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Table 1.  
Seropositivity Ratesa and Anti-HPV GMTs Among Girls Aged 9 to 13 Years Receiving 2 vs 3 Doses of HPV Vaccine at 36 and 60 Months
Seropositivity Ratesa and Anti-HPV GMTs Among Girls Aged 9 to 13 Years Receiving 2 vs 3 Doses of HPV Vaccine at 36 and 60 Months
Table 2.  
Difference Between Anti-HPV GMTs for Month 36 and 60 Since First Vaccination Among Girls Aged 9 to 13 Years Receiving 2 or 3 Doses of the HPV Vaccinea
Difference Between Anti-HPV GMTs for Month 36 and 60 Since First Vaccination Among Girls Aged 9 to 13 Years Receiving 2 or 3 Doses of the HPV Vaccinea
1.
World Health Organization.  Human papillomavirus vaccines: WHO position paper, October 2014. http://www.who.int/wer/2014/wer8943.pdf?ua=1. Accessed January 13, 2013
2.
Dobson  SR, McNeil  S, Dionne  M,  et al.  Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women.  JAMA. 2013;309(17):1793-1802.PubMedGoogle ScholarCrossref
3.
Romanowski  B, Schwarz  TF, Ferguson  L,  et al.  Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule in adolescent girls.  Hum Vaccin Immunother. 2016;12(1):20-29.PubMedGoogle ScholarCrossref
4.
Kaji  AH, Lewis  RJ.  Noninferiority trials: is a new treatment almost as effective as another?  JAMA. 2015;313(23):2371-2372.PubMedGoogle ScholarCrossref
5.
Villa  LL, Costa  RL, Petta  CA,  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.  Br J Cancer. 2006;95(11):1459-1466.PubMedGoogle ScholarCrossref
6.
Olsson  SE, Villa  LL, Costa  RL,  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.  Vaccine. 2007;25(26):4931-4939.PubMedGoogle ScholarCrossref
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Research Letter
April 25, 2017

Immunogenicity of 2 vs 3 Doses of the Quadrivalent Human Papillomavirus Vaccine in Girls Aged 9 to 13 Years After 60 Months

Author Affiliations
  • 1University of British Columbia, Vancouver, British Columbia, Canada
  • 2Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, Quebec, Canada
  • 3Dalhousie University, Halifax, Nova Scotia, Canada
JAMA. 2017;317(16):1687-1688. doi:10.1001/jama.2017.1840

Human papillomavirus (HPV) vaccines were originally approved with 3-dose schedules. However, 2 doses of HPV vaccine have been recommended1 for girls younger than 15 years based on antibody response at 36 months,2,3 although continued research on the duration of antibody persistence was advised. We report antibody response at 60 months after 2 doses of quadrivalent HPV vaccine.

Methods

This study is a post hoc analysis from a phase 3, postlicensure, noninferiority immunogenicity trial conducted at 3 centers in Canada in 2007-2008.2 The study was approved by ethics boards at each center and oral and written informed consent was obtained. In the original trial, designed to examine antibody response to 2 doses vs 3 doses of quadrivalent HPV vaccine, girls (aged 9-13 years) were randomized to receive 2 doses (at 0 and 6 months) or 3 doses (at 0, 2, and 6 months) and women (aged 16-26 years) received 3 doses.2 Noninferiority of 2 doses in girls for all 4 types contained in the vaccine (HPV 6, 11, 16, and 18) compared with 3 doses in women (in whom vaccine efficacy was established) 1 month after the last dose (primary outcome) was shown, which persisted at 36 months. As a secondary outcome, among girls, 2 doses were noninferior to 3 doses for HPV 11 and 16, but noninferiority was lost for HPV 6 and 18 by 36 months.

As part of a long-term efficacy study, in 2013 (60 months after vaccination), girls who were original trial participants were invited to provide a serum sample to evaluate antibodies to HPV 6, 11, 16, and 18 using immunoassay (competitive Luminex Immunoassay; Merck). Women were not part of the long-term study. Antibody testing, conducted by PPD Vaccines and Biologics for Merck, was blinded to group allocation.

Seropositivity rates and geometric mean titers (GMTs)2 for 4 genotypes were compared between 2-dose and 3-dose recipients at 60 months. Seropositivity rates and GMTs with 95% CIs were computed using Wilson method and Tukey–Kramer method, respectively, using SAS (SAS Institute), version 9.4. Noninferiority was defined as a lower bound of the 97.5% CI for the GMT ratio of 2 doses vs 3 doses greater than 0.5.4 Paired sample t test and 2-sample t test with unequal variances were used to compute P values based on the log scale of titer values (α = .05). To determine if there was a significant difference (2-sided P < .05) in trends in antibody concentrations for HPV types between 2 and 3 doses over time, linear mixed-effects models on the natural log-transformed values from assays (modeled on the log-normal scale) were used.

