Clinical trials of human papillomavirus vaccines
- J Thomas Cox, MD
J Thomas Cox, MD
- American Society for Colposcopy and Cervical Pathology (ASCCP)
- Joel M Palefsky, MD
Joel M Palefsky, MD
- University of California San Francisco
- Immediate Past President, International Papillomavirus Society
- Immediate Past President, International Anal Neoplasia Society
Two vaccines have been developed against human papillomavirus (HPV) infection. One is a quadrivalent vaccine (Gardasil) and the other is a bivalent vaccine (Cervarix).
Some of the major clinical trials that have been performed to date in males and females are discussed in detail below. The natural history, epidemiology, and immunology of HPV and indications for use of HPV vaccine in clinical practice are discussed elsewhere. (See "Epidemiology of human papillomavirus infections" and "Recommendations for the use of human papillomavirus vaccines" and "The life cycle, natural history, and immunology of human papillomaviruses".)
The HPV L1 major capsid protein, when recombinantly expressed alone, can self-assemble into virus-like particles (VLPs) for each HPV type [1,2]. The HPV L1 VLPs do not contain the HPV viral genome or any other genetic material and therefore are rendered non-infectious and non-carcinogenic. Preclinical research demonstrated that L1 is highly immunogenic with and without an adjuvant [2,3].
The proof-of-concept vaccine trial with HPV 16 VLP  demonstrated that HPV 16 infection could be effectively prevented. In follow-up studies of this population, women were nearly completely protected against HPV 16 up to 8.5 years after HPV 16 vaccination .
Two vaccines were subsequently developed and tested in phase III efficacy trials for use:
- Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991; 185:251.
- Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992; 89:12180.
- Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001; 93:284.
- Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347:1645.
- Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 2009; 27:5612.
- Kovacic MB, Castle PE, Herrero R, et al. Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality. Cancer Res 2006; 66:10112.
- Rodriguez AC, Schiffman M, Herrero R, et al. Longitudinal study of HPV persistence and CIN2/3: critical role of duration of infection. J Natl Cancer Inst 2009.
- FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007; 356:1915.
- Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928.
- Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 2007; 298:743.
- Castle PE, Schiffman M, Herrero R, et al. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis 2005; 191:1808.
- Muñoz N, Manalastas R Jr, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet 2009; 373:1949.
- Joura EA, Garland SM, Paavonen J, et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012; 344:e1401.
- Brown DR, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis 2009; 199:926.
- Wheeler CM, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. J Infect Dis 2009; 199:936.
- Malagón T, Drolet M, Boily MC, et al. Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:781.
- Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302:750.
- Paavonen J, Naud P, Salmerón J, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009; 374:301.
- Herrero R, Hildesheim A, Rodríguez AC, et al. Rationale and design of a community-based double-blind randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste, Costa Rica. Vaccine 2008; 26:4795.
- Castle PE, Schmeler KM. HPV vaccination: for women of all ages? Lancet 2014; 384:2178.
- Skinner SR, Szarewski A, Romanowski B, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet 2014; 384:2213.
- Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006; 24:5571.
- Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006; 367:1247.
- GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, et al. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 2009; 374:1975.
- Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin 2009; 5:705.
- Giuliano AR, Lu B, Nielson CM, et al. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis 2008; 198:827.
- Nielson CM, Flores R, Harris RB, et al. Human papillomavirus prevalence and type distribution in male anogenital sites and semen. Cancer Epidemiol Biomarkers Prev 2007; 16:1107.
- Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine 2006; 24 Suppl 3:S3/11.
- Petäjä T, Keränen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10-18 years. J Adolesc Health 2009; 44:33.
- Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007; 26:201.
- Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011; 364:401.
- Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365:1576.
- Swedish KA, Factor SH, Goldstone SE. Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clin Infect Dis 2012; 54:891.
- VACCINE DEVELOPMENT
- TOOLS FOR ASSESSMENT OF VACCINE EFFICACY
- QUADRIVALENT HPV 6/11/16/18 L1 VIRUS-LIKE PARTICLE VACCINE
- Efficacy in females
- - The FUTURE II trial
- - The FUTURE 1 trial
- - Prevention of subsequent disease
- Therapeutic effects
- Regulatory approval
- Post-approval safety
- BIVALENT HPV 16/18 L1 VIRUS-LIKE PARTICLE VACCINE
- - Efficacy in older females
- Therapeutic effects
- Regulatory approval
- Post-approval safety
- VACCINE IMMUNOGENICITY
- CLINICAL TRIALS OF HPV VACCINE IN MALES
- Bivalent vaccine (Cervarix) in males
- Quadrivalent vaccine (Gardasil) in males
- - Prevention of genital warts
- - Prevention of anal intraepithelial neoplasia
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS