Use of a 2-Dose Schedule for Human Papillomavirus Vaccination

Morbidity and Mortality Weekly Report

MMWR / December 16, 2016 / Vol. 65 / No. 49 1405

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

Introduction

Vaccination against human papillomavirus (HPV) is rec-

ommended to prevent HPV infections and HPV-associated

diseases, including cancers. Routine vaccination at age 11 or

12 years has been recommended by the Advisory Committee

on Immunization Practices (ACIP) since 2006 for females

and since 2011 for males (1,2). This report provides recom-

mendations and guidance regarding use of HPV vaccines and

updates ACIP HPV vaccination recommendations previously

published in 2014 and 2015 (1,2). This report includes new

recommendations for use of a 2-dose schedule for girls and

boys who initiate the vaccination series at ages 9 through

14 years. Three doses remain recommended for persons who

initiate the vaccination series at ages 15 through 26 years and

for immunocompromised persons.

Background

HPV infection causes cervical, vaginal, and vulvar cancers

in women; penile cancers in men; and oropharyngeal and anal

cancers as well as genital warts in both men and women (3).

Three HPV vaccines are licensed for use in the United States.

All are noninfectious. Quadrivalent and 9-valent HPV vac-

cines (4vHPV and 9vHPV, Gardasil and Gardasil 9, Merck

and Co, Inc., Whitehouse Station, New Jersey) are licensed for

use in females and males aged 9 through 26 years (1). Bivalent

HPV vaccine (2vHPV, Cervarix, GlaxoSmithKline, Rixensart,

Belgium) is licensed for use in females aged 9 through 25 years

(1). As of late 2016, only 9vHPV is being distributed in the

United States. The majority of all HPV-associated cancers are

caused by HPV 16 or 18, types targeted by all three vaccines.

In addition, 4vHPV targets HPV 6 and 11, types that cause

genital warts. 9vHPV protects against these and five additional

types: HPV 31, 33, 45, 52, and 58. All three vaccines have been

approved for administration in a 3-dose series at intervals of

0, 1 or 2, and 6 months. In October 2016, after considering

new clinical trial results (4), the Food and Drug Administration

(FDA) also approved 9vHPV for use in a 2-dose series for

girls and boys aged 9 through 14 years (5). In October 2016,

ACIP recommended a 2-dose schedule for adolescents initiat-

ing HPV vaccination in this age range. This report provides

recommendations for use of 2-dose and 3-dose schedules for

HPV vaccination.

Methods

During November 2015–October 2016, the ACIP HPV

Vaccines Work Group held monthly telephone conferences

to 1) review and evaluate the quality of the evidence assessing

immunogenicity, efficacy, and postlicensure effectiveness of a

2-dose schedule; 2) consider benefits and harms of a 2-dose

schedule; 3) weigh the variability in the values and preferences

of patients and providers for a 2-dose schedule; and 4) examine

health economic analyses. During teleconferences, summaries

of findings were presented for Work Group discussion.

A systematic review was conducted to identify studies

involving human subjects* that reported primary data on

any important or critical health outcomes related to HPV

vaccination

†

after 2 doses of 9vHPV, 4vHPV, or 2vHPV,

administered at an interval of 0 and ≥6 months (±4 weeks) to

Use of a 2-Dose Schedule for Human Papillomavirus Vaccination — Updated

Recommendations of the Advisory Committee on Immunization Practices

Elissa Meites, MD

; Allison Kempe, MD

2,3

; Lauri E. Markowitz, MD

Recommendations for 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 the Centers

for Disease Control and Prevention (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 use of vaccines in children

and adolescents 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, and the American

College of Physicians (ACP). ACIP recommendations

approved by the CDC Director become agency guidelines

on the date published in the Morbidity and Mortality

Weekly Report (MMWR). Additional information about

ACIP is available at https://www.cdc.gov/vaccines/acip.

* No primary data on special populations or medical conditions, including

immunocompromising conditions, were available for 2-dose intervals and age

ranges specified.

†

No primary data on other important and critical outcomes, including genital warts,

precancers, oropharyngeal cancer, anal cancer, cervical cancer, vaginal/vulvar cancer,

and penile cancer, were available for 2-dose intervals and age ranges specified.

Morbidity and Mortality Weekly Report

1406 MMWR / December 16, 2016 / Vol. 65 / No. 49 US Department of Health and Human Services/Centers for Disease Control and Prevention

persons aged 9 through 14 years. The review focused on this

age group given available 2-dose trial data for 9vHPV (4).

