Review and answer 23 questions about the article and the article supplement. Be very detail with each answers

Human Papillomavirus Vaccination Guideline Update: American Cancer Society Guideline Endorsement

Debbie Saslow, PhD1, Kimberly S. Andrews, BA2, Deana Manassaram-Baptiste, PhD3, Lacey Loomer, MSPH4, Kristina E. Lam, MD, MPH5, Marcie Fisher-Borne, MPH, PhD6, Robert A. Smith, PhD7, and Elizabeth T. H. Fontham, MPH, DrPh8 on behalf of the American Cancer Society Guideline Development Group 1Director, Cancer Control Intervention, Human Papillomavirus and Women’s Cancers, American Cancer Society, Atlanta, GA

2Director, Guideline Process, American Cancer Society, Atlanta, GA

3Director, Guideline Process, American Cancer Society, Atlanta, GA

4Graduate Student, Emory University Rollins School of Public Health, Atlanta, GA

5Medical Epidemiologist, Georgia Department of Public Health, Atlanta, GA

6Program Director, Human Papillomavirus Vaccination, American Cancer Society, Atlanta, GA

7Vice President, Cancer Screening, American Cancer Society, Atlanta, GA

8Founding Dean and Professor Emeritus, Louisiana State University School of Public Health, New Orleans, LA

Abstract

The American Cancer Society (ACS) reviewed and updated its guideline on human papillomavirus

(HPV) vaccination based on a methodologic and content review of the Advisory Committee on

Immunization Practices (ACIP) HPV vaccination recommendations. A literature review was

performed to supplement the evidence considered by the ACIP and to address new vaccine

formulations and recommendations as well as new data on population outcomes since publication

of the 2007 ACS guideline. The ACS Guideline Development Group determined that the evidence

Corresponding author: Debbie Saslow, PhD, Cancer Control Department, American Cancer Society, 250 Williams St, Suite 600, Atlanta, GA 30303; [email protected].

Additional supporting information may be found in the online version of this article.

DISCLOSURES: The American Cancer Society (ACS) supported the development of the guideline through the use of general funds. Outside the submitted work, the ACS is the recipient of 2 cooperative agreements from the Centers for Disease Control and Prevention (CDC), Prevention and Public Health Fund, that seek to increase human papillomavirus (HPV) vaccination of girls and boys ages 11 to 12 years within the United States. Debbie Saslow reports being Principal Investigator of both of those cooperative agreements, and Marcie Fisher-Borne reports being co-Principal Investigator and receiving salary support through one of those cooperative agreements. All remaining authors report no conflicts of interest.

Author Contributions: Debbie Saslow: Conceptualization, methodology, validation, formal analysis, investigation, resources, writing–original draft, writing–review and editing, visualization, and project administration. Kimberly S. Andrews: Methodology, writing–original draft, writing–review and editing, and project administration. Deana Manassaram-Baptiste: Investigation, writing– original draft, and writing–review and editing. Lacey Loomer: Formal analysis and writing–review and editing. Kristina E. Lam: Investigation and writing–review and editing. Marcie Fisher-Borne: Writing–review and editing. Robert A. Smith: Writing–review and editing, visualization, supervision, and project administration. Elizabeth T. H. Fontham: Conceptualization, validation, writing– review and editing, and project administration.

HHS Public Access Author manuscript CA Cancer J Clin. Author manuscript; available in PMC 2017 August 14.

Published in final edited form as: CA Cancer J Clin. 2016 September ; 66(5): 375–385. doi:10.3322/caac.21355.

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supports ACS endorsement of the ACIP recommendations, with one qualifying statement related

to late vaccination. The ACS recommends vaccination of all children at ages 11 and 12 years to

protect against HPV infections that lead to several cancers and precancers. Late vaccination for

those not vaccinated at the recommended ages should be completed as soon as possible, and

individuals should be informed that vaccination may not be effective at older ages.

Keywords

American Cancer Society; Advisory Committee on Immunization Practices; guideline; human papillomavirus (HPV); vaccine; cancer prevention

Introduction

The burden of human papillomavirus (HPV)-related diseases, an understanding of the

association of HPV infection with several cancer types, and the availability of vaccines

together present an unprecedented opportunity for cancer prevention. Saraiya et al1

performed a recent study in which archival tissue from patients with cancer in 7 population-

based cancer registries was tested for the presence of high-risk HPV types. HPV infection

was associated with 91% of cervical cancers, 69% of vulvar cancers, 75% of vaginal

cancers, 63% of penile cancers, 89% of anal cancers in males, 93% of anal cancers in

females, and 72% of oropharyngeal cancers in males and 63% of oropharyngeal cancers in

females.1 The Centers for Disease Control and Prevention (CDC) applied these proportions

to the most recently available registry data on HPV-associated cancers to estimate the

number of cancers caused by HPV. They estimated that around 30,700 cancers (based on

2008–2012 data) probably attributable to HPV are diagnosed in the United States each year:

