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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Use of 9-Valent Human Papillomavirus Vaccine (9vHPV) in Females and Males						Print
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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.
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 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
Evidence type for each considered outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations.
Methods Footnote * Protocols 001, 002, 003, 005, 007, 009
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Tables
Table 1: 9vHPV outcome measure ranking and inclusion
9vHPV outcome measure ranking and inclusion
Sex
Outcome
Importance
Included in evidence profileBenefitsFemales
≥CIN2
Critical
YesCervical cancer
Critical
YesDefinitive therapies (cervical)a,b
Critical
NoOropharyngeal cancerc
Critical
NoVaginal/vulvar cancerd
Critical
NoAnal cancerd
Critical
NoAnogenital warts
Important
YesMales
Anal cancer
Critical
YesOropharyngeal cancerc
Critical
NoAnogenital warts
Important
YesHarmsFemales and males
Serious adverse events
Critical
YesAnaphylaxis
Critical
YesTable 1 Footnotesa Include non-ablative procedures, loop electrosurgical excision procedure, conizationb Not considered separately because ≥CIN2 and cervical cancer were included in evidence profilec No data available on outcomesd Not included in evidence profile because of small numbers in trials
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Table 2. Characteristics of included studies
Characteristics of included studies
Vaccine
Protocol
Design
No. of subjects
Per protocol population
Objectives4vHPV
0078
Randomized, placebo controlled
1106
Females aged 16-26 years
Efficacy, immunogenicity,f safety0138
Randomized, placebo controlled
5759
Females aged 16-26 years
Efficacy, immunogenicity,f safety0158
Randomized, placebo controlled
12167
Females aged 16-26 years
Efficacy, immunogenicity,f safety0205
Randomized, placebo controlled
4065a
Males aged 16-26 years
Efficacy, immunogenicity,f safety9vHPV
0012
Randomized, 4vHPV comparator
14215
Females aged 16-26 years
Efficacy, immunogenicity,f safety0029
Observational
2999
Females aged 16-26 years, females and males aged 9-15 years
Adult-to-adolescent immunobridging, safety0034
Observational
2520b
Females and
males aged 16-26 years
Female-to-male immunobridging, safety0059
Observational
1241
Females and
males aged 11-15 years
Concomitant use: Menactra,c Adacel,d safety0079
Observational
1054
Females and
males aged 11-15 years
Concomitant use: Repevax,e safety0099
Randomized, 4vHPV comparator
600
Females aged 9-15 years
4vHPV-to-9vHPV immunobridging, safetyTable 2 Footnotesa Included 3463 heterosexual males (HM) and 602 men who have sex with men (MSM)b Included 1106 HM and 313 MSMc Quadrivalent meningococcal conjugate vaccine (MenACWY-D)d Tetanus, diphtheria, acellular pertussis vaccine (Tdap)e Tdap/polio vaccinef Seroconversion and geometric mean titers; antibody measured by competitive Luminex immunoassay (cLIA) at month 7
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Table 3. Available data for females aged 16-26 years from the 9vHPV trials
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-relatedDirect
Indirect
Direct
Indirect≥CIN2
Noa
Immunogenicityb
Yes
ImmunogenicityCervical cancer
No
Immunogenicityb
No
≥CIN2, immunogenicityAnogenital warts
No
Immunogenicityb
—
—Table 3 Footnotesa Active comparator, 4vHPV, used rather than placebo; too few events for efficacy datab Immunogenicity of 9vHPV compared with 4vHPV was used to infer efficacy
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Table 4. 4vHPV trials considered for 9vHPV GRADE for HPV 6, 11, 16, 18-related outcomes, per protocol population, females aged 16-26 years
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
Efficacy007, 013, 015
Females aged 16-26 years
15729
≥CIN28
98.2%13365
Anogenital warts3
99.0%**Top of Page
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
Efficacy of 9vHPV for prevention of HPV 6, 11, 16, 18-related ≥CIN2 and anogenital warts and HPV
Outcome-related HPV type
Outcome
9vHPV
4vHPV
Vaccine efficacy
Absolute risk
difference per 1000
(95% CI)
Number
needed to vaccinate
(95% CI)No.
