1 

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for 

Use of 9-Valent Human Papillomavirus Vaccine (9vHPV) in Females and Males

Methods: GRADE was used to evaluate 9vHPV for routine vaccination of females and males 

aged 11 or 12 years as well as catch-up vaccination of females aged 13 through 26 years and 

males aged 13 through 21 years who were not vaccinated previously. Evidence of benefits, 

harms, values and preferences, and cost-effectiveness were reviewed in accordance with 

GRADE methods.1 The policy questions were: “Should 9vHPV be recommended for routine 

vaccination of 11 or 12 year olds?” and “Should 9vHPV be recommended for females aged 13 

through 26 years and males aged 13 through 21 years who have not been vaccinated 

previously?” 

The benefits considered critical outcomes in GRADE were the prevention of cervical 

intraepithelial neoplasia grade 2 or 3, or adenocarcinoma in situ (≥CIN2), cervical cancer, 

definitive therapies, oropharyngeal cancer, vaginal/vulvar cancer, and anal cancer in females and 

anal cancer and oropharyngeal cancer in males (Table 1). Anogenital warts were considered an 

important outcome for both females and males. The evidence profile included the most prevalent 

HPV-attributable outcomes for females, ≥CIN2, cervical cancer and anogenital warts, and for 

males, anal cancer and anogenital warts. Evidence was not available for the critical outcome, 

oropharyngeal cancer, in females or males; definitive therapies, vaginal/vulvar cancer, and anal 

cancer in females were not included in the evidence profile for GRADE. 

March 16, 2015

https://www.cdc.gov/vaccines/acip/recs/grade/hpv-9v.pdf
2

Data used for the evidence review were from 9vHPV pre-licensure clinical trials as well as the 

efficacy trials from the quadrivalent HPV vaccine (4vHPV) program (Table 2). The pivotal 

efficacy trial for 9vHPV was conducted in females aged 16 through 26 years.2 This was a 

randomized trial comparing 9vHPV with 4vHPV conducted among approximately 14,000 

females aged 16 through 26 years. This trial provided evidence for all policy questions including 

vaccination of females in the catch-up age group. Evidence used to evaluate efficacy of 9vHPV 

for prevention of HPV 31, 33, 45, 52, 58-related outcomes was directly from this trial. Evidence 

used to evaluate efficacy of 9vHPV for prevention of HPV 6, 11, 16, 18-related outcomes was 

from randomized controlled trials (RCT) of 4vHPV3 and from immunogenicity studies 

comparing 9vHPV with 4vHPV;

4 these data were used to infer 9vHPV efficacy for HPV 6, 11, 

16, 18-related outcomes.

For HPV vaccination of females in the routine age group, evidence from two immunobridging 

trials was also used. One trial compared 9vHPV in females aged 9 through 15 years with females 

aged 16 through 26 years, and another trial compared 9vHPV with 4vHPV in females aged 9 

through 15 years.

4 Noninferior immunogenicity of 9vHPV compared with 4vHPV in females 

aged 9 through 15 years and 9vHPV in females aged 9 through 15 years compared with females 

aged 16 through 26 years was used to infer efficacy for prevention of HPV 6, 11, 16, 18, 31, 33, 

45, 52, 58-related outcomes.

For HPV vaccination of males, evidence used to evaluate efficacy of 9vHPV for prevention of 

HPV 6, 11, 16, 18-related outcomes was from one RCT of 4vHPV among approximately 4,000 

males aged 16 through 26 years, which evaluated anogenital warts; anal precancer outcomes 
3

were evaluated in a subset of approximately 600;

5,6 and an immunogenicity study comparing 

9vHPV in males with females aged 16 through 26 years.

4 Noninferior immunogenicity of 

9vHPV in males compared with females was used to infer efficacy for prevention of HPV 6, 11, 

16, 18-related outcomes.

For HPV vaccination of males in the routine age group, evidence was also from an 

immunobridging trial, which showed noninferior immunogenicity of 9vHPV in males aged 9 

through 15 years compared to females aged 16 through 26 years.4 These data were used to infer 

efficacy for prevention of HPV 6, 11, 16, 18-related outcomes. We also compared 

immunogenicity of 9vHPV in males aged 9 through 15 years with males aged 16 through 26 

years.

The critical harms considered were serious adverse events (SAE) and anaphylaxis. Safety of 

9vHPV was evaluated based on 6 Phase III studies∗ in the clinical development program. 

