for adolescents without their participation in an efficacy trial.

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CONDUCTING HIV VACCINE RESEARCH WITH ADOLESCENTS—PHASE 3 IN DEVELOPING COUNTRIES

In less-developed countries, proving efficacy will pose separate challenges. Because rates of infection are so high in certain countries, no selection of high-risk groups would be necessary and studies could be community based, focusing on communities with high seroincidence. An efficacy trial might optimally be carried out with preadolescents in terms of necessary sample size and rapidity of obtaining an answer. However, there are many ethical issues involved in conducting research in such international settings. Ideally, young girls would be targets for vaccination because of their special risk in the dynamics of HIV in developing countries. However, in many less-developed countries, young girls have an unfortunate demographic combination of age, sex, and socioeconomic status that is already highly vulnerable without carrying the stigma of vaccine-induced HIV seropositivity through their childbearing years.

Internationally, the UNAIDS program has noted that more attention needs to be devoted to combating the social stigma of HIV/AIDS within communities. 39 HIV infection and/or AIDS is a condition that is largely feared and scorned because of its association with illicit activities and death. The UNAIDS program has also endorsed the involvement of communities in the implementation of vaccine trials to give them a sense of ownership in the process and results. 39

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APPROACHES TO AN ADOLESCENT TRIAL

The leadership in pediatrics AIDS research is convinced that HIV vaccine trials must proceed for the adolescent age group. To develop successful HIV vaccine trials with adolescents, the recommendations of the Office of National Aids Policy, the National Institutes of Health consensus meeting, and the UNAIDS program and the results of previous studies involving adolescents together form a strong foundation for future action. It will be vital to elicit the support and assistance of organizations that serve adolescents by establishing community contacts. These contacts should include school administrators, adolescent health care specialists, pediatricians, health department officials, and community HIV/AIDS groups. Their support will allow greater access to the adolescent population and to a variety of subgroups. In addition, these organizations will be a crucial component of the widespread community education effort that must be a component of the vaccine trials. This community education should emphasize the importance of the trials and raise public awareness to decrease the fear and stigma that often accompany HIV/AIDS. Education about the trials will be especially important in those minority communities wherein a heightened sense of distrust and suspicion toward health care providers and researchers exists. The contacts made in community organizations will be vital to the success of these education efforts.

Surveys that accurately assess parental attitudes toward HIV vaccine trials with adolescents will be invaluable in implementing such trials. Focus groups of parents may also be used to assess parental concerns. Through such groups, researchers may determine the best way to approach potential adolescent participants and their parents and gain insight into study designs to which parents might be more likely to consent. These interactions will also serve as initial contact between parents and researchers and will demonstrate to parents that researchers value parental concerns.

Surveys and focus groups involving adolescents could assess their willingness to participate in vaccine studies and ascertain the factors that decrease that willingness. Studies to assess adolescent compliance, retention, or behavior changes during vaccine studies would also be valuable. Early research of this nature, as well as parentally focused studies, will give insight into the feasibility of conducting HIV vaccine trials, particularly efficacy trials, with adolescents in the United States.

Before trials can begin, barriers to recruitment must be considered and addressed. Researchers should take full advantage of adolescent consultants' expertise to optimize the processes of contact and recruitment. These consultants should be age-matched peers of potential trial participants and should represent the varied socioeconomic and ethnic backgrounds of target populations. Some potential avenues for recruitment include school assemblies, presentations in school health classes, adolescent-focused community groups, advertisements at local health departments, and television, newspaper, and radio advertisements. To aid in recruitment and retention, efforts should be made to ensure that the vaccine sites are targeted to adolescents, along the lines of adolescent HIV counseling and testing services. The various AIDS treatment and prevention networks have been very successful in maintaining confidentiality over the past 13 years, and successful formulas for guaranteeing participant confidentiality are well established.

Steps should be taken to ensure comprehension of informed consent and to protect adolescent subjects. Postconsent testing of adolescents enrolled in the vaccine trials can contribute to validating the informed consent process. Adolescents who enroll in the trial should also receive comprehensive prevention counseling tailored to their developmental age. This prevention counseling will be focused on helping the adolescent understand common vaccine trial issues, including that these vaccines are unproven, are experimental, and provide no guarantee of protection from HIV infection and the possibility that they received a placebo. Free condoms and counseling will also be available for the adolescents as part of the HIV prevention behavior package.

The choice of which vaccine candidates enter into trials involving adolescents will be critical. Networks are now established that have the capacity and interest in doing such trials. Many of the challenges can be overcome only in the context of performing a trial. We believe that there are now sufficiently promising vaccine candidates becoming available to warrant proceeding to an adolescent trial.

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CONCLUSIONS

The HIV/AIDS pandemic affects all segments of all societies worldwide. The specter of HIV infection looms regardless of age group, and adolescents are no exception. Indeed, public health practice would seem to say that effective vaccination of this subgroup above all would result in the greatest reduction in new infections. Internationally, HIV epidemiology even more urgently demands that every effort be made to include adolescents and even younger children in the early stages of vaccine trials of promising candidates. No vaccine research will be complete, therefore, without embracing trials that include adolescents with all their associated challenges, and although these are significant, the use of a community-based approach of sound partnerships, including in-depth stakeholder education, represents a likely framework for a successful research effort. With specific attention to parental concerns and the special needs of adolescents regarding recruitment, retention, and informed consent, both parents and adolescents should feel comfortable with their role in this essential research. If phase 1/2 trials can demonstrate that there is not a significant difference between adolescent and adult responses to the vaccine, it may even be possible to obtain licensure for adolescent use without conducting phase 3 efficacy trials for the adolescent population.

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ACKNOWLEDGMENTS

The authors thank Audrey Rogers (NICHD, NIH) and Ellen Clayton (Director Genetics and Health Policy Center, Vanderbilt University) for their invaluable discussions.

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Keywords:

HIV; adolescents; vaccines; HIV infection

© 2004 Lippincott Williams & Wilkins, Inc.

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