19,200 in women and 11,600 in men.2 The incidence rates of several of these cancers are

increasing, with striking socioeconomic disparities for several HPV-associated cancers

among both men and women.3

Three HPV vaccines (the Cervarix [GlaxoSmithKline, London, UK] bivalent vaccine

[2vHPV] and the Gardasil [Merck & Company, Kenilworth, NJ] quadrivalent [4vHPV] and

9-valent [9vHPV] vaccines) are licensed in the United States and around the world (Table

1).4–9 These vaccines protect against the HPV types that are responsible for most cases of

HPV-associated cancers; the 4vHPV and 9vHPV vaccines also protect against nearly all

cases of genital warts. The CDC, the American Cancer Society (ACS), and many provider

groups recommend giving the 3-dose series of the HPV vaccine to children at ages 11 to 12

years (Table 1).4–9

2007 ACS Guideline for HPV Vaccine Use

The ACS first published a guideline for the use of prophylactic HPV vaccines for the

prevention of cervical intraepithelial neoplasia (CIN) and cervical cancer in 2007,10

recommending routine vaccination for females ages 11 to 12 years (with vaccination

permitted in children as young as 9 years) and vaccination for females ages 13 to 18 years to

catch up on a missed vaccine or to complete the vaccination series. The ACS concluded that

there were insufficient data to recommend for or against routine universal vaccination of

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females ages 19 to 26 years; instead, the ACS recommended informed decision making for

vaccination in this population.10

The 2007 ACS guideline has been important in making clear the significance of the HPV

vaccine as a cancer-prevention intervention. However, since publication of the guideline,

there have been additional studies, new vaccine formulations licensed for use in the United

States, and new immunization recommendations.5–9 The 2007 ACS guideline does not

address use of the vaccine in males or use of the most recently available 9-valent vaccine

formulation; nor does it reflect recent evidence on the effectiveness of late vaccination, eg, at

ages 19 to 26 years.

The ACS Consideration of Endorsement of Recommendations of the

Advisory Committee on Immunization Practices

The recommendations for vaccines developed by the Advisory Committee on Immunization

Practices (ACIP) serve as the principal source of guidance on US immunization policy; the

ACS has been represented on the ACIP HPV Vaccine Work Group since 2005. The ACIP

recommendations for HPV vaccination, as for other vaccines in children and adolescents, are

harmonized with recommendations made by the American Academy of Pediatrics, the

American Academy of Family Physicians, and the American College of Obstetricians and

Gynecologists. Recognizing the need to update the ACS HPV vaccine use guideline and the

value in consistency across organizations in HPV immunization efforts as a primary cancer-

prevention strategy, the ACS chose to consider endorsement of the HPV vaccine

recommendations of the ACIP.

HPV vaccination protects against infection with the targeted HPV types and subsequent

related disease; however, it does not protect against disease resulting from previous exposure

to these HPV types. The 2007 ACS guideline and the ACIP recommendations from 2006

through 2015 were primarily based on randomized controlled trial (RCT) evidence of

vaccine efficacy, ie, the percentage reduction in disease incidence in a vaccinated group

compared with the incidence in an unvaccinated control group under optimal conditions, and

noninferior immunogenicity findings in females and males ages 9 to 15 years.4–9 Thus, it is

also important to consider observational data, such as results from ecological studies

measuring vaccine effectiveness, ie, reduction in disease outcomes in a “real-world” setting.

This is especially relevant when evaluating recommendations for vaccination among older

females and males, who are more likely to have been sexually active and thus more likely to

have had previous HPV exposure. Hence, the association between vaccine effectiveness and

age and the implications for late vaccination recommendations were a major focus of this

update.

ACIP Recommendations

The ACIP and the CDC first issued recommendations for routine HPV vaccination of

females ages 11 to 12 years and catch-up vaccination for females ages 13 to 26 years with

the quadrivalent HPV (4vHPV) vaccine in 2006.4 An ACIP work group reviewed published

and unpublished clinical trial data on vaccine efficacy against persistent HPV infections,

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cervical disease, and external genital warts; immunogenicity; and safety and adverse events.

Data on the epidemiology and natural history of HPV, vaccine acceptability, and cost

effectiveness were also considered. The recommendation for catch-up vaccination of

females who were not previously vaccinated was based in part on a review of data from

efficacy clinical trials that included females ages 16 to 23 years or 16 to 26 years and the

recognition that, when HPV vaccination was first introduced, females older than 12 years

would not have had the opportunity to receive the vaccine. The ACIP report noted that

overall vaccine effectiveness would be lower in a population of females who are sexually

active; thus, effectiveness would decrease with increasing age, increasing number of sexual

partners, and greater likelihood of HPV exposure. They concluded, however, that the

majority of females in this age group would derive at least partial benefit from vaccination.4

In 2009, the ACIP updated its recommendation for females to include use of the bivalent

(2vHPV) vaccine and provided guidance that 4vHPV may be given to males ages 9 through

26 years.5,6 The ACIP recommended routine vaccination of males in 2011 based on a review

of data on vaccine efficacy against anal cancer precursors and genital warts, vaccine safety,

disease burden, cost effectiveness, and programmatic considerations.7 For the

recommendations on male vaccination, the ACIP adopted the Grading of Recommendation

