ACIP Evidence to Recommendations Framework

Updated June 26, 2019

Question 2: Should catch-up HPV vaccination be recommended for primary prevention of HPV infection and HPV-related 

disease for all persons ages 27 through 45 years?

Population: Persons aged 27 through 45 years at initiation of vaccination

Intervention: Catch-up vaccination with 3 doses of HPV vaccine

Comparison: Persons aged 27 through 45 years with no catch-up HPV vaccination

Outcome: Primary prevention of HPV infection and HPV-related disease

Background: 

Human papillomavirus (HPV) is a common sexually transmitted infection of the epithelium. Persistent HPV infections can develop into 

cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers, usually after several decades. 

Vaccination against HPV is recommended to prevent HPV infections and HPV-associated diseases, including cancers. HPV vaccination was 

introduced in the United States in 2006 for females and 2011 for males aged 9–26 years. The Advisory Committee on Immunization 

Practices (ACIP) recommends routine HPV vaccination at age 11 or 12 years; vaccination can be given starting at age 9 years. Catch-up 

vaccination has been recommended through age 26 years. 

Three prophylactic HPV vaccines are licensed for use in the United States: 9-valent and quadrivalent HPV vaccines (9vHPV and 4vHPV, 

Gardasil 9 and Gardasil, Merck & Co., Inc., Kenilworth, NJ) and bivalent HPV vaccine (2vHPV, Cervarix, GlaxoSmithKline, Rixensart, 

Belgium). 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 anogenital warts. 9vHPV protects against these and five additional types: HPV 31, 33, 45, 52, and 58. In 

October 2018, based on results from 4vHPV clinical trials in women through age 45 years and bridging immunogenicity and safety data in 

women and men, the Food and Drug Administration (FDA) approved 9vHPV for use in women and men through age 45 years. 

Additional background information can be found in the relevant publication of the recommendation referenced on the ACIP website.

CRITERIA WORK GROUP JUDGMENTS EVIDENCE ADDITIONAL INFORMATION

https://www.cdc.gov/vaccines/acip/recs/grade/HPV-adults-etr-H.pdf
ACIP Evidence to Recommendations Framework

Updated June 26, 2019 PROBLEM

Is the problem 

of public 

health 

importance?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

Approximately 33,700 cancers are 

caused by HPV annually in the United 

States, including 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.

The existing HPV vaccination program 

for U.S. adolescents has the potential to 

prevent the majority of these cancers. 

Mean age of acquisition of causal HPV

infection for cancers is unknown, but 

estimated to be decades before cancer 

is diagnosed. 

It is uncertain how much HPV-related 

morbidity and mortality is related to HPV 

infections acquired at ages 27 through 45 

years. HPV incidence is highest among 

people in the age range of teens to early 

twenties. First HPV infections are 

acquired soon after first sexual activity. 

Most sexually active adults have been 

exposed to HPV, but a new sex partner is 

a risk factor for new HPV infections. The 

percentage of people reporting a new sex 

partner within the past year is lower in

older age groups than among younger 

age groups.

In 2017, coverage with ≥1 dose of 

HPV vaccine was 65.5% among 13–

17 year-olds. Coverage remains 

below the Healthy People 2020 

target of 80% of adolescents. Even 

so, the existing U.S. HPV vaccination 

program has resulted in significant 

declines in prevalence of vaccinetype HPV infections, anogenital 

warts, and cervical precancers. 

Among 14–19 and 20–24 year-old 

females, prevalence of 4vHPV

vaccine-type infection declined 

from 11.5% to 1.8% and from 

18.5% to 5.3%, respectively, in 

2013–2016 compared with the 

prevaccine era. Declines have been 

observed among both vaccinated

and unvaccinated persons, 

suggesting protective herd effects.

BENEFITS & HARMS 

How 

substantial 

are the 

desirable 

anticipated 

effects?

 Minimal Small Moderate Large Don’t 

know

Varies

X

Desirable anticipated effects vary since 

population benefit would be minimal, yet 

some individuals in this age range might 

be able to benefit from vaccination. HPV 

vaccines are most effective when given 

before exposure to any HPV. 

HPV vaccines are prophylactic (i.e., 

they prevent new HPV infections) 

and do not prevent progression of 

infection to disease, decrease time 

to clearance of HPV infection, or 

treat HPV-related disease. Since 

HPV is commonly acquired soon 

after first sex, vaccine effectiveness 
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

Compared with the benefit of the 

existing HPV vaccination program for 

adolescents and young adults through 

age 26 years, the additional benefit of 

vaccinating people age 27 through 45 

years would be minimal. 