Immunogenicity and efficacy evidence used was from analyses of the per protocol populations. 

For the efficacy trials, this included individuals who received all 3 vaccinations within one year 

of enrollment, did not have major deviations from the study protocol, were naïve (PCR negative 

and seronegative) to the relevant HPV type(s) prior to dose 1, and who remained PCR negative 

to the relevant HPV type(s) through one month post-dose 3 (Month 7).7

 ∗ Protocols 001, 002, 003, 005, 007, 009
4

Evidence type for each considered outcome was derived through a review of study design, risk of 

bias, inconsistency, indirectness, imprecision, and other considerations.
5 

Table 1. 9vHPV outcome measure ranking and inclusion

Sex Outcome Importance Included in 

evidence profile

Benefits 

Females

≥CIN2 Critical Yes

Cervical cancer Critical Yes

Definitive therapies(cervical)a,b Critical No

Oropharyngeal cancerc Critical No

Vaginal/vulvar cancerd Critical No

Anal cancerd Critical No

Anogenital warts Important Yes

Males

Anal cancer Critical Yes

Oropharyngeal cancerc Critical No

Anogenital warts Important Yes

 Harms

Females and males

Serious adverse events Critical Yes

Anaphylaxis Critical Yes

a

Include non-ablative procedures, loop electrosurgical excision procedure, conization b

Not considered separately because ≥CIN2 and cervical cancer were included in evidence profile c

No data available on outcomes

d

Not included in evidence profile because of small numbers in trials
6 

Table 2. Characteristics of included studies

Vaccine Protocol Design No. of 

subjects Per protocol population Objectives

4vHPV

0078

Randomized, 

placebo 

controlled

1106 Females aged 16–26 years Efficacy, immunogenicity,f safety

0138

Randomized, 

placebo 

controlled

5759 Females aged 16–26 years Efficacy, immunogenicity,f safety

0158

Randomized, 

placebo 

controlled

12167 Females aged 16–26 years Efficacy, immunogenicity,f safety

0205

Randomized, 

placebo 

controlled

4065a Males aged 16–26 years Efficacy, immunogenicity,f safety

9vHPV

0012

Randomized, 

4vHPV 

comparator

14215 Females aged 16–26 years Efficacy, immunogenicity,f safety

0029 Observational 2999 Females aged 16–26 years, females 

and males aged 9–15 years

Adult-to-adolescent immunobridging, 

safety

0034 Observational 2520b Females and males aged 16–26 years 

Female-to-male immunobridging, 

safety

0059 Observational 1241 Females and males aged 11–15 years

Concomitant use: Menactra,

c Adacel,d

safety

0079 Observational 1054 Females and males aged 11–15 years Concomitant use: Repevax,

e safety

0099

Randomized, 

4vHPV 

comparator

600 Females aged 9–15 years

4vHPV-to-9vHPV immunobridging, 

safety

a

Included 3463 heterosexual males (HM) and 602 men who have sex with men (MSM)

b

Included 1106 HM and 313 MSM

c

Quadrivalent meningococcal conjugate vaccine (MenACWY-D) d

Tetanus, diphtheria, acellular pertussis vaccine (Tdap) e

Tdap/polio vaccine

f

Seroconversion and geometric mean titers; antibody measured by competitive Luminex immunoassay (cLIA) at month 7
7 

Table 3. Available data for females aged 16–26 years from the 9vHPV trials

Outcomes

HPV 6, 11, 16, 18-related HPV 31, 33, 45, 52, 58-related

Direct Indirect Direct Indirect

≥CIN2 Noa Immunogenicityb Yes Immunogenicity

Cervical cancer No Immunogenicityb No ≥CIN2, immunogenicity

Anogenital warts No Immunogenicityb -- --

a

Active comparator, 4vHPV, used rather than placebo; too few events for efficacy data b

Immunogenicity of 9vHPV compared with 4vHPV was used to infer efficacy 

Table 4. 4vHPV trials considered for 9vHPV GRADE for HPV 6, 11, 16, 18-related outcomes, per protocol population, females aged 16–26 years

Protocol Population No. Outcome Efficacy

007, 013, 015 Females aged 16–26 years

15729 ≥CIN28 98.2%

13365 Anogenital warts3 99.0%
8 

Table 5. Efficacy of 9vHPV for prevention of HPV 6, 11, 16, 18-related ≥CIN2 and anogenital warts and HPV 31, 33, 45, 52, 58-related 