Assessment Development and Evaluation (GRADE) methodology to evaluate evidence and

develop recommendations.11 Routine vaccination of males ages 11 or 12 years was a

category A recommendation, indicating that it applies to all persons in an age or risk-based

group. Vaccination was also recommended for males ages 13 to 21 years who have not been

vaccinated previously or who have not completed the 3-dose series. The ACIP stated that

“males ages 22 through 26 years may be vaccinated.”7

In 2015, the ACIP updated their recommendations to include the 9-valent vaccine (9vHPV)

based on data from 9vHPV prelicensure clinical trials as well as efficacy trials from the

4vHPV vaccine program.9 The noninferior immunogenicity of 9vHPV compared with

4vHPV and in males compared with females was used to conclude its efficacy for HPV type

6 (HPV6), HPV11, HPV16, and HPV18. The safety of 9vHPV was evaluated based on 6

phase 3 studies in the clinical development program. All data came from RCTs conducted

by the vaccine manufacturer.9

The current ACIP recommendations also address special populations, including men who

have sex with men; persons who are immunocompromised because of transplantation,

medications, or human immunodeficiency virus (HIV); and children with a history of sexual

assault or abuse.8,9

Methods: ACS Guideline Endorsement

The ACS instituted a Guideline Development Group (GDG) (a volunteer group of clinicians,

methodologists, and public health practitioners) in 2012.12 To update the ACS

recommendations for HPV vaccination, a guideline endorsement process was implemented

similar to the American Society of Clinical Oncology (ASCO) model for endorsing another

organization’s guidelines.13 This model includes a methodologic review using the Appraisal

of Guidelines for Research and Evaluation II (AGREE II) instrument,14 a search for new

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evidence published since completion of a guideline under consideration, and a content

review.13

Following this approach, the ACS endorsement process for the HPV vaccine update

included: 1) a methodologic assessment of the ACIP recommendations, 2) a supplemental

evidence review, 3) a content review of the ACIP recommendations by the ACS GDG, 4)

development and approval of endorsement statements, 5) a review of the evidence report and

endorsement paper by expert advisors, and 6) approval of endorsement statements by the

ACS Board of Directors.

The methodologic assessment of the ACIP recommendations for HPV vaccination was

completed by 4 ACS guideline staff members working independently, using the AGREE II

instrument.14 A written summary of this assessment was provided to the ACS GDG.

A supplemental evidence review was conducted by ACS staff to identify any new data since

the release of the ACIP recommendations (see online supporting information). The scope of

the review also included male vaccination and the new vaccine formulation not covered in

the 2007 ACS guideline, as well as continuing questions about the effectiveness of

vaccination at older ages. This supplemental evidence review was designed to address 3 key

questions:

1. Should HPV “catch-up” or “late” vaccination be recommended for females ages 19 to 26 years who have not been vaccinated previously?

2. Should HPV vaccination be recommended for males ages 9 to 26 years?

3. Should 9-valent HPV vaccination be recommended for males and females?

Methodologic details of the evidence review are described in the online supporting

information. The evidence review report was reviewed by external advisors with expertise in

epidemiology, HPV, HPV vaccines, cervical cancer screening, management and treatment,

adolescent health, and gynecology. Reviewer comments, including those addressing

interpretation of the literature, were incorporated into the final version.

The ACS GDG performed a content review of the ACIP HPV vaccination recommendations

(consistent with its prior adoption of GRADE15) to assess: 1) whether the recommendations

were adequately supported by the evidence, 2) whether there was confidence in the

magnitude of estimates of effects on important outcomes, and 3) whether there was a

favorable balance between desirable and undesirable outcomes. On the basis of the evidence

considered by the ACIP, results of the ACS supplemental evidence review, and comments

from expert advisors, the GDG voted on whether to endorse the ACIP recommendations

either as stated or with commentary and qualifying statements when necessary for

clarification or when the GDG judgments on the evidence and recommendations differed

from those of the ACIP.

The draft endorsement statements were reviewed by the expert advisors and submitted with

a draft supplemental evidence review report to the ACS Mission Outcomes Committee and

Board of Directors for approval.

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ACS Guidelines and Conflicts of Interest

All participants in the guideline development process were required to submit disclosures of

all financial and nonfinancial (personal, intellectual, and practice-related) relationships and

activities that might be perceived as posing a conflict of interest in development of the HPV

vaccination guideline. The chairperson of the ACS GDG had the responsibility to ensure that

balanced perspectives were taken into account in deliberations and decision making.

Results of the ACS Methodologic Assessment

The overall score (the average of the 4 reviewers) of the ACIP recommendations on HPV

vaccination using the AGREE II instrument was 75%. Particular attention was given to the

Rigour of Development subscale, which is designed to assess the quality of the processes

used, evidence synthesis, and the methods used to formulate the guideline recommendation

statements. A slightly lower appraisal rating (69%) was given on this subscale, although the

reviewers noted that some domains of the AGREE II instrument may not be suitable for

evaluating a vaccine use guideline.