Based on modeling data, the number 

needed to vaccinate (NNV) to prevent 

one case of anogenital warts, cervical 

intraepithelial neoplasia (CIN) grade 

2+, or cancer, is 9, 22, and 202, 

respectively, under the existing 

program. In a subset of analyses in the 

HPV-ADVISE model with more 

favorable model assumptions for adult 

vaccination, these NNV would be 120;

800; and 6,500 for expanding 

vaccination to include adults through 

age 45 years. 

Clinical trials have shown that HPV 

vaccines are effective against infection 

and related disease due to HPV types 

that recipients are not infected with at 

the time of vaccination. In per-protocol 

analyses of efficacy results from 

4vHPV and 2vHPV trials among adults 

older than age 26 years who were 

HPV-naïve, across 10 trials, HPV 

vaccines showed significant efficacy 

against a combined endpoint of 

persistent vaccine-type HPV infections, 

anogenital warts, and/or cervical 

intraepithelial neoplasia grade 1 or 

worse. Seroconversion rates to 

vaccine-type HPV following 3 doses of 

any HPV vaccine were 93.6–100% at 7 

months post first dose.

will be much lower in adults than 

among young adolescents. 

In clinical trials, intention-to-treat 

(ITT) results had lower observed 

efficacy than per-protocol analyses, 

since ITT analyses included 

participants with previous 

exposures and prevalent vaccinetype HPV infections at baseline 

before initial vaccination. 

In the FUTURE III trial in 3,819 

women age 24–45 years, ITT 

efficacy of 4vHPV was 47.2% (95% 

CI 33.5, 58.2) against a combined 

endpoint of persistent HPV 

infection, extragenital lesions, 

and/or CIN 1+. No significant 

efficacy was observed against CIN

2+, although the study was not 

powered to evaluate for this 

endpoint specifically. 
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

In the FUTURE III trial in 3,819 women 

age 24 through 45 years, per-protocol 

efficacy of 4vHPV was 88.7% (95% CI

78.1, 94.8) against a combined 

endpoint of persistent HPV infection, 

extragenital lesions, and/or CIN 1+.

When analysis was restricted to 

women age 27 through 45 years, 

efficacy was 87.7% (95% CI, 75.4, 

94.6). No significant efficacy was 

observed against CIN 2+, although the 

study was not powered to evaluate for 

this endpoint specifically. Ten-year 

follow-up of a subset of women in this 

study found no waning protection. 

In a 9vHPV immunogenicity trial, 

geometric mean antibody titers to 7 

high-risk HPV types were non-inferior 

in 642 women age 27–45 years 

compared to 570 women age 16–26 

years; >99% of women in both groups 

seroconverted to all 9vHPV types. 

CRITERIA WORK GROUP JUDGMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION

How 

substantial 

are the 

undesirable 

anticipated 

effects?

 Minimal Small Moderate Large Don’t 

know

Varies

X

There is abundant evidence for safety 

of HPV vaccines. In 9 clinical trials of 

9vHPV, 4vHPV or 2vHPV in adults 

older than age 26 years (n=14,057), 

there were few serious adverse events 

and no vaccine-related deaths. 

Some Work Group members felt 

that adult vaccination might 

detract from the adolescent 

vaccination program, which 

remains the main focus for HPV 

prevention. 
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

Do the 

desirable 

effects 

outweigh the 

undesirable 

effects?

Favors 

intervention

Favors 

comparison

Favors 

both

Favors 

neither

Unclear

X

Given abundant evidence for safety of 

HPV vaccines, undesirable anticipated 

effects are minimal. Also, anticipated 

population-level benefits are minimal 

for vaccinating adults over age 26 

years. In this scenario, other 

considerations including costeffectiveness play an important role in 

guiding policy-making. 

What is the 

overall 

certainty of 

this evidence 

for the critical 

outcomes?

Effectiveness of the intervention

No

included

studies

4 

Very low

3 

Low

2

Moderate

1

High

X

Safety of the intervention

No

included

studies

4

Very low

3

Low

2

Moderate

1

High

X

Refer to GRADE tables for detailed 

assessment of the certainty of the 

evidence. 

