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The End of Human Papillomavirus Vaccine Exceptionalism

      Why was human papillomavirus (HPV) vaccine different from all other vaccines? For other routine vaccines included in the child and adolescent immunization schedules, pediatricians in the United States responded to recommendations from the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics by incorporating the vaccine into their routine practice workflow. For HPV vaccine, for much of the 10 years since the ACIP's first recommendations, receiving HPV vaccine together with other preteen immunizations was the exception, rather than the rule. “HPV exceptionalism” might be reminiscent of HIV exceptionalism
      • Bayer R.
      Public health policy and the AIDS epidemic.
      and might account for the persistent gap between coverage of HPV vaccine and teen coverage of tetanus-diphtheria-acellular pertussis (Tdap) or meningococcal A,C,Y,W-135 conjugate (MenACWY) vaccines. Re-evaluation of the elements that created HPV exceptionalism can prompt an end to differential treatment for HPV vaccination, and strengthen its full integration into routine pediatric practice.
      For all other routine adolescent vaccines, clinicians anticipated benefits of the immunization against an acute infectious disease. HPV vaccination aims to prevent complications of infection that are severe (ie, malignancies and precancers) but that have delayed onset. Pediatricians will not personally witness fewer disease outcomes in their vaccinated patients. Clinicians who were rapid adopters and consistently vaccinated against HPV relied on the presumption that longer-term benefits would occur. Now those who were awaiting proof might be comforted by the impressive vaccine-associated declines that have been reported for vaccine-type HPV prevalence, genital warts, and precancerous lesions.
      • Markowitz L.E.
      • Hariri S.
      • Lin C.
      • et al.
      Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010.
      • Smith L.M.
      • Strumpf E.C.
      • Kaufman J.S.
      • et al.
      The early benefits of human papillomavirus vaccination on cervical dysplasia and anogenital warts.
      These studies confirm expectations from randomized controlled trials conducted prelicensure.
      For all other routine childhood vaccines, boys as well as girls are immunized. The 2007 ACIP and American Academy of Pediatrics HPV vaccine recommendations targeted only girls, consistent with the evidence base for completed clinical trials and initial product indications. This led to different workflows for girls and boys seen during the 11- and 12-year-old office visits, and might have decreased the initial priority clinicians assigned and/or parents perceived for HPV vaccination. Even when updated recommendations in 2011 expanded routine vaccination to include boys, there were different upper limits for catch-up vaccination (ie, 26 years for young women and 21 for most young men). Although the catch-up recommendations corresponded with findings from systematic review of the preventable burden of disease and cost-effectiveness analyses, clinicians and parents might have perceived mixed messages about the importance of routine HPV vaccination. A recent analysis found pediatricians underestimated the value parents placed on HPV compared with other vaccines.
      • Healy C.M.
      • Montesinos D.P.
      • Middleman A.B.
      Parent and provider perspectives on immunization: are providers overestimating parental concerns?.
      HPV vaccine is truly exceptional. HPV is the only routinely recommended vaccine for which ACIP has reduced the number of doses needed to fully immunize an individual.
      • Meites E.
      • Kempe A.
      • Markowitz L.E.
      Use of a 2-dose schedule for human papillomavirus vaccination - updated recommendations of the Advisory Committee on Immunization Practices.
      Postlicensure evaluations of Tdap, MenACWY, and HPV vaccines each resulted in updated dosing recommendations. For MenACWY vaccine, a case-control study of vaccine efficacy and research on antibody levels over time since immunization suggested that protection waned within a few years. These findings led ACIP to recommend a booster dose of MenACWY vaccine in 2011. Postlicensure studies of acellular pertussis vaccines also found waning of protection within several years of vaccination. The findings led ACIP to recommend that pregnant women receive Tdap vaccine in every pregnancy. In contrast, noninferior immunogenicity for 2- versus the standard 3-dose HPV regimens led to ACIP's 2016 recommendation for a 2-dose HPV schedule for those younger than 15 years of age at initial vaccination, which has the added benefit of simplifying the series for parents and pediatricians. Postlicensure data also suggest substantial indirect protection
      • Drolet M.
      • Benard E.
      • Boily M.C.
      • et al.
      Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.
      for HPV vaccine, whereas Tdap epidemiological evaluations and animal model studies suggest acellular pertussis vaccine is not likely to reduce transmission of Bordetella pertussis.
      Exceptionalism appears to have had serious consequences. By 2009, immunization rates for HPV in girls in the United States began to lag behind other preteen vaccines, and by 2012 HPV vaccine first dose coverage levels in girls had stagnated (2011: 53% vs 53.8% for 2012).
      • Reagan-Steiner S.
      • Yankey D.
      • Jeyarajah J.
      • et al.
      National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 Years - United States, 2015.
      Intensified efforts by state and local health departments and clinician organizations, multimedia communication campaigns, and health system interventions might be responsible for the subsequent modest annual increases. HPV first-dose coverage in girls 13 to 17 years of age rose approximately 3 percentage points per year after 2012, reaching 62.8% in 2015.
      • Reagan-Steiner S.
      • Yankey D.
      • Jeyarajah J.
      • et al.
      National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 Years - United States, 2015.
      An estimated 900,000 additional teen-aged girls initiated the HPV series between 2012 and 2015, compared with that expected had the plateau in coverage continued (H. Chesson, PhD, written communication, October 2016).
      Although national and most state-specific levels of first-dose coverage for girls as well as boys continue to lag well behind the coverage achieved for Tdap and MenACWY vaccine, some institutions and clinicians have achieved greater success. Of note, Farmar et al at Denver Health reported nearly 90% coverage for the first dose of HPV vaccine in girls as well as boys, similar to coverage achieved for Tdap and MenACWY vaccine.
      • Farmar A.L.
      • Love-Osborne K.
      • Chichester K.
      • et al.
      Achieving high adolescent HPV vaccination coverage.
      Their approach of bundling (or mainstreaming) HPV together with other vaccines and establishing systemic interventions, such as standing orders, has been successful. The patient and parent characteristics at Denver Health practices might not be generalizable to the entire United States, but the institution's experience suggests that progress in other settings is possible. Other investigators have reported that using presumptive vaccine messaging (eg, “Today your child is due for 3 vaccines”) rather than participatory wording (eg, “What would you like to do about the HPV vaccine?”) is associated with higher uptake.
      • Brewer N.T.
      • Hall M.E.
      • Malo T.L.
      • et al.
      Announcements versus conversations to improve HPV vaccination coverage: a randomized trial.
      The most exceptional feature of HPV vaccination is its ability to prevent serious cancers. Data continue to emerge on the full range of cancers associated with oncogenic HPV types. HPV vaccines are licensed for the prevention of cervical, anal, vulvar, and vaginal cancers, and although not yet demonstrated, might also prevent HPV-associated oropharyngeal cancers. In the meantime, oncologists, gynecologic surgeons, and cancer survivor groups have joined with immunization and public health professionals to form an HPV Roundtable aimed at motivating greater uptake of HPV cancer prevention through immunization (http://www.cancer.org/healthy/informationforhealthcareprofessionals/nationalhpvvaccinationroundtable). The 2-dose extended interval HPV vaccine recommendation for younger teens
      • Meites E.
      • Kempe A.
      • Markowitz L.E.
      Use of a 2-dose schedule for human papillomavirus vaccination - updated recommendations of the Advisory Committee on Immunization Practices.
      holds promise to reset the expectations for HPV immunization, and could end the era of separate and unequal treatment for this lifesaving vaccination.

      Acknowledgments

      Financial disclosure: Publication of this article was supported by the Centers for Disease Control and Prevention.
      Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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