Results

Of 520 girls originally randomized, 101 provided serum samples at 60 months (50 receiving 2 doses and 51 receiving 3 doses). Seropositivity at 60 months for both 2 doses and 3 doses was above 95% for all genotypes except HPV 18 (Table 1). At 60 months, responses for HPV 6, HPV 11, and HPV 16 were all noninferior in the 2-dose vs 3-dose groups. Between 36 and 60 months, there was a significant reduction in GMTs across all HPV types for both the 2-dose and 3-dose groups based on paired sample t test (Table 2). However, there was no significant difference in the reduction between groups (Table 2). For all 4 types in both groups, there was a decline in GMT titers to 60 months, but there was no difference (P > .05) between the trend in decline between 2 and 3 doses.

Discussion

A 2-dose schedule of HPV vaccine could offer cost savings and improve global vaccine access. This study found that although GMTs in both 2-dose and 3-dose recipients decreased significantly at 36 and 60 months, there was no significant difference in the reduction between the 2 groups.

In women aged 16 to 26 years, seropositivity rates at 60 months after 3 doses were all lower than in girls receiving 2 doses at 60 months.6 Because vaccine efficacy against disease in women at 60 months is greater than 95%, this study offers reassurance that girls who received 2 doses should have comparable protection,5 pending studies of long-term efficacy.

The main limitation is the small sample size. Durability of antibody response and vaccine protective efficacy should continue to be monitored.

Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Article Information

Corresponding Author: Gina Ogilvie, MD, DrPH, British Columbia Women's Hospital and Health Centre, Room H203G, 4500 Oak St, Vancouver, BC V6H 3N1, Canada (gina.ogilvie@cw.bc.ca).

Author Contributions: Drs Ogilvie and Dobson had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ogilvie, Dionne, McNeil, Money, Dobson.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ogilvie, Dobson.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ogilvie, Dobson.

Obtained funding: Ogilvie, Dionne, Krajden, Dobson.

Administrative, technical, or material support: Dionne, Dobson.

Supervision: Ogilvie, Dionne, McNeil, Dobson.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dionne reports receiving grant support and travel expenses from GlaxoSmithKline. Dr McNeil reports receiving grant support from the Nova Scotia Department of Health and Wellness and GlaxoSmithKline, payment for lectures from GlaxoSmithKline and Merck, and conducting clinical trials supported by Merck and GlaxoSmithKline. Dr Krajden reports receiving support from Roche, Siemens, Merck, Hologic, and Boehringer Ingelheim. Dr Money reports grants from Michael Smith Foundation for Health Research and grant funding from Merck, GlaxoSmithKline, Canadian Institutes of Health Research, and Merck. Dr Dobson reports conducting clinical trials supported by Merck and being a member of the British Columbia Immunization Committee, which decides on issues relating to implementation of vaccine programs. No other disclosures were reported.

Funding/Support: The Michael Smith Foundation for Health Research, the Canadian Immunization Research Network, and the Ministries of Health in the provinces of British Columbia, Nova Scotia, and Quebec provided the funding for this project. Merck conducted the antibody assays at no cost to the study.

Role of the Funder/Sponsor: As part of its review and approval of the funding application, Michael Smith Foundation for Health Research approved the design, analysis, and conduct of the study. The funders had no role in the collection, management, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Joel Singer, PhD (University of British Columbia), Monika Naus, MD, MHSc, FRCPC (British Columbia Centre for Disease Control), and Vladimir Gilca, MD, PhD (Centre Hospitalier Universitaire de Québec-Université Laval), who are co-investigators of this study and contributed to the study design and oversight. We also thank Heather Pedersen, BSc, MPH (University of British Columbia), for her assistance in writing the article; Shu Yu Fan, MSc (Vaccine Evaluation Centre), for support with the statistical analysis; and Kim Marty, BSc (Vaccine Evaluation Centre), for operational support for the study. None of these contributors received direct compensation for this study.

References
1.
World Health Organization.  Human papillomavirus vaccines: WHO position paper, October 2014. http://www.who.int/wer/2014/wer8943.pdf?ua=1. Accessed January 13, 2013
2.
Dobson  SR, McNeil  S, Dionne  M,  et al.  Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women.  JAMA. 2013;309(17):1793-1802.PubMedGoogle ScholarCrossref
3.
Romanowski  B, Schwarz  TF, Ferguson  L,  et al.  Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule in adolescent girls.  Hum Vaccin Immunother. 2016;12(1):20-29.PubMedGoogle ScholarCrossref
4.
Kaji  AH, Lewis  RJ.  Noninferiority trials: is a new treatment almost as effective as another?  JAMA. 2015;313(23):2371-2372.PubMedGoogle ScholarCrossref
5.
Villa  LL, Costa  RL, Petta  CA,  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.  Br J Cancer. 2006;95(11):1459-1466.PubMedGoogle ScholarCrossref
6.
Olsson  SE, Villa  LL, Costa  RL,  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.  Vaccine. 2007;25(26):4931-4939.PubMedGoogle ScholarCrossref
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