The conclusion of the methodologic assessment was that, overall, ACIP recommendations

are well written and presented, with suitable methods of development. Although extensive

evidence to support the recommendation statements was presented and evidence tables were

provided for the 2011 and 2015 updates, documentation was not provided that a systematic

evidence review was performed for any of the ACIP guideline iterations, and data search

strategies were not clearly described. There also was heavy reliance on data from RCTs

sponsored by the vaccine manufacturers as well as unpublished data provided by the

manufacturer. The possible limitations of such data were not clearly described or

acknowledged in the recommendation statements.

Detailed epidemiologic, efficacy, harms, and vaccine safety information was presented with

the ACIP recommendations. However, the recommendation statements did not address the

benefit of specific catch-up ages (eg, ages 21–26 years) for females or provide a rationale for

the difference in their recommended ages for males (ie, ages 13–21 years) and females (ages

13–26 years). Furthermore, while the ACIP has updated their recommendations several

times and considered new data on efficacy and immunogenicity as well as adverse events, it

is not clear what level of consideration was given to effectiveness data from countries with

high vaccination rates or to evidence on vaccine effectiveness stratified by age.

Despite the aforementioned limitations, the ACIP recommendations are evidence based,

with extensive summaries of the epidemiology of HPV and associated diseases as well as

efficacy and immunogenicity findings for the vaccines presented. The licensed HPV

vaccines are well described, and extensive updated information is provided on vaccine safety

from clinical trials and postlicensure studies and monitoring.

ACS Supplemental Evidence Review

In addition to the methodological review, the ACS conducted a supplemental evidence

review to identify relevant data published since the most recent ACIP recommendations

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were released as well as relevant data that were not included by the ACIP. The report on this

evidence review is provided online (see online supporting information).

A PubMed search updated through October 8, 2015, yielded 4091 articles, of which 338

were potentially relevant based on title; among these, 167 were selected for full review based

on examination of the abstract and 29 articles were included in this review. The included

articles address the critical outcomes of HPV vaccine effectiveness against the development

of precancerous lesions and the important outcomes of HPV vaccine effectiveness against

genital warts and persistent infection. There were 17 studies on late vaccination in females

(ages 18–26 years), 6 on males (ages 9–26 years), and 6 that addressed use of the 9vHPV

vaccine. Given the limited number and size of studies of efficacy for critical and important

outcomes, the additional outcome of immunogenicity was considered for 9vHPV. The major

findings of these studies are described in the online supporting information and summarized

for each key question below.

Although not included in the search terms for this review, reported adverse events potentially

associated with vaccination were included as outcomes of interest (see online supporting

information). The CDC and the ACIP sponsor an extensive, ongoing surveillance and safety

monitoring program related to vaccination, and updated results are publicly reported.16 The

CDC and ACIP regularly monitor postlicensure safety data through several systems in the

United States as well as reports from other countries. Studies from the United States and

Europe, for example, have shown no causal association of HPV vaccination and autoimmune

disease, stroke, Guillain-Barre syndrome, venous thromboembolism, seizures, connective

tissue disorders, or allergic disorders.16 The World Health Organization also monitors

vaccine safety through its Global Advisory Committee on Vaccine Safety, which has

published 6 reports on HPV vaccines, with the most recent report released in December

2015.17 Adverse events associated with the vaccination of males and with the 9vHPV

vaccine were included when they were reported as outcomes in the studies included in the

current supplemental review.

Results of the ACS Supplemental Evidence Review

1. Should HPV “late” vaccination be recommended for females ages 19 to 26 years who have not been vaccinated previously?—Although, in general, the data show efficacy across all age groups included in the RCTs, there is consistency in the

findings from RCTs and observational studies that vaccine effectiveness is highest in

preteens and early teens, lower in middle to late teen age groups, and lowest in young adult

age groups (ie, ages 20 years and older) (see online supporting information). Results from a

pooled analysis of 3 RCTs showed that estimates of benefits against high-grade cervical

lesions are substantially reduced when vaccination occurs after age 21 years compared with

vaccination before age 19 years.18 The results from observational data (3 ecological studies

and 1 case-control study using linked data) provide additional evidence of reduced

vaccination effectiveness at older ages, with greater decline in high-grade cervical lesions

among females younger than 19 years after the introduction of vaccination compared with

older age groups.19–22

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Estimates of the effectiveness of HPV vaccine by age must be regarded with caution. Most

ecological studies did not specifically measure age at vaccination. The majority of these

studies examined population outcomes after the introduction of vaccination and were not

based on linked vaccination and screening data. Conclusions from the included

observational studies are also limited by the time-frame since vaccine introduction and

adoption.

2. Should HPV vaccination be recommended for males ages 9 to 26 years?— The manufacturer-sponsored RCTs have demonstrated vaccine efficacy, high levels of

immunogenicity, and safety in males comparable to those in females. The evaluations of

cancer precursor outcomes are limited by a small number of cases, particularly in

heterosexual males.23,24 Vaccine efficacy for the important outcomes of persistent infection

and genital warts was demonstrated in all men included in the RCTs, and efficacy against

anal intraepithelial neoplasia was demonstrated in men who have sex with men. Modeling

studies also suggest reductions in critical and important outcomes and in HPV-associated

cancer cases and deaths.25,26 None of the studies reported outcomes stratified by age at

vaccination.

