AIDS vaccines for 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 almost half of all new HIV infections, with nearly three million becoming HIV infected each year. 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 preparing for AIDS vaccine trials involving adolescents in South Africa. Research shows that despite increased efforts to reach adolescents and provide them with information about HIV prevention, young people in many communities are having sex and pursuing injection drug use at an earlier age. This makes the optimal age for vaccination even younger, since adolescents should ideally receive a preventive AIDS vaccine before they become sexually active. "That's our big motivation," adds Bekker.
But before AIDS vaccine trials with promising candidates can be initiated in adolescents, researchers must tackle potentially thorny legal, ethical, and regulatory issues, and make sure they adequately address the concerns of parents about their children participating in research. Many organizations are currently working to develop guidelines and protocols that will enable future trials to be conducted successfully with adolescent volunteers. Progress in these areas will help guarantee that an effective AIDS vaccine, when available, will reach both adult and adolescent populations 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 epidemic
In the US, 40% of all new HIV infections are now occurring in individuals younger than 25. Although the risk facing teenagers varies greatly from place to place, in many countries, especially in Africa, the situation facing young women is particularly dire. Young women in South Africa continue to be at very high risk of HIV infection, with studies showing that HIV prevalence rates approach 16% among girls between age 15 and 24, four times the infection rates seen in boys of the same age. In Botswana nearly 25% of girls between the ages of 15 and 19 are already HIV infected.
Statistics like these are helping to fuel discussions amongst researchers, sponsoring organizations, and regulatory agencies 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. "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."
Researchers were given some guidance recently on adolescent trials by the US Food and Drug Administration (FDA). In a document issued in May 2006 (Development of Preventive HIV Vaccines for Use in Pediatric Populations) the agency provided vaccine trial sponsors with direction on the requirements for licensure in adolescent populations. Most regulatory agencies like 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. For most vaccines this is in infants, who are susceptible to many diseases that they would normally catch during early childhood. Infants are also at greatest risk of developing life-threatening symptoms from viral infections because their immune systems haven't fully developed. Extensive childhood immunization programs have been implemented in many countries where sufficient healthcare infrastructure exists, 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 aged 9 to 26 (see February 2006 Spotlight article, Cervical cancer vaccines). The large efficacy trials for the HPV vaccine involved thousands of adolescent (age 12-18) and pre-adolescent girls, and many researchers are closely monitoring the acceptance and inclusion 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. "It's an excellent model for AIDS vaccine researchers," says Jeffrey Safrit of the Elizabeth Glaser Pediatric AIDS Foundation.
Results from HPV and HBV vaccine trials also give researchers good reason to be optimistic that adolescents may respond even better to vaccination than adults. Clinical trials with both vaccines induced stronger immune responses in younger volunteers. The primary concern will be establishing safety data in these populations rather than immunogenicity, says Robertson.
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. The agency also emphasized that efficacy data collected in adults could only be extrapolated to adolescents if researchers could successfully identify the immune responses that are predictive of protection, also known as correlates of protection. Establishing which immune responses correlate with protection is not a simple task and for both HPV and rotavirus vaccines (see July 2006 Spotlight article, Vaccines enter battle against an intestinal virus) correlates of protection have not been identified even after 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 only be done in the US since HIV incidence rates there are generally too low among adolescents to support a conclusive Phase III trial, says Audrey Smith Rogers, an epidemiologist at the US National Institute of Child Health and Human Development. The guidance document by the FDA recommends that trials sponsors discuss AIDS vaccine efficacy trials planned in other countries to ensure that this data can be applied to adolescent approval in the US.
Researchers in South Africa and Botswana are leading the charge due to the high prevalence of HIV infection among adolescents in these countries. The South African AIDS Vaccine Initiative (SAAVI) is currently collaborating with the HIV Vaccine Trials Network (HVTN) to prepare a protocol for an adolescent trial. The World Health Organization (WHO) and the African AIDS Vaccine Program (AAVP) also sponsored a meeting earlier this year in Gaborone, Botswana, to address some of the challenges of including adolescent volunteers in AIDS vaccine trials. And Merck is now considering testing its lead vaccine candidate in adolescents in South Africa as part of a Phase IIb trial that will start there later this year in cooperation with the US National Institutes of Health 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."
But before an actual trial begins these groups 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 both the adolescent and their parent or guardian prior to enrollment (see June 2005 Primer on Understanding Informed Consent). 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 be reticent, at least initially, to allow their children to participate, necessitating education and counseling for both adolescents and 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."
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. This may become even more complicated in efficacy trials, where enrollment is dependent on the volunteer being sexually active and therefore at some risk of HIV infection, says Rogers.
This raises legal and ethical issues about involving adolescents in trials 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 including in efficacy trials only adolescents over the age of sexual consent and reserving Phase I and II trials for younger volunteers.
Regardless of these sexual consent issues, trial protocols are 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. "These are the same issues we faced with our HPV program," says Robertson. The experiences in running these efficacy trials are helping the company plan future AIDS vaccine trials in teenagers.
Another concern for parents when making the decision to allow their child to participate is the potential that volunteers in AIDS vaccine trials may test positive on HIV tests without actually being HIV infected (see November 2005 Primeron Understanding HIV Testing). And researchers will also face obstacles, including the retention of adolescent volunteers who tend to be more mobile than adults. "I don't think these are insurmountable problems," says Rogers.
For these trials to be successful, expertise must come from outside the vaccine field. Involving adolescent organizations and community-advisory boards that can offer peer support to volunteers could greatly 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 who are used to working with adolescents."
Preliminary research indicates that 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. As a result they may continue or increase behaviors that put them at higher 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.
Including adolescents in trials is viewed as a necessary step in making an eventual AIDS vaccine available to this population, but the need to protect this vulnerable group from stigma and other social harms is imperative during the conduct of the trials.