MMWR - Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices

Morbidity and Mortality Weekly Report

698 MMWR / August 16, 2019 / Vol. 68 / No. 32 US Department of Health and Human Services/Centers for Disease Control and Prevention

Human Papillomavirus Vaccination for Adults: Updated Recommendations of

the Advisory Committee on Immunization Practices

Elissa Meites, MD

; Peter G. Szilagyi, MD

; Harrell W. Chesson, PhD

; Elizabeth R. Unger, PhD, MD

; José R. Romero, MD

;

Lauri E. Markowitz, MD

Introduction

Vaccination against human papillomavirus (HPV) is recom-

mended to prevent new HPV infections and HPV-associated

diseases, including some cancers. The Advisory Committee

on Immunization Practices (ACIP)* routinely recommends

HPV vaccination at age 11 or 12 years; vaccination can be

given starting at age 9 years. Catch-up vaccination has been

recommended since 2006 for females through age 26 years, and

since 2011 for males through age 21 years and certain special

populations through age 26 years. This report updates ACIP

catch-up HPV vaccination recommendations and guidance

published in 2014, 2015, and 2016 (1–3). Routine recom-

mendations for vaccination of adolescents have not changed.

In June 2019, ACIP recommended catch-up HPV vaccination

for all persons through age 26 years. ACIP did not recommend

catch-up vaccination for all adults aged 27 through 45 years,

but recognized that some persons who are not adequately

vaccinated might be at risk for new HPV infection and might

benefit from vaccination in this age range; therefore, ACIP

recommended shared clinical decision-making regarding

potential HPV vaccination for these persons.

Background

HPV is a common sexually transmitted infection, with HPV

acquisition generally occurring soon after first sexual activity

(1). Most HPV infections are transient and asymptomatic.

Persistent infections with high-risk (oncogenic) HPV types can

lead to development of cervical, anal, penile, vaginal, vulvar, and

oropharyngeal cancers, usually after several decades (1). Most

* Recommendations for routine use of vaccines in children, adolescents, and

adults are developed by the Advisory Committee on Immunization Practices

(ACIP). ACIP is chartered as a federal advisory committee to provide expert

external advice and guidance to the Director of CDC on use of vaccines and

related agents for the control of vaccine-preventable diseases in the civilian

population of the United States. Recommendations for routine use of vaccines

in children, adolescents, and adults are harmonized to the greatest extent possible

with recommendations made by the American Academy of Pediatrics (AAP),

the American Academy of Family Physicians (AAFP), and the American College

of Obstetricians and Gynecologists (ACOG). Recommendations for routine

use of vaccines in adults are harmonized with recommendations of AAFP,

ACOG, the American College of Physicians (ACP), and the American College

of Nurse-Midwives. ACIP recommendations approved by the CDC Director

become agency guidelines on the date published in the Morbidity and Mortality

Weekly Report. Additional information is available at https://www.cdc.gov/

vaccines/acip.

new HPV infections occur in adolescents and young adults.

Although most sexually active adults have been exposed to

HPV (4), new infections can occur with a new sex partner (5).

Three prophylactic HPV vaccines are licensed for use in the

United States: 9-valent (9vHPV, Gardasil 9, Merck), quad-

rivalent (4vHPV, Gardasil, Merck), and bivalent (2vHPV,

Cervarix, GlaxoSmithKline) (6–8). As of late 2016, only

9vHPV is distributed in the United States. The majority of

HPV-associated cancers are caused by HPV 16 or 18, types

targeted by all three vaccines. In addition, 4vHPV and 9vHPV

target HPV 6 and 11, types that cause anogenital warts. 9vHPV

also protects against five additional high-risk types: HPV 31,

33, 45, 52, and 58.

In October 2018, using results from 4vHPV clinical trials in

women aged 24 through 45 years, and bridging immunogenic-

ity and safety data in women and men, the Food and Drug

Administration expanded the approved age range for 9vHPV

use from 9 through 26 years to 9 through 45 years in women

and men (6). In June 2019, after reviewing evidence related to

HPV vaccination of adults, ACIP updated recommendations

for catch-up vaccination and for vaccination of adults older

than the recommended catch-up age.

Methods

During April 2018–June 2019, the ACIP HPV Vaccines

Work Group held at least monthly conference calls to review

and discuss relevant scientific evidence regarding adult

HPV vaccination using the Evidence to Recommendations

framework. (https://www.cdc.gov/vaccines/acip/recs/grade/

downloads/ACIP-evidence-rec-frame-508.pdf). The Work

Group evaluated the quality of evidence for efficacy, safety, and

effectiveness for HPV vaccination for primary prevention of

HPV infection and HPV-related disease using the Grading of

Recommendations Assessment, Development and Evaluation

(GRADE) approach (https://www.cdc.gov/vaccines/acip/recs/

grade/about-grade.html).