3. Should 9vHPV vaccination be recommended for males and females?—The available data on the 9vHPV vaccine are limited but show efficacy, immunogenicity, and

safety comparable to those demonstrated for the quadrivalent vaccine.

Although several RCTs reported on antibody response and seroconversion rates of the

9vHPV vaccine formulation,27–31 only one reported data on our critical and important

outcomes.32 On the basis of an RCT with 4 years of follow-up, Joura et al found similar

protection against cervical, vulvar, and vaginal lesions caused by the HPV types included in

the 4vHPV vaccine and a lower overall rate of high-grade lesions in the 9vHPV group

compared with the 4vHPV group.32

Given the limited direct evidence of efficacy of the recently approved 9vHPV vaccine

formulation against disease outcomes, data on the endpoints of immunogenicity and

noninferiority have been included, consistent with international recommendations on the use

of surrogate trial endpoints.33 Three RCTs found that the antibody response of the 9vHPV

vaccine for HPV6, HPV11, HPV16, and HPV18 was noninferior to that of the 4vHPV

vaccine, and both had similar safety profiles.30–32

ACS Content Review

The GDG conducted a content review of the ACIP HPV vaccine use recommendations as

part of the ACS endorsement process. The objective of the content review was to assess the

specific recommendations made and the extent to which the available evidence supports

each recommendation.

In the evaluation of the content and evidence presented in the ACIP recommendations, the

GDG members considered these questions:

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• Were the results of the studies supporting these recommendations interpreted and applied according to the GDG’s judgements about the data?

• Is the evidence presented in support of each recommendation sufficient?

• Are the recommendations in the guideline clear, and will they be easily understood by the intended audience?

• Is there agreement with the judgement of the balance of benefits and harms reflected in the recommendations, and is there confidence in the estimates of

effects?

• Do the recommendations adequately take into consideration patient values and preferences?

Upon completion of the content review, the GDG selected among options of full

endorsement, endorsement with qualifying statements or exceptions, or rejection for each

ACIP recommendation (Table 2). The GDG determined that the benefits of HPV vaccination

for prevention of cancer incidence, mortality, and morbidity in both males and females

outweigh the limited, predominantly nonserious side effects. The available evidence strongly

supports an update to the ACS recommendation for HPV vaccination related to the

vaccination of males and the use of the 9vHPV vaccine formulation. The benefits are

reduced at older ages at vaccination, supporting the recommendation for routine vaccination

at ages 11 to 12 years or as soon thereafter as possible. Providers should inform individuals

aged 22 to 26 years who have not been previously vaccinated or who have not completed the

series that vaccination at older ages is less effective in lowering cancer risk.

The ACS Mission Outcomes Committee and Board of Directors then approved the

endorsement and ACS guideline update as recommended by the GDG.

Discussion

Since release of the 2007 ACS guideline for HPV vaccine use to prevent cervical cancer and

its precursors,10 additional evidence has accumulated, and new immunization

recommendations addressing additional populations and new vaccine formulations have

been issued. The ACS conducted a supplemental evidence review and a methodologic

assessment and content review of the current ACIP recommendations.4–9 This update of the

ACS guideline addresses changes since 2007 and endorses current ACIP recommendations

for HPV vaccination, with the addition of one qualifying statement about decreased

effectiveness of the vaccine in persons ages 22 years and older.

The original recommendations for routine vaccination at age 11 or 12 years were based on

considerations of immunogenicity in this age group, including higher antibody titers

compared with older age groups; data on age of initiation of sexual activity; and, for

programmatic purposes, the established young adolescent health care visit at age 11 or 12

years.4,10 This review did not revisit the age for routine vaccination (ie, at ages 11–12 years).

This update and endorsement process focused on 3 key questions. The 2007 ACS guideline

agreed with the recommendations of the ACIP and other organizations in recommending

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routine vaccination for females ages 11 to 12 years and catch-up vaccination for females

ages 13 to 18 years but it differed in recommending informed decision making rather than

routine vaccination for females ages 19 to 26 years. There was a lack of efficacy data for the

prevention of HPV16/HPV18–related CIN2 or CIN3 in women who have had more than 4

lifetime sexual partners because of inclusion criteria for the clinical trials. National survey

data showed that half of females over age 19 years had 4 or more lifetime sexual partners.34

The ACS therefore selected a cutoff of age 18 years and recommended an informed

discussion between a woman and her health care provider regarding her risk of previous

HPV exposure and potential benefit from vaccination for women ages 19 to 26 years. An

additional consideration supporting this cutoff was that the federally funded Vaccines for

Children program provides free vaccination for uninsured and underinsured children,

covering approximately one-half of the US population, through age 18 years.35

There is consistency in findings from the RCTs of greater efficacy among the per-protocol

group (no evidence of current or past infection) compared with the intention-to-treat group

(see online supporting information). The evidence for vaccine efficacy in preventing

precancerous lesions is based primarily on data from RCTs that included women ages 15 to

26 years who had a limited number of lifetime sexual partners. Ecological studies examining

trends in disease outcomes since the introduction of vaccination show either significantly

reduced effectiveness or no effectiveness in older age groups.20–22 These findings suggest

that the “real-world” effectiveness of HPV vaccination in women (and men) older than age

21 years is likely to be lower than that in younger populations.

