Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial.

IMPORTANCE Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible. OBJECTIVE To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses. DESIGN, SETTING, AND PATIENTS Randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%). INTERVENTION Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. MAIN OUTCOMES AND MEASURES Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months. RESULTS The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512-1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36. CONCLUSIONS AND RELEVANCE Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00501137.

[1]  Alai Tan,et al.  Completion of the human papillomavirus vaccine series among insured females between 2006 and 2009 , 2012, Cancer.

[2]  G. Ogilvie,et al.  Age of recipient and number of doses differentially impact human B and T cell immune memory responses to HPV vaccination. , 2012, Vaccine.

[3]  P. Hillemanns,et al.  Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared to the licensed 3-dose schedule , 2011, Human vaccines.

[4]  J. Schiller,et al.  A Murine Genital-Challenge Model Is a Sensitive Measure of Protective Antibodies against Human Papillomavirus Infection , 2011, Journal of Virology.

[5]  D. Moher,et al.  CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials , 2011, BMJ : British Medical Journal.

[6]  D. Lowy,et al.  Proof-of-Principle Evaluation of the Efficacy of Fewer Than Three Doses of a Bivalent HPV16/18 Vaccine , 2011, Journal of the National Cancer Institute.

[7]  Daron G Ferris,et al.  The humoral response to Gardasil over four years as defined by Total IgG and competitive Luminex immunoassay , 2011, Human vaccines.

[8]  D. Lowy,et al.  In vivo mechanisms of vaccine-induced protection against HPV infection. , 2010, Cell host & microbe.

[9]  J. Palefsky,et al.  Human Papillomavirus 16 (HPV 16) and HPV 18 Antibody Responses Measured by Pseudovirus Neutralization and Competitive Luminex Assays in a Two- versus Three-Dose HPV Vaccine Trial , 2010, Clinical and Vaccine Immunology.

[10]  L. Pinto,et al.  Correlation between direct ELISA, single epitope-based inhibition ELISA and Pseudovirion-based neutralization assay for measuring anti-HPV-16 and anti-HPV-18 antibody response after vaccination with the AS04-adjuvanted HPV-16/18 cervical cancer vaccine , 2008, Human vaccines.

[11]  M. Lehtinen,et al.  Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. , 2007, Vaccine.

[12]  Eduardo Lazcano-Ponce,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 , 2007, The Pediatric infectious disease journal.

[13]  G. Krogh,et al.  High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up , 2006, British Journal of Cancer.

[14]  X. Castellsagué,et al.  Comparison of the Immunogenicity and Reactogenicity of a Prophylactic Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine in Male and Female Adolescents and Young Adult Women , 2006, Pediatrics.

[15]  Xavier Castellsagué,et al.  Chapter 1: HPV in the etiology of human cancer. , 2006, Vaccine.

[16]  J. Heyse,et al.  Statistical Considerations for NonInferiority/Equivalence Trials in Vaccine Development , 2006, Journal of biopharmaceutical statistics.

[17]  C. Wheeler,et al.  Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. , 2006, Vaccine.

[18]  S. Arya.  Evaluation of OPV and polio eradication. , 2006, Vaccine.

[19]  K. Jansen,et al.  Optimization and Validation of a Multiplexed Luminex Assay To Quantify Antibodies to Neutralizing Epitopes on Human Papillomaviruses 6, 11, 16, and 18 , 2005, Clinical Diagnostic Laboratory Immunology.

[20]  Kathrin U. Jansen,et al.  Simultaneous Quantitation of Antibodies to Neutralizing Epitopes on Virus-Like Particles for Human Papillomavirus Types 6, 11, 16, and 18 by a Multiplexed Luminex Assay , 2003, Clinical Diagnostic Laboratory Immunology.

[21]  Steven Bird,et al.  A Randomized Trial of Alternative Two- and Three-Dose Hepatitis B Vaccination Regimens in Adolescents: Antibody Responses, Safety, and Immunologic Memory , 2001, Pediatrics.

[22]  K. Syrjänen.  Persistent high-risk human papillomavirus (HPV) infections as surrogate endpoints of progressive cervical disease. Potential new endpoint for efficacy studies with new-generation (non-HPV 16/18) prophylactic HPV vaccines. , 2011, European journal of gynaecological oncology.