≥CIN2, per protocol population, females aged 16–26 yearsa

Outcome-related 

HPV type Outcome

9vHPV 4vHPV Vaccine efficacy Absolute risk difference 

per 1000 (95% CI)

Number needed to 

No. Cases No. Cases % (95% CI) vaccinate (95% CI)

HPV 6, 11, 16, 18

≥CIN22 5823 1 5832 1 -- -- -- --

Anogenital warts2 5876 5 5893 1 -- -- -- --

HPV 31, 33, 45, 52, 

58

≥CIN27

5948 1 5943 27 96.3 (79.5, 99.8) 4 fewer per 1000 

(3, 5)

250

(200, 333)

a

Data from Protocol 001 

Table 6. Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 16–26 

years2a,c

9vHPV 4vHPV

GMT noninferiority

Antibody n % or superiority

GMT

(mMU/mL) n %

GMT

(mMU/mL)

Anti-HPV 6 3993 99.8 893 3975 99.8 875

9vHPV 

noninferior to 4vHPVb 

Anti-HPV 11 3995 100 666 3982 99.9 830

Anti-HPV 16 4032 100 3131 4062 100 3157

Anti-HPV 18 4539 99.8 805 4541 99.7 679

Anti-HPV 31 4466 99.8 658 4377 50.1 10

9vHPV superior 

to 4vHPVb 

Anti-HPV 33 4702 99.7 416 4691 12.7 <4

Anti-HPV 45 4792 99.6 253 4750 9.2 <3

Anti-HPV 52 4455 99.8 380 4335 2.6 <3

Anti-HPV 58 4486 99.8 483 4446 20.4 <4

GMT = Geometric mean titer; mMU, milli-Merck units

a

Data from Protocol 001, antibody measured by cLIA at month 7 b

P <0.001 c

Personal communication, Alain Luxembourg, MD, PhD, September 2014, for anti-HPV 31, 33, 45, 52, 58
9 

Table 7. Evidence type for benefits: 9vHPV vaccination of females in the catch-up age group

Outcome-related 

HPV type Benefits

Design 

(# studies)

Risk 

of bias Inconsistency Indirectness Imprecision

Evidence 

type

HPV 6, 11, 16, 18

≥CIN2 4vHPV RCT (3)a 

Supportive: 9vHPV 

Randomized (1), Obs (2)b 

No serious No serious Seriousc No serious 2

Cervical cancer No serious No serious Seriousc,d No serious 3

Anogenital warts No serious No serious Seriousc No serious 2

HPV 31, 33, 45, 52, 58

≥CIN2 9vHPV Randomized (1)e 

Supportive: 9vHPV Obs (2)f 

No serious No serious No serious No serious 1

Cervical cancer No serious No serious Seriousd No serious 2 a

Data from Protocols 007, 013, 015 b

Supportive data from Protocols 001, 002, 003 c

Downgraded by 1 for indirectness due to use of immunobridging to 4vHPV d

Downgraded by 1 for indirectness due to use of ≥CIN2 as surrogate marker for cervical cancer e

Data from Protocol 001 f

Supportive data from Protocols 002, 003
10

Table 8. Seroconversion and geometric mean titers:9vHPV in females aged 9–15 years compared with females aged 16–26 years, per 

protocol population7a

9vHPV in females aged 9–15 years 9vHPV in females aged 16–26 years

GMT noninferiority

Antibody n % or superiority c

GMT

(mMU/mL) n %

GMT

(mMU/mL)

Anti-HPV 6 503 99.8 1703 328 99.7 901

Females aged 9–15 years

noninferior to females aged 

16–26 yearsb

Anti-HPV 11 503 100 1292 332 100 707

Anti-HPV 16 513 100 6934 329 100 3523

Anti-HPV 18 516 99.8 2148 345 99.7 883

Anti-HPV 31 506 100 1895 340 99.7 754

Anti-HPV 33 518 100 986 354 99.7 467

Anti-HPV 45 518 99.8 708 368 99.5 272

Anti-HPV 52 517 100 962 337 99.7 420

Anti-HPV 58 516 100 1288 332 100 591

GMT = Geometric mean titer; mMU, milli-Merck units

a

Data from Protocol 002, antibody measured by cLIA at month 7 b

P <0.001 c

Personal communication, Alain Luxembourg, MD, PhD, September 2014

Table 9. Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 9–15 years9a,c

9vHPV 4vHPV

GMT noninferiority

Antibody n % or superiority

GMT

(mMU/mL) n %

GMT

(mMU/mL)