Two studies that were published after the completion of our supplemental evidence review

provide individual-level data on outcomes by age. By using linkage data from Scotland

measuring HPV prevalence in a population of women who had been eligible for the catch-up

vaccination program and who presented for their first screening at age 20 or 21 years,

Cameron et al36 reported that the odds of testing positive for HPV16 or HPV18 were 7.7%

for women who were vaccinated at age 15 or 16 years, 12.5% for those vaccinated at age 17

years, 16.6% for those vaccinated at age 18 years, and 30.3% for those vaccinated at ages 19

to 21 years, with an odds ratio of 5.31 when the age at vaccination was from 19 to 21 years

compared with 15 to 16 years.36 In a nationwide study that included the entire female

population of Sweden ages 13 to 29 years,37 Herweijer et al used national register-based

data to measure the effectiveness of HPV vaccination stratified by age at vaccination. In

their study, vaccine effectiveness against CIN2 or greater was 75% for individuals who were

vaccinated before age 17 years, 46% for those vaccinated at ages 17 to 19 years, and 22%

for those vaccinated at age 20 years or older. When the results were restricted to individuals

in the organized cervical screening program (ie, women ages 23–29 years who had recently

been screened), the authors found a strong protective effect of vaccination for women who

were vaccinated before age 20 years and a much smaller level of protection that was not

statistically significant for those vaccinated at age 20 years or older.37

Although some women (and, by inference, men) ages 22 to 26 years will benefit from HPV

vaccination, and vaccination is both licensed and safe for this age group, the efficacy and

effectiveness for preventing precancerous lesions are reduced compared with vaccination at

a younger age (see online supporting information). In 2007, the ACIP report acknowledged

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that, “although overall vaccine effectiveness would be lower when administered to a

population of females who are sexually active, and would decrease with older age and

likelihood of HPV exposure with increasing number of sex partners, the majority of females

in this age group will derive at least partial benefit from vaccination.”4 Similarly, the ACIP

2011 report on male vaccination reported that, “the population level benefits decrease with

increasing age at vaccination, especially after age 21 years.”7

The supplemental evidence review included articles that stratified outcomes by age, with

most studies reporting outcomes for females younger than 18 to 20 years compared with

females older than 19 or 20 years. There are limited data on precise age distinctions. In

considering endorsement, the ACS qualified the ACIP recommendation for late vaccination

of individuals older than 21 years based on: 1) evidence of greater benefit for females

vaccinated at ages 18 to 20 years compared with 21 to 26 years, 2) opportunities for young

women and men to get vaccinated at college, 3) opportunities for young women and men to

access vaccination without parental consent, and 4) consistency with the ACIP

recommendation for males.

On the basis of the available evidence, the ACS endorses the ACIP recommendations for late

vaccination with the caveat that providers should inform individuals aged 22 to 26 years who

have not been previously vaccinated or who have not completed the series that vaccination at

older ages is less effective in lowering cancer risk. Adherence to routine vaccination at age

11 or 12 years should be emphasized, and vaccination should not be deferred with the

expectation that later vaccination will be similarly effective.

The second key question addressed in this update is whether males as well as females should

be vaccinated. The 2007 ACS guideline was developed before the availability of data from

studies of male vaccination and before US Food and Drug Administration review and

approval for this indication. Evidence published since 2007 has shown vaccine efficacy and

immunogenicity in males and safety comparable to that in females. For average-risk men

(excluding men who have sex with men and immunocompromised/HIV-positive men), there

is no direct evidence of efficacy for cancer or precancer prevention because of the small

number of disease outcomes. There is also no evidence for prevention of oropharyngeal

cancers in males or females; however, there is limited evidence of prevention of oral HPV

infection.38 On the basis of data on immunogenicity and efficacy against persistent

infections and anogenital warts in young males, as well as efficacy against precancers in

men who have sex with men, it is possible to conclude that vaccination will be effective

against cancer outcomes in the general male population, as has been shown for

females.23,24,39,40

Modeling results suggest that vaccination of males, through herd immunity, may provide

additional protection to females in addition to providing protection against HPV-associated

cancers in males. Evidence from Australia has already demonstrated that HPV vaccination

offers strong herd immunity, as shown by the 80% decrease in genital warts among

adolescent boys before inclusion of males in the national vaccination program.41,42

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On the basis of the available evidence, the ACS endorses the ACIP recommendation for

vaccination of males. Furthermore, based on the high burden of HPV infection and HPV-

related cancers among men who have sex with men, particularly anal cancer and precancers,

as well as anogenital warts,43 the ACS concurs with the recommendation for vaccination of

men who have sex with men through age 26 years.

