Enrolling Teens in Trials
Researchers consider the special circumstances of AIDS vaccine clinical trials among adolescents
By Kristen Jill Kresge
As HIV continues to infect millions of people throughout the world, more and more of the newly infected are between the ages of 15 and 24. Young people in this age group now account for 40% of the 4.3 million new HIV infections that occurred globally in 2006. Despite these startling statistics, AIDS vaccines have so far not been tested in adolescent volunteers.
"The epidemic is becoming more youth-driven," says Linda-Gail Bekker of the Desmond Tutu HIV Centre in Cape Town, who is one of several researchers preparing for AIDS vaccine trials involving adolescents in South Africa. Studies show that despite increased efforts to reach adolescents with information about HIV prevention, young people in some communities are having sex and pursuing injection drug use at an earlier age. In the Russian Federation, where injection drug use is fueling the epidemic, 80% of the people with HIV are under 30 years of age. The greatest hope for slowing the spread of HIV is vaccinating young people before they begin engaging in activities that place them at potential risk of infection. But before a preventive AIDS vaccine can be administered to adolescents, researchers must show that it is both safe and effective in this age group, making clinical trials a necessity. This has researchers, vaccine trial sponsors, and regulatory agencies considering the obstacles for evaluating promising AIDS vaccine candidates in adolescent volunteers. "That's our big motivation," says Bekker.
Many organizations are currently working to develop guidelines and protocols that will specifically address the potentially thorny legal, ethical, and regulatory issues that are involved in the conduct of adolescent trials, including the need to protect younger volunteers from stigma and other social harms and ensuring that the concerns of parents are also adequately met. Progress in these areas will help guarantee that an effective AIDS vaccine, when available, will reach both adult and adolescent populations simultaneously and as quickly as possible, offering the greatest chance for curbing the pandemic. "I think we need to keep the pressure on," says Bekker. "As we move closer to more promising candidates, we don't want to be caught short."
An adolescent pandemic
The risk facing teenagers varies greatly from place to place. In the US, 40% of all new HIV infections are now occurring in individuals younger than 25. But the situation in sub-Saharan Africa is particularly gloomy. Two-thirds of all new HIV infections among adolescents are occurring there and young women in particular continue to be at a much greater risk of HIV infection than their male peers, due to both biological and social factors. In South Africa studies show that HIV prevalence rates approach 17% among girls age 15 to 24, four times the infection rates seen in boys of the same age. In Swaziland, a staggering 39% of young women in this age group are already HIV infected. And nearly a quarter of girls between the ages of 15 and 19 are now HIV infected in Botswana.
These trends clearly illuminate the need for introducing AIDS vaccines into these populations as quickly as possible and are helping to fuel discussions about how and when to test AIDS vaccine candidates in younger volunteers. "Everyone has been cautious about moving into adolescents with AIDS vaccines," says Michael Robertson, a lead investigator on Merck's Phase IIb AIDS vaccine trial that is being conducted through the HIV Vaccine Trials Network (HVTN). "But when you look at the epidemic in Africa, adolescents are the highest incidence group. And if you're going to make headway in dealing with the epidemic you need to involve them."
A few years ago little conversation was focused on adolescent trials but recently the discussions have gained momentum and now many groups, including the National Institute of Allergies and Infectious Diseases (NIAID) at the US National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the World Health Organization (WHO), and the African AIDS Vaccine Program (AAVP) are preparing protocols and involving scientists, ethicists, and community groups in the process.
An important step in formulating these protocols is finding out what regulatory agencies will require to license a vaccine for use in adolescent populations. Most regulatory agencies, including the FDA, that oversee the approval and licensure of medicines and vaccines require that experimental products are tested in the population in which they will be used. Historically for vaccines this population has been infants, who are susceptible to many diseases that are typically contracted during early childhood and who are also at greatest risk of developing life-threatening symptoms because their immune systems haven't fully developed. Extensive childhood immunization programs have been implemented in many countries and have drastically reduced mortality rates.
But there is much less of a precedent for adolescent vaccination. A vaccine against hepatitis B virus (HBV) was the only one to target this age group until a vaccine for human papillomavirus (HPV) was recently licensed by the FDA for girls age 9 to 26 (see Cervical cancer vaccines, IAVI Report 9, 5, 2005). Clinical trials to determine the safety and efficacy of the HBV vaccine were not conducted in adolescents until after the vaccine was approved and licensed for adults, delaying access to a critical group. It was only after the license was extended to younger people that the course of the HBV epidemic began to reverse. This offers a sobering lesson to AIDS vaccine researchers who want to ensure that a vaccine is available to adolescents and adults simultaneously.