Anti-HPV 6 273 100 1679 261 100 1566

9vHPV

noninferior to 4vHPVb

Anti-HPV 11 273 100 1316 261 100 1417

Anti-HPV 16 276 100 6740 270 100 6887

Anti-HPV18 276 100 1957 269 100 1796

Anti-HPV 31 276 100 1770 268 73.5 22

9vHPV superior

to 4vHPVb

Anti-HPV 33 275 100 937 269 20.4 4

Anti-HPV 45 275 99.6 622 271 21.0 3

Anti-HPV 52 276 100 927 269 3.3 2

Anti-HPV 58 267 100 1349 261 54.8 9

GMT = Geometric mean titer; mMU, milli-Merck units

a

Data from Protocol 009, antibody measured by cLIA at month 7 b

P <0.001 c

Personal communication, Alain Luxembourg, MD, PhD, September 2014, for anti-HPV 31, 33, 45, 52, 58
11

Table 10. Evidence type for benefits: 9vHPV vaccination of females in the routine age group

Outcome-related 

HPV type Benefits

Design 

(# studies)

Risk 

of bias Inconsistency Indirectness Imprecision

Evidence 

type

HPV 6, 11, 16, 18

≥CIN2 4vHPV RCT (3)a 

Supportive: 9vHPV

Randomized (2), Obs (4)b

No serious No serious Seriouse No serious 2

Cervical cancer No serious No serious Seriouse No serious 3

Anogenital warts No serious No serious Seriouse No serious 2

HPV 31, 33, 45, 52,

58

≥CIN2 9vHPV Randomized (1)c 

Supportive: 9vHPV Obs (4)

d 

No serious No serious No seriouse No serious 1

Cervical cancer No serious No serious Seriouse No serious 2 a

Data from Protocols 007, 013, 015 b

Supportive data from Protocols 001, 002, 003, 005, 007, 009 c

Data from Protocol 001 d

Supportive data from Protocols 002, 003, 005, 007, 009 e

Started with evidence type for females in the catch-up age group; not downgraded due to noninferior immunogenicity among females aged 9–15 years compared with 

females aged 16–26 years, and because efficacy data were from per protocol population
12

Table 11. 4vHPV RCT considered for 9vHPV GRADE for HPV 6, 11, 16, 18-related outcomes, per protocol population, males

aged 16–26 years

Protocol Population No. Outcome Efficacy

020 Males aged 16–26 years

402 AIN2/35 74.9%

2798 Anogenital warts10 89.3%

AIN2/3 = Anal intraepithelial neoplasia grade 2 or 3

Table 12. Seroconversion and geometric mean titers: 9vHPV in malesa aged 16–26 years compared with females aged 16–26 

years, per protocol population4b,d

9vHPV in males aged 16–26 years 9vHPV in females aged 16–26 years

GMT noninferiority

Antibody n % or superiority

GMT

(mMU/mL) n %

GMT

(mMU/mL)

Anti-HPV 6 847 99.6 782 708 99.6 704

Males

noninferior to femalesc

Anti-HPV 11 851 100 617 712 99.9 565

Anti-HPV 16 899 100 3346 781 99.9 2788

Anti-HPV 18 906 99.9 808 831 99.8 680

GMT = Geometric mean titer; mMU, milli-Merck units

a

Heterosexual males

b

Data from Protocol 003, antibody measured by cLIA at month 7 c

P <0.001

d

Personal communication, Alain Luxembourg, MD, PhD, September 2014
13

Table 13. Evidence type for benefits: 9vHPV vaccination of males in the catch-up age group

Benefits

Design 

(# studies) Risk of bias Inconsistency Indirectness Imprecision

Evidence 

type

Anal cancer 4vHPV RCT (1)a 

Supportive: 9vHPV

Randomized (1), Obs (1)b 

No serious No serious Seriousc,d No serious 3 

Anogenital warts No serious No serious Seriousc No serious 2

a

Data from Protocol 020 b

Supportive data from Protocols 001, 003 c

Downgraded by 1 for indirectness due to use of immunobridging to females aged 16–26 years d

Downgraded by 1 for indirectness due to use of anal intraepithelial neoplasia grade 2 or 3 as surrogate marker for anal cancer
14

