HIV has infected and affected more than 60 million individuals worldwide. Adolescents and young adults bear a disproportionate burden in this pandemic, with half of all new HIV infections occurring among 15 to 24 year olds.1 Globally, although infection rates among adolescents and young adults vary substantially among countries (Table 1), it is clear that the risk of acquiring HIV infection increases dramatically in adolescence, concurrent with the initiation of sexual activity. Risk may be enhanced by factors such as cervical ectopy,2 hormonal contraception,3 and high sexually transmitted disease rates. This risk is particularly high when sexual debut occurs early and may be amplified when sex is not consensual4 or when it is with older partners.5-7 Many of these factors put young women at higher risk, as reflected in the earlier rise in HIV infection rates in young women than in young men.8
Experience with HIV and other communicable diseases suggests that despite behavioral risk reduction interventions and increasingly widespread access to antiretroviral therapy, the HIV epidemic is likely to continue to spread until an effective preventive vaccine is developed and made widely available. Adolescents and preadolescents are a logical and critically important target for primary immunization with a preventive HIV vaccine. In this context, it is imperative to include adolescents routinely in trials of HIV vaccine candidates as soon as safety and immunogenicity profiles have been established in adults and the product is considered sufficiently promising that it is ready to enter efficacy trials in adults. A delay in implementing HIV vaccine trials in this vulnerable population would extend the time to licensure for adolescents, resulting in many unnecessary infections and deaths. To achieve the goal of routine inclusion of adolescents in clinical trials of preventive HIV vaccines, there is an urgent need to consider a number of trial design issues and to address safety, legal, ethical, regulatory, and operational challenges.12 This position paper discusses these issues and challenges and, building on lessons learned from trials of other vaccines, summarizes the approach that is being adopted by the Adolescent Trials Working Group (ATWG), a group composed of representatives from the HIV Vaccine Trials Network (HVTN); Adolescent Trials Network (ATN); International Maternal, Pediatric, and Adolescent AIDS Clinical Trials Network (IMPAACT, formerly PACTG); and National Institutes of Health (NIH).
DESIGN OF HIV VACCINE TRIALS IN ADOLESCENTS
Definitions of Adolescents
Adolescence has been defined as covering various age ranges by different groups.13,14 In this article, adolescents are defined as 12 to 18 years of age and preadolescents as 9 to 12 years of age. We distinguish 16 and 17 year olds as “older adolescents” and 12 to 15 year olds as “younger adolescents” because these 2 groups are often marked by cognitive and physical developmental differences and differences in legality of consensual sex, factors that are potentially important considerations in the design of HIV vaccine trials.
Although regulatory authorities may differ with regard to exact requirements, it is a general policy of the Office of Vaccines Research and Review (OVRR) of the US Food and Drug Administration (FDA) that product package inserts must be supported by data from clinical trials conducted among individuals similar to the proposed users. Thus, if the vaccine indication is to include adolescents, safety and immunogenicity data, at a minimum, must be obtained in adolescents. The World Health Organization guidelines on clinical evaluation of vaccines: regulatory expectations,15 the International Conference on Harmonization,16,17 the NIH,18 and the FDA19 provide guidance on such clinical evaluations, including bridging studies, which are designed to facilitate extrapolation of data from one formulation, population, or dose regimen to another. The absence of a correlate of immune protection in HIV infection makes the use of bridging studies challenging. Nevertheless, it may be possible to conduct bridging studies using state-of-the-art immunogenicity assays in accordance with or in close consultation with regulatory agencies.
Several trial design strategies for providing data to support label claims for an HIV vaccine in adolescents are outlined in the following section. Trials must not only demonstrate efficacy in adolescents, directly or through bridging to efficacy studies in adults, but should collect sufficient safety data from randomized controlled trials in adolescents to support a label claim. Failure to provide sufficient safety and efficacy data for subgroups may result in implementation delays, as was the case in December 2002, when the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the FDA evaluated safety and efficacy data for a novel influenza virus vaccine (a live-attenuated vaccine). Most of the data were collected in adolescents and younger adults. Eight of the 18 committee members voted that the safety data in 622 adults aged 50 years and older, a population considered to be an important target for influenza vaccination, were insufficient to support a label claim in this population.20 In addition, 14 of the 18 committee members voted that the efficacy data in this group were also insufficient. Consequently, the FDA initially licensed this vaccine only for those aged 5 to 49 years.