The clinical trials, licensure, and eventual implementation of the HPV vaccine both in the US and in developing countries is also of great interest to those preparing for AIDS vaccine trials. "It's an excellent model for AIDS vaccines," says Jeffrey Safrit of the Elizabeth Glaser Pediatric AIDS Foundation. The Phase III efficacy trials for Merck's HPV vaccine involved thousands of adolescent (age 12-18) and pre-adolescent girls and issues about informed consent and parental involvement, which will also be central to AIDS vaccine trials, were fully addressed for enrollment. "Many of these issues are the same ones we faced with our HPV program," says Robertson, who is using this experience to plan the company's strategy for evaluating its lead AIDS vaccine candidate in adolescent volunteers. Many researchers are also closely monitoring the acceptance of this new vaccine into immunization programs to help gauge the response to vaccines still in development that aim to prevent other sexually-transmitted infections, including HIV and herpes simplex virus type 2 (HSV-2).
Results from the HPV and HBV vaccine trials give researchers good reason to be optimistic that adolescents may respond even better to vaccination than adults. "From what we know, vaccines are generally safer in people with fewer health problems," says Jorge Flores, chief of vaccine clinical research at NIAID. There are also several physiological and immunological differences between infants, adolescents, and adults, and in clinical trials with both the HPV and HBV vaccines younger volunteers had stronger immune responses to the vaccine, which is encouraging to AIDS vaccine researchers. Fewer doses of the HBV vaccine are required to induce a similar immune response to adults and now researchers are closely studying different vaccination strategies, including response to bacterial and viral vectors, to see how age affects the induction of immune responses (AIDS 20, 483, 2006).
Overall, scientists are optimistic that, if anything, a vaccine will be more effective in clinical trials involving adolescents. "The primary concern will be establishing safety data in these populations, rather than immunogenicity," says Robertson.
Before an AIDS vaccine trial begins enrolling adolescents many researchers, bioethicists, and international organizations are working to overcome some of the key challenges that are unique to adolescent trials. Chief among these is the need to obtain informed consent from the adolescent and their parent or guardian prior to enrollment. US and South African law both require that parental consent be provided for any trial involving minors where the vaccine isn't guaranteed to provide some benefit, and Bekker predicts that many parents may, at least initially, be reticent to allow their children to participate. A focus of any of these trials will therefore be on education and counseling for adolescents and their parents. "Once you give them the statistics, you can easily change people's perception," she says. "Parents are very aware that their children are in danger."
Trial protocols are currently being developed to protect these adolescent volunteers by tailoring the informed consent process and counseling sessions to specifically address their concerns, as well as those of their parents. But parental consent also requires striking a balance between involving parents and protecting the confidentiality and privacy of the volunteer. Adolescents may be uncomfortable disclosing their potential risk behaviors to a parent or guardian, so researchers will be given the task of making volunteers comfortable while ensuring that parents are informed about the trial. This may become even more complicated in efficacy trials where enrollment will likely hinge on the volunteer being at some risk of HIV infection either through sexual activity or drug use, says Audrey Smith Rogers, an epidemiologist at the National Institute of Child Health and Human Development, part of the NIH.
This raises legal and ethical issues about involving adolescents before they have reached the legal age for sexual consent, which varies from country to country. "The implication is that you're saying the age of consent isn't applicable," says Bekker. "I'm a bit squeamish about that, even though I've been a great protagonist." A possible solution to this dilemma is enrolling older adolescents who are over the age of sexual consent in efficacy trials and enrolling younger volunteers in smaller Phase I and II trials that deal primarily with safety and immunogenicity and don't require that participants are at high risk of infection.
Another concern in adolescent trials is the possibility that volunteers in AIDS vaccine trials may test positive on HIV antibody tests because an effective vaccine will elicit HIV-specific antibodies, which could compromise their enrollment in school, insurance coverage, or any other applications that require medical testing. Most clinical trials sites have already developed systems to handle these misunderstandings and researchers are confident that this will not be a significant barrier to adolescent enrollment.
There will be other considerations, including the social risks and stigma associated with adolescent involvement in an AIDS vaccine trial. Although these are issues central to all clinical trials, many of them are more complex or heightened in trials with younger volunteers. "Before we start a trial we need to understand as much as possible about the problems that could face adolescents who volunteer," says Flores. "Additional care must be put into the conduct of these trials."