Immunogenicity outcomes of interest were seroconversion,

geometric mean titers (GMTs), or antibody avidity. Studies

were excluded if they lacked a comparison group in which

efficacy of 3 doses of HPV vaccine against clinical endpoints

was demonstrated in clinical trials (e.g., females aged 15

through 26 years).

Evidence regarding a 3-dose schedule for

HPV vaccine was reviewed previously (1,2).

Quality of evidence was evaluated using the Grading of

Recommendations Assessment, Development and Evaluation

(GRADE) approach. Detailed methods and GRADE tables

can be found online (6). Other studies from the search and

from the broader literature informed additional expert guid-

ance that extended beyond the research question addressed

formally via GRADE analysis (7). Evidence was reviewed by

the Work Group, summarized, and publicly presented at the

February and June 2016 ACIP meetings. CDC vaccine rec-

ommendations are developed using the GRADE framework

(8). Proposed recommendations were presented, and after a

public comment period, were approved unanimously

by the

voting ACIP members at the October 2016 ACIP meeting.

Summary of Key Findings

Immunogenicity. In the 9vHPV clinical trial that was the

basis for FDA approval of a 2-dose series, participants were

girls and boys aged 9 through 14 years, compared with young

females aged 16 through 26 years (4). Among 1,377 partici-

pants, ≥97.9% seroconverted to all nine vaccine-preventable

HPV types by 4 weeks after the last dose. For girls and boys

who received 2 doses of 9vHPV 6 months apart (0, 6 month

schedule) or 12 months apart (0, 12 month schedule), non-

inferiority criteria were met for seroconversion and GMTs.

Furthermore, GMTs were significantly higher for all 9vHPV

types among persons aged 9 through 14 years who received 2

doses compared with females aged 16–26 years who received

3 doses (0, 2, 6 month schedule). Six additional studies found

similar results for 4vHPV and 2vHPV (6). Immunogenicity

was found to be noninferior with 2 doses in persons aged 9

through 14 years compared with 3 doses in a group in which

clinical efficacy was demonstrated (GRADE evidence type 3).

Efficacy and effectiveness. Although efficacy and postlicen-

sure effectiveness studies were reviewed, none met the inclusion

criteria detailed above. The prelicensure HPV vaccine efficacy

trials were conducted with 3-dose series; post hoc analyses con-

ducted with data from some of these trials found high efficacy

against infection among vaccinees who received 2 doses and

those who received 3 doses (9,10). A large study comparing

2 doses with 3 doses also suggested similar efficacy against

infection (11). Postlicensure effectiveness studies have found

lower effectiveness against various HPV-associated outcomes

among vaccinees who received 2 doses compared with those

who received 3 doses, but methodologic challenges with these

studies limit interpretation of the findings.**

Duration of protection. Through 10 years of follow-up

from clinical trials, no evidence of waning protection after

a 3-dose series of HPV vaccine has been found (1). Because

antibody kinetics are similar with 2-dose and 3-dose series,

duration of protection is also expected to be long-lasting after

a 2-dose series (12,13).

Health impact and cost-effectiveness modeling.

Population-level effectiveness and cost-effectiveness of 2-dose

and 3-dose schedules of 9vHPV in the United States have been

modeled (14). Assuming both efficacy and duration of protec-

tion are similar with either schedule, a 2-dose series would be

cost-saving and have similar population impact to a 3-dose

series. Even if duration of protection is 20 years for a 2-dose

series and lifelong for a 3-dose series, additional benefits of

a 3-dose series would be relatively small, and a 2-dose series

would be more cost-effective (14).

Rationale

HPV vaccines are highly effective and safe, and a powerful pre-

vention tool for reducing HPV infections and HPV-associated

cancers (1,2). Based on the available immunogenicity evidence,

a 2-dose schedule (0, 6–12 months) will have efficacy equivalent

to a 3-dose schedule (0, 1–2, 6 months) if the HPV vaccination

series is initiated before the 15th birthday (GRADE evidence

type 3) (6). ACIP recommends a 2-dose schedule for HPV vac-

cination of girls and boys who initiate the vaccination series at

ages 9 through 14 years (Category A recommendation).

Recommendations

Routine and catch-up age groups. ACIP recommends

routine HPV vaccination at age 11 or 12 years. Vaccination

can be given starting at age 9 years. ACIP also recommends

vaccination for females through age 26 years and for males

through age 21 years who were not adequately vaccinated

previously. Males aged 22 through 26 years may be vaccinated.