The FDA recognizes that products are often not adequately tested in pediatric and adolescent populations, and pediatric clinical trials have become imperative through the Pediatric Research Equity Act. This act requires that manufacturers of products to be used in children provide sufficient efficacy data and safety information to support the product directions.21
Safety and Immunogenicity
It is likely that biologic vaccine safety and immunogenicity in adolescents, and particularly in older adolescents, are comparable to those seen in adults. Even among younger adolescents, there may be few differences in these parameters, although immune responses may be more robust and preexisting immunity to vaccine vectors may be different from that in older populations. It is possible that biologic safety and immunogenicity data collected in adults may not accurately predict outcomes in adolescents, however. Immune responses to several licensed vaccines seem to be different and often greater at younger ages (reviewed by Jaspan et al22). This may result in vaccine candidates with poor adult immunogenicity being prematurely discarded when they may be immunogenic in younger populations. Additionally, the increased risk of autoimmunity in adolescents may reflect an effect of rapidly changing levels of sex steroids on the immune system.22-24 In mice and humans, estrogen stimulates polyclonal B-cell activation and cytokine secretion with increased production of autoantibodies,25 whereas androgens suppress T and B cells.26 This is consistent with the observation that rubella vaccination is associated with higher rates of arthropathy in older children and adults compared with younger children.27 Although biologic adverse events are unlikely to be substantially more common in adolescents than in adults, social harms such as discrimination attributable to vaccine-induced seropositivity, disruption of relationships, or behavioral disinhibition may be more frequent or more difficult to address in young people participating in HIV vaccine trials.12 To date, there are few data on these potential harms in this context.
Taken together, these data reinforce that the availability of sufficient safety and immunogenicity data in adults to warrant advancement of an HIV vaccine candidate into efficacy trials in adults should trigger the rapid initiation of trials in adolescents to measure safety, immunogenicity, and/or efficacy data to support licensure for this population. In preparation for and during these trials, data should be collected on potential social harms and risk behavior. Furthermore, trials in adults should enroll adequate numbers of 18- to 20-year-old subjects to generate meaningful data in this age group. This could obviate the need for phase 1 trials in older adolescents and, instead, permit lagged enrollment of this group in an adult efficacy trial, as described elsewhere in this article.
Trial Design Strategies
A number of approaches may be considered to gather the information about vaccine safety and efficacy in adolescents that regulatory bodies are likely to require to license vaccine products for use in this group. It is helpful to discuss older and younger adolescents separately. Requirements for additional safety and immunogenicity data are likely to be more limited for 16 and 17 year olds than for younger adolescents because of their biologic similarity to 18 to 20 year olds, for whom these data are available before initiation of efficacy trials in adults. Additionally, it may be difficult to enroll younger adolescents in efficacy trials that include sexual activity as an eligibility criterion because of laws classifying sex in this age group as statutory rape in many parts of the world. In these settings, inclusion of at-risk younger adolescents would require investigators and consenting legal guardians to document and perhaps report an illegal activity, although precedents for addressing these issues exist in trials that have enrolled commercial sex workers and drug users.28,29 Researchers would need to work with institutional review board (IRB) and regulatory authorities in each relevant country.
Evaluation of Safety and Immunogenicity in Adolescents
When sufficient safety and immunogenicity data have been accrued in adults to warrant advancement to efficacy trials in that population, verification of safety and immunogenicity in adolescents may be approached in 2 ways. One is the verification of safety and immunogenicity in older adolescents by enrolling sexually active 16 and 17 year olds as part of the efficacy trial in adults and including additional safety pauses and monitoring as well as an early examination of immunogenicity data by the data safety monitoring board (DSMB) for this subgroup. After confirmation of safety and immunogenicity in older adolescents, a phase 1/IIA trial among younger adolescents could evaluate safety and immunogenicity in this group. The second more conservative option is the initiation of a phase 1/IIA trial starting with older adolescents and subsequently rolling down to younger adolescents after reactogenicity and early safety data have been obtained in 16 and 17 year olds. This might be considered when there are specific biologic reasons to anticipate less favorable safety or immunogenicity profiles in older adolescents than in young adults or when experience with the vaccine construct is limited among 18 to 24 year olds. Sexual activity would not be an eligibility requirement for phase 1/IIA trial enrollment using either approach.