Table 14. Seroconversion and geometric mean titers: 9vHPV in males aged 9–15 years compared with females aged 16–26 years, per 

protocol population7a

Antibody

9vHPV in males aged 9–15 years 9vHPV in females aged 16–26 years

GMT noninferiority

n % or superiority c

GMT

(mMU/mL) n %

GMT

(mMU/mL)

Anti-HPV 6 537 99.8 2083 328 99.7 901

Males aged 9–15 years

noninferior to females aged 16–

26 yearsb

Anti-HPV 11 537 100 1486 332 100 707

Anti-HPV 16 546 100 8683 329 100 3523

Anti-HPV 18 544 100 2855 345 99.7 883

GMT = Geometric mean titer; mMU, milli-Merck units

a

Data from Protocol 002, antibody measured by cLIA at month 7 b

P <0.001 c

Personal communication, Alain Luxembourg, MD, PhD, September 2014

Table 15. Seroconversion and geometric mean titers: 9vHPV in males aged 9–15 yearsa compared with males aged 16–26 

years,

b per protocol population4,7

Antibody

9vHPV in males aged 9–15 yearsa 9vHPV in males aged 16–26 yearsb

n %c

GMT

(mMU/mL) n %

GMT

(mMU/mL)

Anti-HPV 6 537 99.8 2083 847 99.6 782

Anti-HPV 11 537 100 1486 851 100 617

Anti-HPV 16 546 100 8683 899 100 3346

Anti-HPV 18 544 100 2855 906 99.9 808

GMT = Geometric mean titer; mMU, milli-Merck units

a

Data from Protocol 002, antibody measured by cLIA at month 7 b

Data from Protocol 003, antibody measured by cLIA at month 7 c

Personal communication, Alain Luxembourg, MD, PhD, September 2014
15

 

Table 16. Evidence type for benefits: 9vHPV vaccination of males in the routine age group

Benefits

Design 

(# studies) Risk of bias Inconsistency Indirectness Imprecision

Evidence 

type

Anal cancer 4vHPV RCT (1)a 

Supportive: 9vHPV

Randomized (1), Obs (2)b 

No serious No serious Seriousc No serious 3

Anogenital warts No serious No serious Seriousc No serious 2

a

Data from Protocol 020 b

Supportive data from Protocols 001, 002, 003 c

Started with evidence type for males in the catch-up age group; not downgraded because of noninferior immunogenicity, and because efficacy data were from per 

protocol population
16

Table 17. Harms data in females and males9c

Females and males aged 16–26 years Females and males aged 9–15 years

Harms

Protocol 

(Design)

Incidence in 

9vHPV

% (n/N)

Incidence in 

4vHPV

% (n/N)

Protocol 

(Design)

Incidence in 

9vHPV

% (n/N)

Incidence in 

4vHPV

% (n/N)

Serious adverse event day 1–15

001 

(Randomized)

0.03 (2/7071)a 0.01 (1/7078)

009 

(Randomized)

0 (0/299) 0 (0/300)

Serious adverse event any time 0.03 (2/7071) 0.03 (2/7078) 0 (0/299) 0 (0/300)

Anaphylaxis day 1–15 0.01 (1/7071)b 0 (0/7078) 0 (0/299) 0 (0/300)

Serious adverse event day 1–15

002, 003 

(Obs)

0.03 (1/2930) --

002, 005, 007 

(Obs)

0.02 (1/4793) --

Serious adverse event any time 0.03 (1/2930) -- 0.02 (1/4793) --

Anaphylaxis day 1–15 0 (0/2930) -- 0 (0/4793) --

a

Determined to be vaccine-related; study medication withdrawn for one case b

Determined to be due to non-study medication c

Personal communication, Alain Luxembourg, MD, PhD, March 2015

Table 18. Evidence type for harms: 9vHPV in males and females

Harms Design (# studies)

Risk of 

bias Inconsistency Indirectness Imprecision Evidence type

Serious adverse event

Randomized (2), Obs (4)

a No serious No serious No serious Seriousb 2

Anaphylaxis No serious No serious No serious Seriousb 2

a

Data from Protocols 001, 002, 003, 005, 007, 009 b

Downgraded by 1 for imprecision due to small sample size
17

Table 19. Summary of evidence for 9vHPV vaccination of females in the catch-up age group

Comparison Outcome

Design

(# studies) Findings

Evidence 

type Overall

9vHPV

vs.