Cases
No.
Cases
%
(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)Table 5 Footnotesa Data from Protocol 001
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Table 6. Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 16-26 years2 a,c
Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 16-26 years
Antibody
9vHPV
4vHPV
GMT noninferiority or superiorityn
%
GMT
(mMU/mL)
n
%
GMT
(mMU/mL)Anti-HPV 6
3993
99.8
893
3975
99.8
875
9vHPV noninferior to 4vHPVbAnti-HPV 11
3995
100
666
3982
99.9
830Anti-HPV 16
4032
100
3131
4062
100
3157Anti-HPV 18
4539
99.8
805
4541
99.7
679Anti-HPV 31
4466
99.8
658
4377
50.1
10
9vHPV superior to 4vHPVbAnti-HPV 33
4702
99.7
416
4691
12.7
<4Anti-HPV 45
4792
99.6
253
4750
9.2
<3Anti-HPV 52
4455
99.8
380
4335
2.6
<3Anti-HPV 58
4486
99.8
483
4446
20.4
<4Table 6 FootnotesGMT = Geometric mean titer; mMU, milli-Merck unitsa Data from Protocol 001, antibody measured by cLIA at month 7b *P* <0.001c Personal communication, Alain Luxembourg, MD, PhD, September 2014, for anti-HPV 31, 33, 45, 52, 58
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Table 7: Evidence type for benefits: 9vHPV vaccination of females in the catch-up age group
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 typeHPV
6, 11, 16, 18
≥CIN2
4vHPV RCT (3)a
Supportive: 9vHPV
Randomized (1), Obs (2)b
No serious
No serious
Seriousc
No serious
2Cervical cancer
No serious
No serious
Seriousc,d
No serious
3Anogenital warts
No serious
No serious
Seriousc
No serious
2HPV
31, 33, 45, 52, 58
≥CIN2
9vHPV Randomized (1)eSupportive: 9vHPV Obs (2)f
No serious
No serious
No serious
No serious
1Cervical cancer
No serious
No serious
Seriousd
No serious
2Table 7 Footnotesa Data from Protocols 007, 013, 015b Supportive data from Protocols 001, 002, 003c Downgraded by 1 for indirectness due to use of immunobridging to 4vHPVd Downgraded by 1 for indirectness due to use of ≥CIN2 as surrogate marker for cervical cancere Data from Protocol 001f Supportive data from Protocols 002, 003
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Table 8: Seroconversion and geometric mean titers: 9vHPV in females aged 9-15 years compared with females aged 16-26 years, per protocol population7a
Seroconversion and geometric mean titers: 9vHPV in females aged 9-15 years compared with females aged 16-26 years, per protocol population
Antibody
9vHPV in females aged 9-15 years
9vHPV in females aged 16-26 years
GMT noninferiority
or superiorityn
%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 yearsbAnti-HPV 11
503
100
1292
332
100
707Anti-HPV 16
513
100
6934
329
100
3523Anti-HPV 18
516
99.8
2148
345
99.7
883Anti-HPV 31
506
100
1895
340
99.7
754Anti-HPV 33
518
100
986
354
99.7
467Anti-HPV 45
518
99.8
708
368
99.5
272Anti-HPV 52
517
100
962
337
99.7
420Anti-HPV 58
516
100
1288
332
100
591Table 8 FootnotesGMT = Geometric mean titer; mMU, milli-Merck unitsa Data from Protocol 002, antibody measured by cLIA at month 7b *P* <0.001c Personal communication, Alain Luxembourg, MD, PhD, September 2014
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Table 9: Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 9-15 years9a,c
Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 9-15 years
Antibody
9vHPV
4vHPV
GMT noninferiority or superiorityn
%
GMT
(mMU/mL)
n
%
GMT
(mMU/mL)Anti-HPV 6
273
100
1679
261
100
1566
9vHPV noninferior to 4vHPVbAnti-HPV 11
273
100
1316
261
100
1417Anti-HPV 16
276
100
6740
270
100
6887Anti-HPV18
276
100
1957
269
100
1796Anti-HPV 31
276
100
1770
268
73.5
22
9vHPV superior to 4vHPVbAnti-HPV 33
275
100
937
269
20.4
4Anti-HPV 45
275
99.6
622
271
21.0
3Anti-HPV 52
276
100
927
269
3.3
2Anti-HPV 58
267
100
1349
261
54.8
9Table 9 FootnotesGMT = Geometric mean titer; mMU, milli-Merck unitsa Data from Protocol 009, antibody measured by cLIA at month 7b *P* 0.001c Personal communication, Alain Luxembourg, MD, PhD, September 2014, for anti-HPV 31, 33, 45, 52, 58