Scientific literature published during January 1, 2006–

October 18, 2018, was searched to identify clinical trials of

any licensed HPV vaccine in adults aged 27 through 45 years.

Detailed search methods and results for the GRADE tables

are available at https://www.cdc.gov/vaccines/acip/recs/grade/

HPV-adults.html. Benefits were based on per-protocol analyses

Morbidity and Mortality Weekly Report

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US Department of Health and Human Services/Centers for Disease Control and Prevention

of vaccine efficacy; immunogenicity data were also considered.

Harms were any vaccine-related serious adverse events. Of

1,388 references identified, 100 were selected for detailed

review, and 16 publications were included in GRADE tables

presented at the October 2018 ACIP meeting; tables were

updated in June 2019 to include new results from a 9vHPV

trial. At the June 2019 ACIP meeting, two policy issues were

considered: 1) harmonization of catch-up vaccination for all

persons through age 26 years, and 2) vaccination of adults aged

>26 years. Two Evidence to Recommendations documents

were developed (https://www.cdc.gov/vaccines/acip/recs/

grade/HPV-harmonization-etr.html) (https://www.cdc.gov/

vaccines/acip/recs/grade/HPV-adults-etr.html) and presented

along with proposed recommendations; after a public com-

ment period, ACIP members voted unanimously to harmonize

catch-up vaccination recommendations across genders for

all persons through age 26 years. ACIP members also voted

10–4 in favor of shared clinical decision-making for adults

aged 27 through 45 years, recognizing that some persons who

are not adequately vaccinated might be at risk for new HPV

infection and might benefit from vaccination in this age range.

Summary of Key Findings

Vaccine efficacy and safety. Data were considered from

11 clinical trials of 9vHPV, 4vHPV, and/or 2vHPV in adults

aged 27 through 45 years, along with supplemental bridging

immunogenicity data. In per-protocol analyses from three

trials, 4vHPV and 2vHPV demonstrated significant efficacy

against a combined endpoint of persistent vaccine-type HPV

infections, anogenital warts, and cervical intraepithelial neo-

plasia (CIN) grade 1 (low-grade lesions) or worse. In nine

trials, seroconversion rates to vaccine-type HPV after 3 doses

of any HPV vaccine were 93.6%–100% at 7 months after

the first dose. Overall evidence on benefits was GRADE

evidence level 2, for moderate-quality evidence. In nine tri-

als, few serious adverse events and no vaccine-related deaths

were reported. Overall evidence on harms was also GRADE

evidence level 2, for moderate-quality evidence. In the efficacy

trial that was the basis for 9vHPV licensure for adults through

age 45 years, per-protocol efficacy of 4vHPV among women

aged 24 through 45 years was 88.7% (95% confidence interval

[CI] = 78.1–94.8), and intention-to-treat efficacy was 47.2%

(95% CI = 33.5–58.2) against a combined endpoint of per-

sistent infections, extragenital lesions, and CIN 1+ related to

HPV types 6, 11, 16, or 18 (9).

HPV burden of disease and impact of the vaccination

program in the United States. Approximately 33,700 cancers

are caused by HPV in the United States each year, includ-

ing 12,900 oropharyngeal cancers among men and women,

10,800 cervical cancers among women, and 6,000 anal cancers

among men and women; vaginal, vulvar, and penile cancers

are less common (10). HPV vaccination for adolescents has

been routinely recommended for females since 2006 and for

males since 2011 (1). The existing HPV vaccination program

for adolescents has the potential to prevent the majority of

these cancers. Mean age at acquisition of causal HPV infec-

tion for cancers is unknown, but is estimated to be decades

before cancer is diagnosed. In 2017, coverage with ≥1 dose of

HPV vaccine was 65.5% among adolescents aged 13 through

17 years (11). Although coverage with the recommended

number of doses remains below the Healthy People 2020

target of 80% for adolescents (12), the U.S. HPV vaccination

program has resulted in significant declines in prevalences of

vaccine-type HPV infections, anogenital warts, and cervical

precancers (13). For example, prevalences of 4vHPV vaccine-

type infection during 2013–2016, compared with those of the

prevaccine era, declined from 11.5% to 1.8% among females

aged 14 through 19 years and from 18.5% to 5.3% among

females aged 20 through 24 years (14). In addition, declines

have been observed among unvaccinated persons, suggesting

protective herd effects (15).

Health economic analyses. Five health economic models

of HPV vaccination in the United States were reviewed (16).