The third key question addresses vaccination with the 9vHPV vaccine. Although there are

limited data available on the efficacy of the 9vHPV vaccine for the designated critical and

important outcomes, results from one RCT showed noninferior immunogenicity for the

types shared with the 4vHPV vaccine and efficacy for the 5 additional types.30–32 Safety

comparable to that of the 4vHPV vaccine was reported for the 9vHPV vaccine.

To supplement the ACIP recommendations, the CDC published additional guidance to

answer questions and address issues that may arise during the transition from 4vHPV to

9vHPV.44 In particular, individuals who start the vaccine series with 4vHPV may finish the

series with 9vHPV, and there is no ACIP recommendation for routine additional 9vHPV

vaccination of individuals who previously completed a 4vHPV or 2vHPV vaccination series.

The evidence reviewed by the ACIP and the additional studies examined in our supplemental

review support national recommendations for HPV vaccination, particularly for early

adolescents. The benefits of HPV vaccination for both males and females in terms of

protection against multiple cancers as well as precancers and genital warts outweigh the

limited, predominantly nonserious harms. The benefits are reduced at older ages at

vaccination, supporting the recommendation to vaccinate at ages 11 to 12 years or as soon

thereafter as possible.

Vaccination with 4vHPV or 2vHPV could prevent an estimated 24,600 cases of cancer in the

U.S. annually; vaccination with 9vHPV could prevent an additional 3800 cases; in sum an

estimated total of 28,500 cases could be prevented by the 9-valent vaccine.2 Population-level

decreases in cervical precancers have been observed in countries with high vaccination rates,

including Denmark45 and Australia,46 and the prevalence of vaccine-type HPV has

decreased by 64% among females ages 14 to 19 years in the United States.47 Yet vaccination

rates in the United States remain far lower than the rates of other vaccines given at the same

age that were introduced at about the same time (ie, 2006–2007).48 Many studies have

identified key barriers to routine vaccination at the recommended ages.49 Provider

recommendation has been consistently identified as a factor of primary importance in HPV

vaccine acceptance and utilization.49 National efforts addressing barriers to vaccine uptake

should focus on the recommendation for initiation of HPV vaccination at age 11 or 12 years.

Clinicians and parents should not delay vaccination based on their speculation about the age

at which the child is likely to become sexually active.

Given the importance as well as challenges of this public health priority, the ACS Board of

Directors recently voted to make prevention of HPV-associated cancers through increased

vaccination a nationwide priority for the organization. The ACS convened and leads the

National HPV Vaccination Roundtable, a national coalition of over 70 organizations

working together to prevent HPV-associated cancers and precancers by increasing and

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sustaining US HPV vaccination. Through the Vaccinate Adolescents against Cancer (VACs)

program, ACS staff across the country work with health systems to increase provider

awareness and education and to improve system-wide processes that can increase HPV

vaccination uptake, with a focus on federally qualified health centers and state health

systems. The ACS also continues to monitor data that will inform future changes to cervical

cancer screening recommendations. It is important that all women, regardless of whether

they have been vaccinated, get screened according to current guideline recommendations.50

HPV vaccination can potentially avert tens of thousands of cancers and hundreds of

thousands of precancers each year with associated morbidity. It is critical that cancer

prevention, immunization, health care provider, and other stakeholder organizations at the

national, state, and local levels continue to prioritize HPV vaccination so that prevention of

the vast majority of cervical, vaginal, vulvar, anal, penile, and oropharyngeal cancers can

become a reality.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

Acknowledgments

We thank the following individuals who served as expert advisors and reviewed the recommendations, the article, and the evidence review: L. Stewart Massad, MD (Professor, Division of Gynecologic Oncology, Washington University School of Medicine, St Louis, MO); Anna-Barbara Moscicki, MD (Professor of Pediatrics, University of California-LA, Los Angeles, CA); Rebecca B. Perkins, MD, MS (Associate Professor of Obstetrics and Gynecology, Boston University School of Medicine, Boston, MA); Cosette M. Wheeler, PhD (Regents Professor and Director, New Mexico HPV Pap Registry, University of New Mexico Health Sciences Center, Albuquerque, NM).

Members of the American Cancer Society Guideline Development (GDG) Group: Elizabeth T. H. Fontham, MPH, DrPH, Chair (Founding Dean and Professor Emeritus, Louisiana State University School of Public Health, New Orleans, LA); Timothy R. Church, MS, PhD (Professor, Masonic Cancer Center and the University of Minnesota, Minneapolis, MN); Ruth Etzioni, PhD (Biostatistician, University of Washington and the Fred Hutchinson Cancer Research Center, Seattle, WA); Christopher R. Flowers, MD (Associate Professor, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA); Samuel J. LaMonte, MD (independent retired physician and patient advocate); Kevin C. Oeffinger, MD (Director, Cancer Survivorship Center, Memorial Sloan Kettering Cancer Center, New York, NY); Ya-Chen Tina Shih, PhD (Professor, The University of Texas MD Anderson Cancer Center, Houston, TX); Louise C. Walter, MD (Professor of Medicine, University of California-San Francisco and San Francisco VA Medical Center, San Francisco, CA); and Andrew M. D. Wolf, MD (Associate Professor of Medicine, University of Virginia School of Medicine, Charlottesville, VA).