Evaluation of Efficacy in Adolescents
Enrollment of at-risk adolescents in efficacy trials should be conducted as soon after initiation of adult efficacy trials of the vaccine candidate as possible. As in adults, the efficacy evaluation may be designed as a test of concept (TOC)/phase 2B trial or as a pivotal/phase 3 licensure trial, depending on the stage of development of the specific vaccine candidate.30 Two operational models for either approach are possible. One is to add an additional stratum of adolescent participants to an adult efficacy evaluation. Thus, a single trial would be performed with adult and adolescent strata, maximizing standardization across populations within a single protocol. A second model would be to conduct 2 separate trials but with harmonized protocols. This would provide operational robustness and the potential for pursuing the 2 trials on different timelines, although this latter approach might reduce standardization or comparability across trials.
Bridging Studies Involving Adolescents
Direct assessment of efficacy in younger adolescents would be ideal and should be conducted as outlined previously wherever considered ethically appropriate and legally feasible. Where legal statutes preclude the enrollment of sexually active youth, however, a strategy may be to design protocols in close consultation with regulatory authorities to allow bridging based on immunogenicity using state-of-the-art assays, obviating the need for sexual activity as an eligibility criterion.
The development of HIV vaccine candidates has been challenging. Many candidates, although safe, have failed to illicit the desired immune responses; as a result, they have failed to warrant further testing. The prospects are broadening, however. As founding partners in the Global HIV Vaccine Enterprise, the US National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation have each launched landmark initiatives to accelerate HIV vaccine discovery and strengthen laboratory capacity. In addition, HIV vaccine regimens are showing sufficient safety and immunogenicity to move into advanced clinical development in TOC efficacy trials in adults. The ATWG believes that it is essential to initiate trials of these candidates in adolescents.
OVERCOMING THE CHALLENGES
For vaccine trials to be successfully conducted among adolescents, high-risk youth and the communities in which they live must be meaningfully engaged. Trial participants and their parents must fully understand the trials to be able to provide informed assent or consent for participation.
Recruitment and Retention
Populations that bear the heaviest burden of HIV infection, and therefore are most in need of a safe and effective preventive vaccine, often endure other social challenges such as poverty, homelessness, and drug use amid unstable social situations. Nevertheless, recruitment from these populations has been demonstrated in successful research projects in the United States and Africa.31-35 These studies have shown that when one provides youth-friendly care in at-risk neighborhoods, one can identify and recruit youth and facilitate their participation in trials. The US-based Reaching for Excellence in Adolescent Care and Health (REACH) study, an observational study of HIV infection in teens, had 87% follow-up of high-risk adolescents at the end of 4 years.32 In the human papillomavirus (HPV) vaccine efficacy trial in Brazil and North America that enrolled participants from 15 to 25 years old, 86% of the intention-to-treat cohort completed to month 18 of the study.36
Several efforts are underway to evaluate strategies that could facilitate adolescent enrollment in HIV vaccine trials. The PACTG conducted a pilot Family Mapping Project in the United States, employing peer recruitment by HIV-positive youth by means of their social and sexual network contacts into a vaccine preparedness cohort. Knowledge of HIV and vaccine trials and willingness to participate in future trials have been evaluated in this cohort. The PACTG also funded smaller pilot projects in South Africa based on this model.
Another strategy being used by the ATN is community focused and aims to establish a primary prevention infrastructure based on epidemiologic intelligence, community partnerships, and capacity building. Its 6-year Connect to Protect Program intervenes at the structural level to change community attitudes, policies, and programs to improve health and decrease HIV risk for community youth. Enrollment in HIV vaccine trials is one of the prevention research opportunities to be offered to the participating communities.