Overall evidence on benefits in the perprotocol population was GRADE evidence 

level 2 (moderate quality evidence). 

Overall evidence on harms was also 

GRADE evidence level 2 (moderate 

quality evidence).

Evidence in the GRADE tables has 

to do with individual-level 

outcomes on vaccine safety and 

effectiveness; outcomes in GRADE 

do not speak to population-level 

outcomes or programmatic 

concerns. 

VALUES

Does the 

target 

population 

feel that the 

desirable 

effects are 

large relative 

to undesirable 

effects?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

In 9 published studies of adults (N=2841 

women and N=1195 men), acceptability 

varied across studies, although was 

moderate to high overall. 

Acceptability was higher when the 

vaccine was assumed to be free and/or a 

health care provider made a 

recommendation.

CRITERIA WORK GROUP JUDGMENTS RESEARCH EVIDENCE ADDITIONAL INFORMATION

Is there 

important 

uncertainty 

about or 

variability in 

how much 

people value 

the main 

outcomes?

Important 

uncertainty 

or 

variability

Possibly 

important 

uncertainty 

or 

variability

Probably 

no 

important 

uncertainty 

or 

variability

No 

important 

uncertainty 

or variability

No known 

undesirable 

outcomes

X

Acceptability of HPV vaccine among 

adults varied by study population and 

methodology.
ACIP Evidence to Recommendations Framework

Updated June 26, 2019 ACCEPTABILITY

Is the 

intervention 

acceptable to 

key 

stakeholders?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

There are no recently published data 

assessing U.S. stakeholder acceptability of 

routine HPV vaccination among 27

through 45 year-olds. However, vaccines 

for other conditions are routinely given

to adults in this age range. 

In a 2019 survey about HPV 

vaccination recommendations

based on clinical decision making 

for individuals among 45 

immunization programs, the 

majority (60%) anticipated that it 

would be very or somewhat 

challenging to communicate a 

recommendation for clinical 

decision-making to vaccine 

providers in their jurisdiction. 

Almost half (42%) thought it would 

be easy or somewhat easy for 

vaccine providers to determine 

patients in this age group who 

might benefit from vaccination. 

Most (69%) anticipated challenges 

to implementing such a 

recommendation.

RESOURCE USE

Is the 

intervention a 

reasonable 

and efficient 

allocation of 

resources?

No Probably

no

Uncertain Probably

yes

Yes

X

Five health economic models of HPV 

vaccination in the United States were 

reviewed. The cost-effectiveness ratio for 

the current HPV vaccination program 

ranged from cost-saving to about $35,000 

per quality-adjusted life year (QALY). In 

the context of the existing program, 

vaccinating adults aged 30 years or older 

would produce relatively small additional 

health benefits. The incremental cost per 

QALY gained by also vaccinating adults 

through age 30 years exceeded $300,000 

in four of five models. In most models, 

expanding vaccination to older ages 

would result in less favorable costeffectiveness ratios. 

Variation in results across models was 

likely due to uncertainties about HPV 

natural history (e.g., burden of HPVGlobally, there is an HPV vaccine 

shortage as production capacity is 

not adequate to meet demand

currently. The demand/supply 

imbalance is expected to remain 

over the next 3–5 years. In some 

countries, including those with Gavi 

and UNICEF support, cohort 

expansion efforts and vaccination 

of multi-age cohorts of girls are not 

able to proceed due to lack of 

vaccine availability. Although no 

domestic vaccine shortage is 

anticipated, some Work Group 

members had equity concerns 

about HPV vaccination 

recommendations being extended 

to 27 through 45 year-olds in the 

United States in this context. 
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

associated disease caused by new HPV 

infections after age 26 years, and 

prevalence of immunity following 

clearance of natural infections) and level 

of herd protection from the existing HPV 

vaccination program. 

It is not clear whether any

recommendation for HPV

vaccination in this age range would 

lead to greater uptake among 

individuals who are likely versus 

unlikely to benefit. 

FEASIBILITY

Is the 

intervention 

feasible to 

implement?

No Probably

no

Uncertain Probably

yes

Yes Varies

X

Delivering any adult vaccination can be 

challenging in the United States. 

Programs and funding for adult 

vaccination are not available in all 

jurisdictions. Adult immunization is 

performed primarily in the private 

sector.

In a 2015 survey of 353 

obstetrician/gynecologists, 81% reported 

that they stock and administer HPV 

vaccine. 