(See also: Special populations, Medical conditions)

Dosing schedules. For persons initiating vaccination before

their 15th birthday, the recommended immunization sched-

ule is 2 doses of HPV vaccine. The second dose should be

Studies were excluded when 2-dose interval was not ≥5 months.

Twelve votes to none, with one recusal.

** In studies conducted in the setting of a 3-dose HPV vaccine recommendation

or policy, many 2-dose recipients received HPV vaccine doses at a 1–2 month

interval; in addition, 2-dose recipients differed from 3-dose recipients in ways

that suggested differences in HPV exposure.

Morbidity and Mortality Weekly Report

MMWR / December 16, 2016 / Vol. 65 / No. 49 1407

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

administered 6–12 months after the first dose (0, 6–12 month

schedule)

††

(Table).

For persons initiating vaccination on or after their 15th

birthday, the recommended immunization schedule is 3 doses

of HPV vaccine. The second dose should be administered

1–2 months after the first dose, and the third dose should be

administered 6 months after the first dose (0, 1–2, 6 month

schedule)

§§

(Table).

Persons vaccinated previously. Persons who initiated vac-

cination with 9vHPV, 4vHPV, or 2vHPV before their 15th

birthday, and received 2 doses of any HPV vaccine at the

recommended dosing schedule (0, 6–12 months), or 3 doses

of any HPV vaccine at the recommended dosing schedule (0,

1–2, 6 months), are considered adequately vaccinated.

Persons who initiated vaccination with 9vHPV, 4vHPV, or

2vHPV on or after their 15th birthday, and received 3 doses

of any HPV vaccine at the recommended dosing schedule, are

considered adequately vaccinated.

9vHPV may be used to continue or complete a vaccination

series started with 4vHPV or 2vHPV.

For persons who have been adequately vaccinated with

2vHPV or 4vHPV, there is no ACIP recommendation regard-

ing additional vaccination with 9vHPV.

Interrupted schedules. If the vaccination schedule is inter-

rupted, the series does not need to be restarted. The number

of recommended doses is based on age at administration of

the first dose.

Special populations. For children with a history of sexual

abuse or assault, ACIP recommends routine HPV vaccination

beginning at age 9 years.

For men who have sex with men,

¶¶

ACIP recommends

routine HPV vaccination as for all males, and vaccination

through age 26 years for those who were not adequately vac-

cinated previously.

For transgender persons, ACIP recommends routine

HPV vaccination as for all adolescents, and vaccination

through age 26 years for those who were not adequately

vaccinated previously.

Medical conditions. ACIP recommends vaccination with 3

doses of HPV vaccine (0, 1–2, 6 months) for females and males

aged 9 through 26 years with primary or secondary immuno-

compromising conditions that might reduce cell-mediated

or humoral immunity,*** such as B lymphocyte antibody

deficiencies, T lymphocyte complete or partial defects, HIV

infection, malignant neoplasms, transplantation, autoimmune

disease, or immunosuppressive therapy, because immune

response to vaccination might be attenuated (Table) (7).

Contraindications and precautions. Contraindications

and precautions, including those related to pregnancy, are

unchanged from previous recommendations (1,2). Adverse

events occurring after administration of any vaccine should

be reported to the Vaccine Adverse Event Reporting System

(VAERS). Reports can be submitted to VAERS online, by fax,

or by mail. Additional information about VAERS is available by

telephone (1-800-822-7967) or online (https://vaers.hhs.gov).

TABLE. Recommended number of doses and intervals for human papillomavirus (HPV) vaccine, by age at series initiation and medical conditions —

United States, 2016

Population

Recommended number of

HPV vaccine doses

Recommended interval

between doses

Persons initiating HPV vaccination at ages 9 through 14 years,* except

immunocompromised persons

†

2 0, 6–12 months

Persons initiating HPV vaccination at ages 15 through 26 years

and

immunocompromised persons

†

initiating HPV vaccination at ages 9 through 26 years

3 0, 1–2, 6 months**

* ACIP recommends routine HPV vaccination for adolescents at age 11 or 12 years; vaccination may be given starting at age 9 years.

†

Persons with primary or secondary immunocompromising conditions that might reduce cell-mediated or humoral immunity (see also: Medical conditions)

In a 2-dose schedule of HPV vaccine, the minimum interval between the first and second doses is 5 months.