The Perinatal HIV Research Unit in Soweto and the Desmond Tutu HIV Centre in Cape Town have conducted interviews and focus groups around the feasibility of HIV vaccine trials in adolescents with adolescents, their parents, and key stakeholders. In addition, both vaccine trials sites are creating adolescent cohorts to explore issues of consent, recruitment, and retention in adolescent and preadolescent age groups. Lessons from all these projects, in concert with the experience gleaned by years of vaccine research in children and adolescents, particularly information from the new sexually transmitted infection vaccine trials in teens (HPV and herpes simplex virus [HSV]), should inform the adolescent recruitment efforts for all HIV prevention trials in this population.
Including youth who may be at increased risk of HIV infection in future vaccine trials requires sensitive and sustained attention to the concerns of the families and communities in which they live, which may not be addressed within the current community advisory board (CAB) structure. This may require expansion of existing CABs or additional community structures to include teens, parents, and/or school staff as well as clinicians. New formative work with these stakeholders, community groups serving adolescents, local opinion leaders, and policy makers is likely to be essential in many sites to prepare communities for trials in adolescents. Prior consultation with representatives of American and South African communities has indicated that a successful strategy would be one in which participation of youth in vaccine research is implemented in the context of a broad primary prevention initiative.37,38
Informed Consent and Assent
There are numerous country-specific regulations and guidelines stipulating at which age, or under which conditions, a minor may independently consent to participate in research without parental permission or consent. Most countries specify that minors require the proxy consent of a parent or guardian in addition to their assent and specify the age of majority at which independent consent is permitted (Table 2). In addition to varying age of majority, conditions under which parental consent can be waived or a minor can be considered “emancipated” differ globally. This is a complex area that must be fully understood in each country in which adolescent HIV vaccine trials are to be conducted, and some countries have not yet established laws or guidelines. The purpose of parental permission is to ensure the protection of the minor's interests. Although some adolescents as young as 14 years of age have developed adult-level cognitive ability,53 they may lack the life experiences on which judgment is based. Adolescent participation in clinical trials with investigational vaccine products requires the involvement of a parent or guardian to provide that judgment. It also requires the research staff to assume more responsibilities than with adults.
The requirement for parental permission introduces potential challenges that must be considered in trial design and recruitment. Teens who meet a vaccine trial's risk behavior eligibility criteria may not be willing or able to disclose that particular behavior to their parents. One possible strategy is to separate screening for the trial (which could be conducted with a waiver of parental permission) from the consent process for the actual trial (during which the adolescent's general risk is presented but the adolescent's personal risk is not disclosed). Alternatively, the consent form can state that the parent or guardian waives his or her right to access the adolescent's private information.
Despite obstacles to participation of minors, several trials of interventions to prevent sexually transmitted disease among sexually active adolescents have been conducted. Examples include HPV vaccine studies that enrolled sexually active female adolescents from the United States aged 16 years or older (with parental permission and knowledge of their daughter's sexual activity)54 and the HPV vaccine trial conducted in North America and Brazil among 15 to 25 year olds (with parental consent and participant assent for all those <18 years of age).36 A phase 1/II HSV vaccine trial is currently underway for 10 to 17 year olds.55 There remain potential surmountable issues that are unique to or heightened for HIV vaccine trials, such as vaccine-induced seropositivity and possible disinhibition of sexual behavior, which may be exaggerated in adolescents (reviewed by McClure et al12).
CRITICAL NEXT STEPS
The ATWG is committed to the conduct of high-quality HIV vaccine clinical trials and to the inclusion of adolescents in trials with the ultimate goal of licensure of an effective HIV vaccine for youth. We believe that once appropriate candidate HIV vaccines have sufficient safety and immunogenicity data to move to proof-of-concept trials, the routine inclusion of adolescents in clinical trials with those products should be planned. Thus, in light of these data and the challenges ahead, we propose that the following steps be taken to expedite this process and change the trial paradigm so that the inclusion of adolescents becomes the norm. Some of the items listed are already in progress:
1. Develop a community presence among adolescents and identify community requirements for conducting HIV vaccine trials among adolescents. This includes but is not limited to the following:
A. Establishing adolescent and parent CABs where these do not already exist
B. Auditing the existing adolescent-targeted primary prevention initiatives at each site and building on these where necessary
C. “Auditing” the international communities' requirements for conducting adolescent HIV vaccination trials
2. Conduct additional preparatory work to overcome the logistic difficulties of trials in youth. This includes but is not limited to the following:
A. Determining true HIV incident rates of adolescents at potential and existing efficacy trial sites
B. Recruiting and following up cohorts to determine feasibility and techniques for recruiting and retaining adolescents
C. Preliminary assessment of potential social harms
D. Detailed auditing of current ethical and legal guidelines for clinical trials in children for each relevant country involved
3. Develop protocols that include adolescents, bearing in mind issues of recruitment, retention, consent, confidentiality, and community that are unique to adolescents and are addressed previously.