Routine recommendations are 

easier to implement than shared 

clinical decision making. 

Identifying individual patients 

likely to benefit from adult HPV 

vaccination could be challenging for 

vaccine providers, especially those 

who do not regularly assess sexual 

risk behaviors. 

Some Work Group members felt 

that recommending vaccination in 

this age range might reduce health 

disparities, by increasing access to 

vaccination among adults with 

health insurance coverage. Others 

felt that recommending vaccination 

in this age range might enhance 

health disparities, as underinsured 

adults would be less likely to have 

access to vaccination since states 

have limited funds for adult 

vaccination programs.
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

Balance of 

consequences

Undesirable 

consequences 

clearly outweigh

desirable 

consequences

in most settings

Undesirable 

consequences 

probably outweigh

desirable 

consequences

in most settings

The balance 

between 

desirable and 

undesirable 

consequences 

is closely balanced 

or uncertain

X

Desirable 

consequences 

probably outweigh 

undesirable 

consequences

in most settings

Desirable 

consequences 

clearly outweigh

undesirable 

consequences

in most settings

There is 

insufficient 

evidence to 

determine the 

balance of 

consequences

Is there sufficient information to move forward with a recommendation?

Yes No 

Policy options for 

ACIP 

consideration ACIP does not recommend the 

intervention

X

ACIP recommends the intervention for 

individuals based on shared clinical 

decision-making

X

ACIP recommends the intervention

Recommendation 

(text)

Option for “ACIP does not recommend the intervention”:

Individuals older than the catch-up age group

ACIP does not recommend HPV vaccination for adults older than age 26 years. 

Option for “ACIP recommends the intervention for individuals based on shared clinical decision making”:

Individuals older than the catch-up age group

ACIP recommends HPV vaccination based on shared clinical decision making for individuals ages 27 through 45 

years who are not adequately vaccinated.* HPV vaccines are not licensed for use in adults older than age 45 years.

Special populations and medical conditions

The above recommendations for individuals older than the catch-up age group also apply to MSM;† transgender 

people; and people with immunocompromising conditions.

 *

Definitions of persons considered adequately vaccinated are unchanged from prior publication (Meites et al, MMWR 2016).

†Men who have sex with men; includes men who identify as gay or bisexual, or who intend to have sex with men
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

Additional 

considerations

(optional)

The HPV Vaccines Work Group was unanimous that routine or catch-up HPV vaccination should not be 

recommended for 27 through 45 year-olds. A majority felt that ACIP should recommend the intervention for adults

based on shared clinical decision making, while a large minority felt that ACIP should not recommend the 

intervention in this age range. Thus two policy options were presented to ACIP for consideration. 

No prevaccination physical examination (e.g., Pap and/or HPV testing) is required to establish the appropriateness 

of HPV vaccination. Cervical cancer screening guidelines and recommendations should be followed. 

CDC continues to monitor HPV vaccine safety and impact of the vaccination program on HPV-attributable outcomes, 

including prevalence of HPV infections, anogenital warts, precancers, and cancers. ACIP reviews results from 

ongoing studies, vaccine trials, and health economic analyses as data become available, and updates vaccine policy 

as appropriate. 
ACIP Evidence to Recommendations Framework

Updated June 26, 2019

Final deliberation and decision by the ACIP

Final ACIP 

recommendation

ACIP does not recommend the 

intervention

ACIP recommends the intervention 

for individuals based on shared 

clinical decision-making

X

ACIP recommends the intervention

ACIP 

considerations

ACIP members voted 10:4 in favor of shared clinical decision making for adults aged 27 through 45 years, 

recognizing that some individuals who are at risk for new HPV infection might benefit from vaccination in this age 

range. 

ACIP members in favor of shared clinical decision making cited data on vaccine safety and efficacy, and data 

suggesting that some adults in this age range might benefit from vaccination against HPV. ACIP members not in favor 

noted that little public health benefit is expected from vaccinating adults in this age range, compared to benefits of 

the existing vaccination program for adolescents. ACIP noted that most U.S. adults ages 27 through 45 years will not 

need to be vaccinated against HPV, since most people are unlikely to benefit from vaccination in this age range.

This Evidence to Recommendation table is based on the GRADE Evidence to Decision framework developed through the DECIDE project. Further 

information is available athttp://www.decide-collaboration.eu/evidence-decision-etd-framework. Framework last updated 19 June 2019.