For persons who were not adequately vaccinated previously, ACIP recommends vaccination for females through age 26 years and for males through age

21 years; males ages 22 through 26 years may be vaccinated. Vaccination is recommended for some persons aged 22 through 26 years; see Medical conditions

and Special populations.

** In a 3-dose schedule of HPV vaccine, the minimum intervals are 4 weeks between the first and second doses, 12 weeks between the second and third doses, and

5 months between the first and third doses.

††

In a 2-dose schedule of HPV vaccine, the minimum interval between the first

and second doses is 5 months. If the second dose is administered after a shorter

interval, a third dose should be administered a minimum of 12 weeks after

the second dose and a minimum of 5 months after the first dose.

§§

In a 3-dose schedule of HPV vaccine, the minimum intervals are 4 weeks

between the first and second doses, 12 weeks between the second and third

doses, and 5 months between the first and third doses. If a vaccine dose is

administered after a shorter interval, it should be readministered after another

minimum interval has elapsed since the most recent dose.

¶¶

Including men who identify as gay or bisexual, or who intend to have sex

with men.

*** The recommendation for a 3-dose schedule of HPV vaccine does not apply

to children aged <15 years with asplenia, asthma, chronic granulomatous

disease, chronic liver disease, chronic lung disease, chronic renal disease,

central nervous system anatomic barrier defects (e.g., cochlear implant),

complement deficiency, diabetes, heart disease, or sickle cell disease.

Morbidity and Mortality Weekly Report

1408 MMWR / December 16, 2016 / Vol. 65 / No. 49 US Department of Health and Human Services/Centers for Disease Control and Prevention

Acknowledgments

Members of the Advisory Committee on Immunization Practices

(ACIP) (member roster for July 2016–June 2017 is available online

at https://www.cdc.gov/vaccines/acip/committee/members-archive.

html); ACIP HPV Vaccines Work Group: Jorge E. Arana, MD,

Atlanta, Georgia; Joseph Bocchini, MD, Shreveport, Louisiana;

Harrell Chesson, PhD, Atlanta, Georgia; Tamera Coyne-Beasley,

MD, Chapel Hill, North Carolina; C. Robinette Curtis, MD, Atlanta,

Georgia; Carolyn D. Deal, PhD, Bethesda, Maryland; Shelley Deeks,

MD, Toronto, Ontario, Canada; John Douglas, MD, Greenwood

Village, Colorado; Linda Eckert, MD, Seattle, Washington; Sandra

Adamson Fryhofer, MD, Atlanta, Georgia; Julianne Gee, MPH,

Atlanta, Georgia; Bruce G. Gellin, MD, Washington, DC; Samuel

Katz, MD, Durham, North Carolina; Alison Kempe, MD, Denver,

Colorado (Chair); Aimée R. Kreimer, PhD, Bethesda, Maryland;

Joohee Lee, MD, Silver Spring, Maryland; Lauri E. Markowitz,

MD, Atlanta, Georgia (CDC Lead); Elissa Meites, MD, Atlanta,

Georgia; Amy B. Middleman, MD, Oklahoma City, Oklahoma;

Chris Nyquist, MD, Denver, Colorado; Sean O’Leary, MD, Aurora,

Colorado; Sara E. Oliver, MD, Atlanta, Georgia; Cynthia Pellegrini,

Washington, DC; Jeff Roberts, MD; Rockville, Maryland; José R.

Romero, MD, Little Rock, Arkansas; Jeanne Santoli, MD, Atlanta,

Georgia; Mona Saraiya, MD, Atlanta, Georgia; Debbie Saslow,

PhD, Atlanta, Georgia; Margot Savoy, MD, Wilmington, Delaware;

Shannon Stokley, DrPH, Atlanta, Georgia; Lakshmi Sukumaran,

MD, Atlanta, Georgia; Elizabeth R. Unger, PhD, MD, Atlanta,

Georgia; Patricia Whitley-Williams, MD, New Brunswick, New

Jersey; Rodney Willoughby, MD, Wauwatosa, Wisconsin; JoEllen

Wolicki, Atlanta, Georgia; Sixun Yang, MD, Rockville, Maryland;

Jane Zucker, MD, New York, New York.

Division of Viral Diseases, National Center for Immunization and Respiratory

Diseases, CDC;

HPV Vaccines Work Group, Advisory Committee on

Immunization Practices, Atlanta, Georgia;

Department of Pediatrics, University

of Colorado Anschutz Medical Campus, Denver, Colorado.

Corresponding author: Elissa Meites, [email protected], 404-639-8253.

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