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Editorial
November 21, 2016

Two vs Three Doses of Human Papillomavirus VaccineNew Policy for the Second Decade of the Vaccination Program

Author Affiliations
  • 1Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, US Centers for Disease Control and Prevention, Atlanta, Georgia
  • 2Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, US Centers for Disease Control and Prevention, Atlanta, Georgia
JAMA. Published online November 21, 2016. doi:10.1001/jama.2016.16393

This year marks the 10th year of the human papillomavirus (HPV) vaccination program in the United States. In 2006, the first HPV vaccine, quadrivalent HPV vaccine, was licensed by the US Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices and the US Centers for Disease Control and Prevention (CDC). In subsequent years, 2 additional HPV vaccines were licensed, bivalent HPV vaccine in 2009 and 9-valent HPV vaccine in 2014.1 All 3 vaccines were initially licensed and recommended for use in a 3-dose series. In 2006, vaccination was recommended for girls at the age of 11 or 12 years with catch-up vaccination through the age of 26 years; in 2011, the United States was the first country to include boys and men in the routine HPV vaccination program. Following national introductions of HPV vaccination, significant declines in vaccine-type HPV prevalence, genital warts, and cervical precancers have been observed in the United States and other countries.2

For all 3 HPV vaccines, licensure was based on data from large pivotal clinical trials establishing efficacy in young adult populations; immunogenicity studies compared postvaccination HPV antibody titers in young adolescents (aged 9-15 years) with those achieved in the age group (15-26 years) for which efficacy was demonstrated.3 This immunobridging approach demonstrated that titers were not only noninferior but also consistently higher in younger age groups. Post hoc analysis of 1 early 3-dose efficacy trial suggested protection with fewer than 3 vaccine doses.4 Interest in reduced dose vaccination schedules then arose as evidence of high and durable antibody responses to vaccination accumulated.3 The rationale for the 3-dose schedule used in the efficacy trials for all 3 HPV vaccines was that 2 priming vaccine doses would be needed followed by a boosting dose at 6 months. Two-dose schedules, eliminating the second priming dose but retaining the boosting dose, were evaluated in immunogenicity trials.57 Based on immunobridging analyses, 2-dose schedules for quadrivalent and bivalent HPV vaccines were approved by some regulatory authorities, such as the European Medicines Agency, and recommended by the World Health Organization (WHO) in 2014.8

In October 2016, the CDC recommended a 2-dose schedule for adolescents starting the HPV vaccination series before the age of 15 years. This important policy change for the United States is supported by previously published data as well as results from the clinical trial by Iversen and colleagues9 in this issue of JAMA. This clinical trial, which included 1518 participants, was the basis for the recent approval from the Food and Drug Administration of a 2-dose series of the 9-valent HPV vaccine for adolescents.10 The trial included girls and boys aged 9 to 14 years who received 2 doses of the 9-valent HPV vaccine either 6 or 12 months apart. Two comparison groups received a 3-dose schedule: adolescent girls and young women aged 16 to 26 years (the age group for which efficacy trials have demonstrated protection against clinical end points of cervical and other precancers)11 and girls aged 9 to 14 years. This trial found greater than 98% seroconversion to all 9 HPV types targeted by the vaccine, in all groups, at 1 month after the last vaccine dose. Compared with adolescent girls and young women aged 16 to 26 years who received 3 doses of the vaccine, antibody titers were noninferior in girls and boys aged 9 to 14 years who received 2 doses, with ratios of geometric mean titers ranging from 1.60 to 2.99 in the groups that received the vaccine at 0 and 6 months and from 1.96 to 6.31 in the group that received the vaccine at 0 and 12 months.

Although neutralizing antibodies are understood to be the basis for protection after HPV vaccination, the minimum protective level has not been identified. Achieving titers comparable with those found to be protective in efficacy trials remains one of the best options for evaluating new dosing schedules or vaccine formulations. For example, the 9-valent HPV vaccine efficacy trial used the quadrivalent HPV vaccine in the comparison group. For the 4 HPV types targeted by both formulations (HPV-6, HPV-11, HPV-16, and HPV-18), noninferior antibody titers were the primary end point because infection or disease end points for those HPV types could not be assessed.11 The increasing importance of immunoassays in these trials provides an impetus to standardize HPV serology assays and improve interassay comparability. International standards for HPV-16 and HPV-18 antibodies are available from the National Institute for Biological Standards and Control (WHO International Laboratory for Biological Standards). Clinical trials of HPV vaccines have yet to use these key standards to report titers in international units that are comparable between assays.