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Practical Implications for Continuing Education

> HPV causes most cervical, vulvar, vaginal, anal, and oropharyngeal cancers in females and most oropharyngeal, anal, and penile cancers in males. About

28,500 cancers could be prevented annually in the US by HPV vaccination.

> Clinicians should strongly recommend that all of their patients be vaccinated against HPV at age 11–12 years (bundled with the other routine adolescent

vaccines, ie, Tdap and MCV4), with completion of the series by the 13th

birthday for greatest effectiveness.

> Clinicians and their staff should be ready to answer FAQs accurately and succinctly. The CDC has scripts, tips, time-savers, and other free resources to

help educate parents or guardians and answer their questions.

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TABLE 1

Advisory Committee on Immunization Practices (ACIP) Recommendations for Vaccination, 2006 to 2015

YEAR OF RELEASE ACIP RECOMMENDATIONS LICENSED HPV VACCINES

2006 (Markowitz 20074) Females: Routine vaccination with 3-dose series at age 11 or 12 y, starting as early as age 9 y, and through age 26 y if not vaccinated previously

Quadrivalent (4vHPV), females aged 9–26 y

2009 (CDC 20105,6) Females: Either vaccine for routine vaccination with 3-dose series at age 11 or 12 y, starting as early as age 9 y, and through age 26 y if not vaccinated previously

4vHPV, females and males aged 9–26 y; bivalent (2vHPV), females aged 9–25 y

(Guidance) Males: aged 9–26 y may be vaccinated, but vaccination not routinely recommended for males (vaccination would be most effective when given before exposure to HPV through sexual contact)

2011 (ACIP 20117) Females: Either vaccine for routine vaccination with 3-dose series at age 11 or 12 y, starting as early as age 9 y, and through age 26 y if not vaccinated previously

4vHPV, females and males aged 9–26 y; 2vHPV, females aged 9–25 y

Males: Routine vaccination with 3-dose series at age 11 or 12 y and through age 21 y if not vaccinated previously; males aged 22–26 y may be vaccinated (vaccination recommended through age 26 y for men who have sex with men and men who are immunocompromised, including those with HIV infection)

2014 (Markowitz 20148) Females and males: Routine vaccination with 3-dose series at age 11 or 12 y (the vaccination series can be started beginning at age 9 y)

4vHPV, females and males aged 9–26 y; 2vHPV, females aged 9–25 y

Females aged 13–26 y and males aged 13–21 y who have not been vaccinated previously or who have not completed the 3- dose series

Males aged 22–26 y may be vaccinated (vaccination recommended through age 26 y for men who have sex with men and persons who are immunocompromised, including those with HIV infection)

2015 (Petrosky 20159) Females and males: Routine vaccination with 3-dose series at age 11 or 12 y (the vaccination series can be started beginning at age 9 y)

4vHPV, females and males aged 9–26 y; 2vHPV, females aged 9–25 y only; 9-valent (9vHPV), licensure in 2014 for females and males aged 9– 26 y

Vaccination recommended for females aged 13–26 y and for males aged 13–21 y who have not been vaccinated previously or who have not completed the 3-dose series

Males aged 22–26 y may be vaccinated

Vaccination recommended through age 26 y for men who have sex with men and for persons who are immunocompromised, including those with HIV infection

CDC indicates Centers for Disease Control and Prevention; HIV, human immunodeficiency virus; HPV, human papillomavirus. Adapted from: Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization

Practices (ACIP). MMWR Recomm Rep. 2014;63:1–308; and Petrosky E, Bocchini JA Jr, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly

Rep. 2015;64:300–304.9

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TABLE 2

Summary of Recommendations

The American Cancer Society (ACS) endorses the Advisory Committee on Immunization Practices (ACIP) HPV vaccination recommendations, listed below, with one qualifying statement in bold italics

Routine recommendations

Routine HPV vaccination should be initiated at age 11 or 12 y. The vaccination series can be started beginning at age 9 y.

Vaccination of females is recommended with 2vHPV, 4vHPV (as long as these formulations remain available), or 9vHPV. Vaccination of males is recommended with 4vHPV (as long as this formulation remains available) or 9vHPV.

Recommendations for those not vaccinated at the routine age

Vaccination is also recommended for females aged 13–26 y and for males aged 13–21 y who have not been vaccinated previously or who have not completed the 3-dose series.

Males aged 22–26 y may be vaccinated.a

ACS Qualifying Statement: Providers should inform individuals aged 22–26 y who have not been previously vaccinated or who have not completed the series that vaccination at older ages is less effective in lowering cancer risk.

Special populations

Vaccination is also recommended through age 26 y for men who have sex with men and for immunocompromised persons (including those with HIV infection) if not vaccinated previously.

2vHPV indicates bivalent human papillomavirus (HPV) vaccination; 4vHPV, quadrivalent HPV vaccination; 9vHPV, 9-valent HPV vaccination; HIV, human immunodeficiency virus.

a ACIP recommendation for individual clinical decision making.

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