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Table 10: Evidence type for benefits: 9vHPV vaccination of females in the routine age group
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 typeHPV
6, 11, 16, 18
≥CIN2
4vHPV RCT (3)a
Supportive: 9vHPV
Randomized  (2), Obs (4)b
No serious
No serious
Seriouse
No serious
2Cervical cancer
No serious
No serious
Seriouse
No serious
3Anogenital warts
No serious
No serious
Seriouse
No serious
2HPV
31, 33, 45, 52, 58
≥CIN2
9vHPV Randomized (1)c
Supportive: 9vHPV Obs (4)d
No serious
No serious
No seriouse
No serious
1Cervical cancer
No serious
No serious
Seriouse
No serious
2Table 10 Footnotesa Data from Protocols 007, 013, 015b Supportive data from Protocols 001, 002, 003, 005, 007, 009c Data from Protocol 001d Supportive data from Protocols 002, 003, 005, 007, 009e 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
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Table 11: 4vHPV RCT considered for 9vHPV GRADE for HPV 6, 11, 16, 18-related outcomes, per protocol population, males aged 16-26 years
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
Efficacy020
Males aged 16-26 years
402
AIN2/35
74.9%2798
Anogenital warts10
89.3%Table 11 FootnotesAIN2/3 = Anal intraepithelial neoplasia grade 2 or 3
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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
Seroconversion and geometric mean titers: 9vHPV in males
Antibody
9vHPV in males aged 16-26 years
9vHPV in females aged 16-26 years
GMT noninferiority or superiorityn
%
GMT
(mMU/mL)
n
%
GMT
(mMU/mL)Anti-HPV 6
847
99.6
782
708
99.6
704
Males noninferior to femalescAnti-HPV 11
851
100
617
712
99.9
565Anti-HPV 16
899
100
3346
781
99.9
2788Anti-HPV 18
906
99.9
808
831
99.8
680Table 12 FootnotesGMT = Geometric mean titer; mMU, milli-Merck unitsa Heterosexual malesb Data from Protocol 003, antibody measured by cLIA at month 7c *P* <0.001d Personal communication, Alain Luxembourg, MD, PhD, September 2014
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Table 13: Evidence type for benefits: 9vHPV vaccination of males in the catch-up age group
Evidence type for benefits: 9vHPV vaccination of males in the catch-up age group
Benefits
Design (#studies)
Risk of bias
Inconsistency
Indirectness
Imprecision
Evidence typeAnal cancer
4vHPV RCT (1)a
Supportive: 9vHPV
Randomized  (1), Obs (1)b
No serious
No serious
Seriousc,d
No serious
3Anogenital warts
No serious
No serious
Seriousc
No serious
2Table 13 Footnotesa Data from Protocol 020b Supportive data from Protocols 001, 003c Downgraded by 1 for indirectness due to use of immunobridging to females aged 16-26 yearsd Downgraded by 1 for indirectness due to use of anal intraepithelial neoplasia grade 2 or 3 as surrogate marker for anal cancer
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Table 14: Seroconversion and geometric mean titers: 9vHPV in males aged 9-15 years compared with females aged 16-26 years, per protocol population7a
Seroconversion and geometric mean titers: 9vHPV in males aged 9-15 years compared with females aged 16-26 years, per protocol population
Antibody
9vHPV in males aged 9-15 years
9vHPV in females aged 16-26 years
GMT noninferiority
or superiorityn
%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 yearsbAnti-HPV 11
537
100
1486
332
100
707Anti-HPV 16
546
100
8683
329
100
3523Anti-HPV 18
544
100
2855
345
99.7
883Table 14 FootnotesGMT = Geometric mean titer; mMU, milli-Merck unitsa Data from Protocol 002, antibody measured by cLIA at month 7b *P* <0.001c Personal communication, Alain Luxembourg, MD, PhD, September 2014