The cost effectiveness ratio for the current HPV vaccination

program ranged from cost-saving to approximately $35,000

per quality-adjusted life year (QALY) gained (16). In the

context of the existing vaccination program, the incremental

cost per QALY for expanding male vaccination through age

26 years was $178,000 in a subset of analyses in one of the five

models reviewed using more favorable model assumptions for

adult vaccination (16). In the context of the existing program,

expanding vaccination to adults through age 45 years would

produce relatively small additional health benefits and less

favorable cost-effectiveness ratios. The incremental cost per

QALY for also vaccinating adults through age 30 or 45 years

exceeded $300,000 in four of five models (16). Variation in

results across models was likely due to uncertainties about

HPV natural history, such as prevalence of immunity after

clearance of natural infections, and level of herd protection

from the existing program. Under the existing program, in

a subset of analyses in one of the five models reviewed using

more favorable model assumptions for adult vaccination, the

number needed to vaccinate (NNV) to prevent one case of

anogenital warts, CIN grade 2 or worse (high-grade lesions),

or cancer would be 9, 22, and 202, respectively. For expanding

recommendations for males through age 26 years to harmonize

catch-up vaccination across genders, these NNV would be 40,

450, and 3,260, respectively. For expanding recommendations

to include adults through age 45 years, these NNV would be

120, 800, and 6,500, respectively (16).

Morbidity and Mortality Weekly Report

700 MMWR / August 16, 2019 / Vol. 68 / No. 32 US Department of Health and Human Services/Centers for Disease Control and Prevention

Rationale

Adolescents remain the most important focus of the HPV

vaccination program in the United States. Recommendations

harmonized across genders will simplify the immunization

schedule and be more feasible to implement. HPV vaccination

is most effective when given before exposure to any HPV, as

in early adolescence (1–3). Clinical trials have indicated that

HPV vaccines are safe and effective against infection and dis-

ease attributable to HPV vaccine types that recipients are not

infected with at the time of vaccination.

Because HPV acquisition generally occurs soon after first

sexual activity, vaccine effectiveness will be lower in older age

groups because of prior infections. Some previously exposed

adults will have developed natural immunity already. Exposure

to HPV decreases among older age groups. Evidence sug-

gests that although HPV vaccination is safe for adults aged

27 through 45 years, population benefit would be minimal;

nevertheless, some adults who are not adequately vaccinated

might be at risk for new HPV infection and might benefit

from vaccination in this age range.

Recommendations

Children and adults aged 9 through 26 years. HPV vac-

cination is routinely recommended at age 11 or 12 years;

vaccination can be given starting at age 9 years. Catch-up

HPV vaccination is recommended for all persons through age

26 years who are not adequately vaccinated.

†

Adults aged >26 years. Catch-up HPV vaccination is not

recommended for all adults aged >26 years. Instead, shared

clinical decision-making regarding HPV vaccination is recom-

mended for some adults aged 27 through 45 years who are not

adequately vaccinated. (Box). HPV vaccines are not licensed

for use in adults aged >45 years.

Administration. Dosing schedules, intervals, and defini-

tions of persons considered adequately vaccinated have not

changed (3). No prevaccination testing (e.g., Pap or HPV

testing) is recommended to establish the appropriateness of

HPV vaccination.

Cervical cancer screening. Cervical cancer screening guide-

lines and recommendations should be followed (17).

Special populations and medical conditions. These

recommendations for children and adults aged 9 through

26 years and for adults aged >26 years apply to all persons,

†

For persons initiating vaccination before their 15th birthday, the recommended

immunization schedule is 2 doses of HPV vaccine (0, 6–12 month schedule).

For persons initiating vaccination on or after their 15th birthday, or for persons

with certain immunocompromising conditions, the recommended

immunization schedule is 3 doses of HPV vaccine (0, 1–2, 6 month schedule).

BOX. Considerations for shared clinical decision-making regarding

human papillomavirus (HPV) vaccination of adults aged 27 through 45

Ideally, HPV vaccination should be given in early

adolescence because vaccination is most effective before

exposure to HPV through sexual activity. For adults aged

27 through 45 years who are not adequately* vaccinated,

clinicians can consider discussing HPV vaccination with

persons who are most likely to benefit. HPV vaccina-

tion does not need to be discussed with most adults

aged >26 years.

• HPV is a very common sexually transmitted infection.

Most HPV infections are transient and asymptomatic

and cause no clinical problems.

• Although new HPV infections are most commonly

acquired in adolescence and young adulthood, some

adults are at risk for acquiring new HPV infections.

At any age, having a new sex partner is a risk factor

for acquiring a new HPV infection.