With data from the trial reported in JAMA,9 evidence now supports a 2-dose schedule in adolescents (aged 9-14 years) for all 3 licensed HPV vaccines. When the vaccination series is initiated before the age of 15 years, 2 doses administered at a 0- and 6-month interval or at a 0- and 12-month interval were found to be just as immunogenic as (or even better than) 3 doses. The 9-valent HPV vaccine study design also allowed a direct comparison of 2 doses with 3 doses in girls aged 9 to 14 years, although these analyses were considered exploratory.9 Compared with girls in the same age group who received 3 doses, antibody titers were noninferior for most HPV vaccine types; in girls who received 2 doses at a 6-month interval, titers were numerically higher for 5 of 9 HPV types, and in the 12-month interval group for 8 of 9 HPV types. These findings differ somewhat from other comparisons of 2 vs 3 doses of vaccine in the same age group, which have generally found that 2 doses produce lower, although mostly noninferior, antibody titers.5 Nevertheless, even low levels of antibody may be protective.3 An important unanswered question is whether evidence can be obtained to support a 2-dose schedule in persons initiating HPV vaccination at the age of 15 years or older.

In addition to immunogenicity data, evidence reviewed by the CDC and the Advisory Committee on Immunization Practices for this policy change included data from postlicensure effectiveness studies, post hoc analyses of clinical trials, evaluation of duration of protection, and health effect modeling. Although postlicensure studies have provided important evidence for policy considerations for other vaccines, these studies have substantial limitations for evaluation of HPV vaccine schedules at this time.1214 In these studies, most recipients of 2 doses had a short interval between doses because they started but did not complete a 3-dose schedule (at 0, 1-2, and 6 months). In addition, in some studies 2-dose vaccinees differed from 3-dose vaccinees in ways suggesting the former had higher risk of HPV exposure prior to vaccination. As a result, postlicensure effectiveness studies evaluating HPV prevalence, genital warts, and cervical precancer outcomes have not shown that 2 doses are as effective as 3, in contrast to immunobridging trials that have consistent results supporting 2-dose schedules.

Health effect modeling efforts over the past 10 years have been valuable for understanding the potential effect of HPV vaccine policy and programs.15,16 Models have informed policy decisions about target age groups for routine and catch-up vaccination of females as well as including males in vaccination programs. For evaluation of 2-dose schedules, modeling identified duration of protection as one of the most important parameters to consider when evaluating a switch to a 2-dose schedule.17 All available data suggest long-lasting protection after HPV vaccination. To date, the longest follow-up of participants in 3-dose trials has been about 10 years.1820 Data are not available on long-term efficacy after 2-dose HPV vaccination schedules; however, the similar antibody kinetics after 2-dose and 3-dose schedules, available through 3 to 5 years for some studies, suggest long-lasting duration of protection for 2-dose schedules.5,6 Further follow-up of 2-dose studies will provide needed data on duration of antibody response and protection. Although duration of protection is expected to be long lasting regardless of dosing schedule, duration of protection following either a 2-dose or 3-dose HPV vaccine series is not known at this time.

The decision by the CDC to recommend a 2-dose series of HPV vaccine was based on a variety of data supporting efficacy of this schedule. An added benefit of this recommendation could be that it may increase vaccine acceptability and uptake. The coverage of HPV vaccination in the United States is lower than that for other vaccines recommended for adolescents, such as quadrivalent meningococcal conjugate vaccine and tetanus, diphtheria, and acellular pertussis vaccine.21 In 2015, 3-dose HPV vaccination coverage among 13- to 17-year-olds was only 41.9% for girls and 28.1% for boys; at least 1-dose coverage was 62.8% for girls and 49.8% for boys. Going forward, a 2-dose schedule should make it easier to complete the recommended vaccination series. A 2-dose schedule (at 0 and 6-12 months) will decrease health care appointments needed for HPV vaccination and facilitate clinicians’ ability to deliver vaccine at preventive health visits. Nevertheless, efforts will be needed to increase vaccine initiation and ensure delivery of the second dose.

During the first decade of the HPV vaccination program, knowledge has increased about these highly effective HPV vaccines. Population-level effects of vaccination programs on infection and disease outcomes have exceeded expectations in many countries,2 and extensive safety evaluations have not identified concerns.22 In the second decade, reduced dose schedules might help achieve higher HPV vaccination coverage, advance HPV vaccine program introductions in more countries, and further reduce the burden of HPV-associated cancers and disease worldwide.

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Article Information

Corresponding Author: Lauri E. Markowitz, MD, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, US Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS A34, Atlanta, GA 30329 (lem2@cdc.gov).

Published Online: November 21, 2016. doi:10.1001/jama.2016.16393

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.

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