To this end, studies have commenced at pilot sites in the United States and internationally. Preparedness studies, as mentioned previously, are underway to establish the feasibility of enrollment and retention of at-risk youth, through cohorts as well as qualitative research.
Youth worldwide are at significant risk of HIV infection and have great potential to benefit from an efficacious vaccine. Adolescents and younger children have successfully participated in many vaccine trials for other infections. Despite their greater potential vulnerability and the logistic difficulties of trials in youth, we believe it is imperative that adolescents be routinely included in trials of products from which they stand to benefit. As more promising HIV vaccine candidates enter efficacy trials in adults, it is essential to plan for trials of these vaccine candidates in youth. The HVTN, ATN, IMPAACT, and other stakeholders are working to begin adolescent vaccine trials in the near future. The operational and ethical issues can and must be addressed so that this population, which accounts for one quarter of all new HIV infections in the world, may benefit from an effective HIV vaccine as quickly as possible.
1. UNAIDS. 2005 Report on the Global AIDS Epidemic
. Geneva, Switzerland: UNAIDS; 2005.
2. Abma J, Driscoll A, Moore K. Young women's degree of control over first intercourse: an exploratory analysis. Fam Plann Perspect
3. DiClemente RJ, Wingood GM, Crosby RA, et al. Sexual risk behaviors associated with having older sex partners: a study of black adolescent females. Sex Transm Dis
4. Miller KS, Clark LF, Moore JS. Sexual initiation with older male partners and subsequent HIV risk behavior among female adolescents. Fam Plann Perspect
5. Sturdevant MS, Belzer M, Weissman G, et al. The relationship of unsafe sexual behavior and the characteristics of sexual partners of HIV infected and uninfected adolescent females. J Adolesc Health
6. Myer L, Wright TC Jr, Denny L, et al. Nested case-control study of cervical mucosal lesions, ectopy, and incident HIV infection among women in Cape Town, South Africa. Sex Transm Dis
7. Lavreys L, Baeten JM, Martin HL, et al. Hormonal contraception and risk of HIV-1 acquisition: results of a 10-year prospective study. AIDS
8. UNAIDS. 2003 Report on the Global AIDS Epidemic
. Geneva, Switzerland: UNAIDS; 2003.
9. Pretoria Department of Health. Department of Health National HIV and Syphilis Antenatal Sero-Prevalence Survey in South Africa. Pretoria, South Africa: Department of Health; 2005.
10. Reproductive Health Research Unit, Medical Research Council. National Survey of HIV and Sexual Behaviour among Young South Africans. Johannesburg, South Africa: Reproductive Health Research Unit; 2004.
11. Valleroy LA, MacKellar DA, Karon JM, et al. HIV prevalence and associated risks in young men who have sex with men. JAMA
12. McClure CA, Gray G, Rybczyk K, et al. Challenges to conducting HIV preventative vaccine trials with adolescents. J Acquir Immune Defic Syndr
14. International Conference on Harmonization E6. Good Clinical Practice Consolidated Guidelines
. Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), ICH Topic E 6, Step 5, Consolidated Guideline 1.5.1996. London: EMEA 1997.
16. International Conference on Harmonization E5. Ethnic factors in the acceptability of foreign clinical data. Fed Regist
17. International Conference on Harmonization E11. Clinical investigations of medicinal products in the pediatric population. Fed Regist
18. Vaccine Clinical Research Branch, Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health. Considerations for HIV vaccine clinical trials in adolescents. April 2007. Available at: http://www3.niaid.nih.gov/research/topics/HIV/vaccines/conpapers.htm
. Accessed July 2, 2007.