• Persons who are in a long-term, mutually

monogamous sexual partnership are not likely to

acquire a new HPV infection.

• Most sexually active adults have been exposed to some

HPV types, although not necessarily all of the HPV

types targeted by vaccination.

• No clinical antibody test can determine whether a

person is already immune or still susceptible to any

given HPV type.

• HPV vaccine efficacy is high among persons who have

not been exposed to vaccine-type HPV before

vaccination.

• Vaccine effectiveness might be low among persons with

risk factors for HPV infection or disease (e.g., adults

with multiple lifetime sex partners and likely previous

infection with vaccine-type HPV), as well as among

persons with certain immunocompromising conditions.

• HPV vaccines are prophylactic (i.e., they prevent new

HPV infections). They do not prevent progression of

HPV infection to disease, decrease time to clearance

of HPV infection, or treat HPV-related disease.

* Dosing schedules, intervals, and definitions of persons considered

adequately vaccinated have not changed.

regardless of behavioral or medical risk factors for HPV

infection or disease.

For persons who are pregnant, HPV

Persons with specific behavioral or medical risk factors for HPV infection or

disease include men who have sex with men, transgender persons, and persons

with immunocompromising conditions.

Morbidity and Mortality Weekly Report

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US Department of Health and Human Services/Centers for Disease Control and Prevention

Summary

What is already known about this topic?

Vaccination against human papillomavirus (HPV) is routinely

recommended at age 11 or 12 years. Catch-up recommenda-

tions apply to persons not vaccinated at age 11 or 12 years.

What is added by this report?

After reviewing new evidence, CDC updated HPV vaccination

recommendations for U.S. adults.

What are the implications for public health practice?

Routine recommendations for HPV vaccination of adolescents

have not changed. Catch-up HPV vaccination is now recom-

mended for all persons through age 26 years. For adults aged

27 through 45 years, public health benefit of HPV vaccination in

this age range is minimal; shared clinical decision-making is

recommended because some persons who are not adequately

vaccinated might benefit.

vaccination should be delayed until after pregnancy; however,

pregnancy testing is not needed before vaccination. Persons

who are breastfeeding or lactating can receive HPV vaccine.

Recommendations regarding HPV vaccination during

pregnancy or lactation have not changed (1).

Future Research and Monitoring Priorities

CDC continues to monitor safety of HPV vaccines and impact

of the vaccination program on HPV-attributable outcomes,

including prevalences of HPV infections, anogenital warts,

cervical precancers, and cancers. ACIP reviews relevant data as

they become available and updates vaccine policy as needed.

Acknowledgments

Members of the Advisory Committee on Immunization Practices

(member roster for June 2019 is available at https://www.cdc.gov/

vaccines/acip/members/index.html).

ACIP HPV Vaccines Work Group

Chair: Peter Szilagyi, University of California at Los Angeles.

ACIP members: Kevin Ault, University of Kansas Medical Center;

José Romero, University of Arkansas for Medical Sciences, Arkansas

Children’s Hospital. Ex Officio Members: Joohee Lee, Jeff Roberts,

Food and Drug Administration. Liaison representatives: Shelley

Deeks, National Advisory Committee on Immunization; Linda

Eckert, American College of Obstetricians and Gynecologists;

Sandra Fryhofer, American College of Physicians; Amy Middleman,

Society for Adolescent Health and Medicine; Chris Nyquist,

American Academy of Pediatrics; Sean O’Leary, Pediatric Infectious

Disease Society; Robin O’Meara, American Academy of Family

Physicians; Patricia Whitley-Williams, National Medical Association;

Jane Zucker, Association of Immunization Managers. Consultants:

Joseph Bocchini; Tamera Coyne-Beasley; John Douglas; Allison

Kempe; Aimee Kreimer, National Cancer Institute; Debbie Saslow,

American Cancer Society; Rodney Willoughby; Rachel Winer.

CDC Lead: Lauri Markowitz. CDC contributors: Harrell Chesson;

Julianne Gee; Elissa Meites; Lakshmi Panagiotakopoulos; Jeanne

Santoli; Mona Saraiya; Shannon Stokley; John Su; Elizabeth Unger;

Charnetta Williams.

Corresponding author: Elissa Meites, [email protected].

National Center for Immunization and Respiratory Diseases, CDC;

University of California at Los Angeles;

National Center for HIV, Viral

Hepatitis, STD, and TB Prevention, CDC;

National Center for Emerging

and Zoonotic Infectious Diseases, CDC;

University of Arkansas for Medical

Sciences, Little Rock, Arkansas.

All authors have completed and submitted the ICMJE form for

disclosure of potential conflicts of interest. No potential conflicts of

interest were disclosed.

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