Researchers must also be prepared to face obstacles with volunteer retention and reliability because younger people tend to be more mobile and may move away for school during the middle of a trial. Researchers remain committed to testing AIDS vaccine candidates in adolescents despite all of these confounding factors and are confident they can overcome many of the extra challenges. "I don't think these are insurmountable problems," says Rogers.
Involving expertise from outside the vaccine field is one way to facilitate these trials and many trial sponsors are already integrating organizations that are familiar with adolescent populations into the planning process. Community advisory boards will also be an important component since they can offer peer support that will help improve the experience of adolescent volunteers. "My take has always been that this can be done, but it can't be done by everyone," says Bekker. "You have to have groups that are used to working with adolescents."
As the planning process for adolescent AIDS vaccine trials gets underway, researchers are looking to regulatory and legal authorities for recommendations on how to proceed. In response to a bill from the US Congress requiring the FDA to advise both industry and other AIDS vaccine trial sponsors, the agency issued a guidance document in May 2006 (Development of Preventive HIV Vaccines for Use in Pediatric Populations) that provided general direction on their requirements for licensure in the US.
"The big question is when is the best time to bring a vaccine into trials with adolescents," says Flores. "Some people are more conservative and say not to test a vaccine in adolescents until you know it's effective. But this doesn't take into account the urgency," he adds. The guidance document issued by the FDA suggested that strong safety and immunogenicity data for AIDS vaccine candidates should be collected in adults before adolescent trials begin. Flores suggests that when a sponsor is considering taking a vaccine candidate into efficacy trials, Phase IIb or III, they should also be preparing for adolescent trials.
The FDA document also emphasized that efficacy data collected in adults could only be extrapolated to adolescents if researchers could successfully identify the immune correlates of protection, but this can often be difficult even with highly effective vaccines. For both HPV and rotavirus vaccines (see Rotavirus vaccines rolled out) correlates of protection have not been identified even after very large Phase III efficacy trials.
For AIDS vaccine candidates it may therefore be necessary to run large efficacy trials in adolescents. It is unlikely that these can be done exclusively in the US since HIV incidence rates there are generally, outside of certain urban centers, too low among adolescents to support a conclusive Phase III trial, says Rogers. If efficacy trials are conducted primarily outside of the US, the FDA recommends that trial sponsors submit their plans to the agency for review and comment to ensure that this data will be applicable to adolescent approval within the US.
Other regulatory agencies are also involved, including in South Africa where researchers are leading the charge for adolescent trials due to the especially high prevalence of HIV infection in young people there. The South African AIDS Vaccine Initiative (SAAVI) is currently collaborating with the HVTN to prepare an adolescent trial protocol. The WHO and the AAVP also sponsored a meeting earlier this year in Gaborone, Botswana, to address some of the challenges related to including adolescent volunteers in AIDS vaccine trials. Flores is in the process of preparing a document on adolescent trials for the NIH which he hopes will inspire discussion among researchers on the critical issues.
And now Merck is considering testing its lead vaccine candidate in adolescents in South Africa as part of a Phase IIb trial that will start there soon in cooperation with the NIH and the HVTN. "The plans are very much in the discussion phase," says Robertson. "We've discussed expanding the planned trial and amending the age cutoff to include adolescents, or adding another small safety and immunogenicity trial there just for adolescents."
Merck's candidate induces primarily cellular immune responses and some researchers predict this type of vaccine will not be able to prevent infection but rather slow disease progression in those who later become HIV infected. "That adds an additional level of complication," says Flores, especially for adolescents. "We're hard pressed to define what success is for this type of vaccine," and he thinks this may negatively influence how both adolescent volunteers and their parents view the trial.
Researchers are encouraged by preliminary research that indicates many adolescents are eager to participate in AIDS vaccine research. Results from a feasibility study conducted by Bekker in South Africa indicate that 53% of 256 adolescents (age 11-19) were willing to participate in a trial. However the most common reason given for participation was the perception that it would offer them protection from HIV infection. This raises the concern of behavioral disinhibition in trials, where volunteers feel a false sense of protection from a vaccine candidate that hasn't yet proven effective and as a result they may continue or increase behaviors that elevate their risk of HIV infection. Disinhibition is an important consideration in any prevention trial, but may be even more critical for adolescents. "It's a valid concern but I don't know that there's data out there to support it," says Bekker.
But the need to protect this vulnerable group from stigma and other social harms is still a substantial concern for researchers who are actively discussing the possibility of such trials in the near future. "We will have adolescents in AIDS vaccine trials within the next three years," says Flores. "And once the first trial is done, it will pave the way for all future trials."