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Table 15: Seroconversion and geometric mean titers: 9vHPV in males aged 9-15 yearsa compared with males aged 16-26 yearsb per protocol population4,7
Seroconversion and geometric mean titers: 9vHPV in males aged 9-15 years
Antibody
9vHPV in males aged 9-15 yearsa
9vHPV in males aged 16-26 yearsbn
%c
GMT
(mMU/mL)
n
%
GMT
(mMU/mL)Anti-HPV 6
537
99.8
2083
847
99.6
782Anti-HPV 11
537
100
1486
851
100
617Anti-HPV 16
546
100
8683
899
100
3346Anti-HPV 18
544
100
2855
906
99.9
808Table 15 FootnotesGMT = Geometric mean titer; mMU, milli-Merck unitsa Data from Protocol 002, antibody measured by cLIA at month 7b Data from Protocol 003, antibody measured by cLIA at month 7c Personal communication, Alain Luxembourg, MD, PhD, September 2014
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Table 16: Evidence type for benefits: 9vHPV vaccination of males in the routine age group
Evidence type for benefits: 9vHPV vaccination of males in the routine age group
Benefits
Design (#studies)
Risk of bias
Inconsistency
Indirectness
Imprecision
Evidence typeAnal cancer
4vHPV RCT (1)a
Supportive: 9vHPV
Randomized (1), Obs (2)b
No serious
No serious
Seriousc
No serious
3Anogenital warts
No serious
No serious
Seriousc
No serious
2Table 16 Footnotesa Data from Protocols 020b Supportive data from Protocols 001, 002, 003c 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
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Table 17: Harms data in females and males9c
Pediatric Influenza Vaccine Price List
Harms
Females and males aged 16-26 years
Females and males aged 9-15 yearsProtocol (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)
—Table 17 Footnotesa Determined to be vaccine-related; study medication withdrawn for one caseb Determined to be due to non-study medicationc Personal communication, Alain Luxembourg, MD, PhD, March 2015
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Table 18: Evidence type for harms: 9vHPV in males and females
Evidence type for harms: 9vHPV in males and females
Harms
Design (#studies)
Risk of bias
Inconsistency
Indirectness
Imprecision
Evidence typeSerious adverse event
Randomized (2), Obs (4)a
No serious
No serious
No serious
Seriousb
2Anaphylaxis
No serious
No serious
No serious
Seriousb
2Table 18 Footnotesa Data from Protocols 001, 002, 003, 005, 007, 009b Downgraded by 1 for imprecision due to small sample size
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Table 19: Summary of evidence for 9vHPV vaccination of females in the catch-up age group
Summary of evidence for 9vHPV vaccination of females in the catch-up age group
Comparison
Outcome
Design (#studies)
Findings
Evidence type
Overall9vHPV 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
1-2Serious adverse event
9vHPV Randomized (1), Obs (2)e
Few cases
2Anaphylaxis
9vHPV Randomized (1), Obs (2)e
No vaccine-related cases
2Table 19 Footnotesa Data from Protocols 007, 013, 015b Supportive data from Protocols 001, 002, 003c Data from Protocol 001d Supportive data from Protocols 002, 003e Data from Protocols 001, 002, 003
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Table 20: Summary of evidence for 9vHPV vaccination of females in the routine age group
Summary of evidence for 9vHPV vaccination of females in the routine age group
Comparison
Outcome
Design (#studies)
Findings
Evidence type
Overall9vHPV 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)
Non-inferior 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)
Non-inferior immunogenicity compared with females in age group in efficacy trials
1-2Serious adverse event
9vHPV Randomized (1), Obs (3)e
No cases
2Anaphylaxis
9vHPV Randomized (1), Obs (3)e
No cases
2Table 20 Footnotesa Data from Protocols 007, 013, 015b Supportive data from Protocols 001, 002, 003, 005, 007, 009c Data from Protocol 001d Supportive data from Protocols 002, 003, 005, 007, 009e Data from Protocols 002, 005, 007, 009