4vHPV

HPV 6, 11, 16, 18-

related:

≥CIN2 

Cervical cancer 

Anogenital warts

4vHPV RCT (3)a

,

9vHPV Randomized (1), Obs (2)b

4vHPV has high efficacy; 9vHPV 

has noninferior immunogenicity for 

HPV 6, 11, 16, 18 and comparable 

risk for outcomes

2–3

2

(Moderate) HPV 31, 33, 45, 52, 

58-related:

≥CIN2 

Cervical cancer

9vHPV Randomized (1)c

,

9vHPV Obs (2)d

9vHPV has high efficacy for HPV 

31, 33, 45, 52, 58-related outcomes 1–2

Serious adverse event

9vHPV Randomized (1), Obs (2)e Few cases

2

Anaphylaxis No vaccine-related cases

a

Data from Protocols 007, 013, 015 b

Supportive data from Protocols 001, 002, 003 c

Data from Protocol 001 d

Supportive data from Protocols 002, 003 e

Data from Protocols 001, 002, 003
18

Table 20. Summary of evidence for 9vHPV vaccination of females in the routine age group

Comparison Outcome

Design 

(# studies) Findings

Evidence 

type Overall

9vHPV

vs.

4vHPV

HPV 6, 11, 16, 18-

related:

Cervical cancer 

≥CIN2 

Anogenital warts

4vHPV RCT (3)a

9vHPV Randomized (2), Obs (4)b

(See findings in Table 19)

Noninferior immunogenicity compared 

with females in age group in efficacy 

trials

2–3

2 

(Moderate)

HPV 31, 33, 45, 52, 58-

related:

Cervical cancer

≥CIN2

9vHPV Randomized (1)c

9vHPV Randomized (1), Obs (4)d

(See findings in Table 19)

Noninferior immunogenicity compared 

with females in age group in efficacy 

trials

1–2

Serious adverse event

9vHPV Randomized (1), Obs (3)

e No cases

2

Anaphylaxis No cases

a

Data from Protocols 007, 013, 015 b

Supportive data from Protocols 001, 002, 003, 005, 007, 009 c

Data from Protocol 001 d

Supportive data from Protocols 002, 003, 005, 007, 009 e

Data from Protocols 002, 005, 007, 009
19

Table 21. Summary of evidence for 9vHPV vaccination of males in the catch-up age group

Comparison Outcome

Design 

(# studies) Findings

Evidence 

type Overall

9vHPV

vs.

4vHPV

HPV 6, 11, 16, 18-

related:

Anal cancer

Anogenital warts

4vHPV RCT (1)a

9vHPV Randomized (1), Obs (1)b

4vHPV has high efficacy; 9vHPV 

has noninferior immunogenicity for 

HPV 6, 11, 16, 18 and comparable 

risk for outcomes

2–3

3 

(Low)

Serious adverse event

9vHPV Randomized (1), Obs (2)c Few cases2

Anaphylaxis No vaccine-related cases

a

Data from Protocol 020 b

Supportive data from Protocols 001, 003 c

Data from Protocols 001, 002, 003

Table 22. Summary of evidence for 9vHPV vaccination of males in the routine age group

Comparison Outcome

Design 

(# studies) Findings

Evidence 

type Overall

9vHPV

vs.

4vHPV

HPV 6, 11, 16, 18-

related:

Anal cancer

Anogenital warts

4vHPV RCT (1)a

9vHPV Randomized (1), Obs (1)b

(See findings in table 21)

Noninferior immunogenicity

compared with females and males in 

age group in efficacy trials

2–3

3

(Low)

Serious adverse event

Randomized (1), Obs (3)

c No cases

2

Anaphylaxis No cases

a

Data from Protocol 020 b

Supportive data from Protocols 001, 002 c

Data from Protocols 002, 005, 007, 009
20

Table 23. Considerations for formulating recommendations for 9vHPV

Key factors Comments

Evidence type for 

benefits and harms

• 9vHPV evidence from a randomized trial comparing 9vHPV with 

4vHPV in approximately 14,000 females aged 16–26 years,

immunobridging studies, and randomized trials comparing 4vHPV 

with placebo

• Evidence type 2 (moderate) for females

• Evidence type 3 (low) for males

Balance of benefits 

versus harms

• Benefits outweigh harms

Values • ACIP HPV Work Group placed high value on prevention of 

outcomes due to HPV 6, 11, 16, 18, 31, 33, 45, 52, 58

Cost-effectiveness • 9vHPV is cost saving compared to 4vHPV11

Summary • Category A recommendation
21

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