19. US Food and Drug Administration. Guidance for industry. Development of preventative HIV vaccines for use in pediatric populations. Available at: www.fda.gov/cber/gdlns/pedhiv.htm
. Accessed September 23, 2007.
22. Jaspan HB, Lawn SD, Safrit JT, et al. The maturing immune system: implications for development and testing of HIV-1 vaccines for children and adolescents. AIDS
23. Sizonenko PC, Paunier L. Hormonal changes in puberty III: correlation of plasma dihydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche. J Clin Endocrinol Metab
24. Verthelyi D. Sex hormones as immunomodulators in health and disease. Int Immunopharmacol
25. Sandborg C. Expression of autoimmunity in the transition from childhood to adulthood: role of cytokines and gender. J Adolesc Health
. 2002;30(4 Suppl):76-80.
26. Kovacs EJ, Messingham KAN. Influence of alcohol and gender on immune response. Alcohol Res Health
27. Howson CP, Fineberg HV. Adverse events following pertussis and rubella vaccines-summary of a report of the Institute-Of-Medicine. JAMA
28. Sikkema KJ, Anderson ES, Kelly JA, et al. Outcomes of a randomized, controlled community-level HIV prevention intervention for adolescents in low-income housing developments. AIDS
29. Pal D, Raut DK, Das A. A study of HIV/STD infections amongst commercial sex workers in Kolkata (India). Part-I: some socio-demographic features of commercial sex workers. J Commun Dis
30. UNAIDS/WHO/IAVI Expert Group. Executive summary and recommendations from the UNAIDS/WHO/IAVI Expert Group Consultation on: phase IIB-TOC (Test of Concept) trials as a novel strategy for evaluation of HIV vaccines. 31 January-2 February 2006, IAVI, New York, USA. AIDS
31. Rogers AS, Futterman D, Moscicki AB, et al. The REACH Project of the Adolescent Medicine HIV/AIDS Research Network: design, methods, and selected characteristics of participants. J Adolesc Health
32. Stanford PD, Monte DA, Briggs FM, et al. Recruitment and retention of adolescent participants in HIV research: findings from the REACH (Reaching for Excellence in Adolescent Care and Health) Project. J Adolesc Health
33. Mbonye AK. Disease and health seeking patterns among adolescents in Uganda. Int J Adolesc Med Health
34. Mmari KN, Magnani RJ. Does making clinic-based reproductive health services more youth-friendly increase service use by adolescents? J Adolesc Health
35. Cowan FM, Langhaug LF, Mashungupa GP, et al. School based HIV prevention in Zimbabwe: feasibility and acceptability of evaluation trials using biological outcomes. AIDS
36. Harper DM, Franco EL, Wheeler C, et al, for the GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet
37. Report on NIH-Community Consultation on including adolescents in HIV prevention vaccine research. Crystal City, VA; January 11-12, 2001.
38. Slack C, Strode A, Grant C, et al. Implications of the ethical-legal framework for adolescent HIV vaccine trials-report of a consultative forum. S Afr Med J
42. Fombad CM. Protecting children's rights in social science research in Botswana: some ethical and legal dilemmas. Int J Law Policy Fam
44. Indian Council of Medical Research. Ethical Guidelines for Biomedical Research on Human Subjects. New Delhi, India: Indian Council of Medical Research; 2000.
45. National Health Act, No. 61 of 2003. Cape Town, South Africa: Government Gazette. July 23, 2004;469. No. 26595. Available at: http://www.doh.gov.za/docs/legislation
. Accessed October 25, 2007.
50. US Department of Health and Human Services. Code of Federal Regulations. Title 21-Food and Drugs. Chapter I Food and Drug Administration, Department of Health and Human Services, Subchapter A-General Part 50. Protection of Human Subjects, Subpart D: Additional Safeguards for Children in Clinical Investigations. Available at: http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr50_06.html
. Accessed October 26, 2007.
52. Government of Zimbabwe, Legal Age of Majority Act. Gazette No. 15, 1982, p. 96.
53. Weithorn LA. Children's capacities to decide about participation in research. IRB
54. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med
55. Rupp R, Stanberry LR, Rosenthal SL. New biomedical approaches for sexually transmitted infection prevention: vaccines and microbicides. Adolesc Med Clin