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Table 21: Summary of evidence for 9vHPV vaccination of males in the catch-up age group
Summary of evidence for 9vHPV vaccination of males in the catch-up age group
Comparison
Outcome
Design (#studies)
Findings
Evidence type
Overall9vHPV 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 cases
2Anaphylaxis
9vHPV Randomized (1), Obs (2)c
No vaccine-related cases
2Table 21 Footnotesa Data from Protocols 020b Supportive data from Protocols 001, 003c Data from Protocols 001, 002, 003
**Top of Page
Table 22: Summary of evidence for 9vHPV vaccination of males in the routine age group
Summary of evidence for 9vHPV vaccination of males in the routine age group
Comparison
Outcome
Design (#studies)
Findings
Evidence type
Overall9vHPV 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)
Non-inferior 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
2Anaphylaxis
Randomized (1), Obs (3)c
No cases
2Table 22 Footnotesa Data from Protocol 020b Supportive data from Protocols 001, 002c Data from Protocols 002, 005, 007, 009
**Top of Page
Table 23: Considerations for formulating recommendations for 9vHPV
Considerations for formulating recommendations for 9vHPV
Key factors
CommentsEvidence 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 malesBalance of benefits
versus harms
Benefits outweigh harmsValues
ACIP HPV Work Group placed high value on prevention of outcomes due to HPV 6, 11, 16, 18, 31, 33, 45, 52, 58Cost-effectiveness
9vHPV is cost saving compared to 4vHPV11Summary
Category A recommendation**Top of Page
References
Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ. ACIP Evidence Based Recommendations Work Group (EBRWG). Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). *Vaccine* 2011;29:9171-6.
Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women, and supplementary appendix. *N Engl J Med* 2015;372:711-23.
Dillner J, Kjær SK, Wheeler CM, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. *BMJ* 2010;341:c3493.
Luxembourg A. Program summary and new 9-valent HPV vaccine trial data [3.3 MB, 160 pages]. Presentation before the Advisory Committee on Immunization Practices (ACIP), October 30, 2014. Atlanta, GA: US Department of Health and Human Services, CDC; 2014.
Palefsky J, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. *N Engl J Med* 2011;365:1576-85.
Dunne EF, Markowitz LE, Chesson H, et al. Recommendations on the use of quadrivalent human papillomavirus vaccine in males—Advisory Committee on Immunization Practices (ACIP), 2011. *MMWR* 2011;50:1705-8.
Food and Drug Administration. Highlights of prescribing information. Gardasil 9 (human papillomavirus 9-valent vaccine, recombinant) [18 pages]. Silver Spring, MD: US Department of Health and Human Services; Food and Drug Administration; 2014.
Kjær SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. *Cancer Prev Res* 2009;2:868-78.
Yang S, Miller N, Fink D, Hulse A. Original application: human papillomavirus 9-valent vaccine, recombinant [1.4 MB, 157 pages]. Silver Spring, MD: US Department of Health and Human Services; Food and Drug Administration; 2014.
Food and Drug Administration. Highlights of prescribing information. (human papillomavirus quadrivalent types 6, 11, 16, and 18 vaccine, recombinant) [27 pages]. Silver Spring, MD: US Department of Health and Human Services; Food and Drug Administration; 2006.
Brisson M.  Cost-effectiveness of 9-valent HPV vaccination [3.3 MB, 160 pages]. Presentation before the Advisory Committee on Immunization Practices (ACIP), October 30, 2014. Atlanta, GA: US Department of Health and Human Services, CDC; 2014.**Top of Page
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