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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

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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 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

Table 1 Footnotes
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

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Table 2. Characteristics of included studies

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

Table 2 Footnotes
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

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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-related
Direct Indirect Direct Indirect
≥CIN2 Noa Immunogenicityb Yes Immunogenicity
Cervical cancer No Immunogenicityb No ≥CIN2, immunogenicity
Anogenital warts No Immunogenicityb

Table 3 Footnotes
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

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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 Efficacy
007, 013, 015 Females aged 16-26 years 15729 ≥CIN28 98.2%
13365 Anogenital warts3 99.0%

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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 Footnotes
a 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 superiority
n % 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

Table 6 Footnotes
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

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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 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

Table 7 Footnotes
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

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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 population7 a

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 superiority
n %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

Table 8 Footnotes
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

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Table 9: Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 9-15 years9 a,c

Seroconversion and geometric mean titers: 9vHPV compared with 4vHPV, per protocol population, females aged 9-15 years
Antibody 9vHPV 4vHPV GMT noninferiority or superiority
n % 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

Table 9 Footnotes
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

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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 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

Table 10 Footnotes
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

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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 Efficacy
020 Males aged 16-26 years 402 AIN2/35 74.9%
2798 Anogenital warts10 89.3%

Table 11 Footnotes
AIN2/3 = 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 population4 b,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 superiority
n % 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

Table 12 Footnotes
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

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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 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

Table 13 Footnotes
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

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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 population7 a

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 superiority
n %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

Table 14 Footnotes
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

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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 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

Table 15 Footnotes
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

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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 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

Table 16 Footnotes
a Data from Protocols 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

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Table 17: Harms data in females and males9 c

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Harms Females and males aged 16-26 years Females and males aged 9-15 years
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)

Table 17 Footnotes
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

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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 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

Table 18 Footnotes
a Data from Protocols 001, 002, 003, 005, 007, 009
b 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 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 9vHPV Randomized (1), Obs (2)e No vaccine-related cases 2

Table 19 Footnotes
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

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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 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)
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
1-2
Serious adverse event 9vHPV Randomized (1), Obs (3)e No cases 2
Anaphylaxis 9vHPV Randomized (1), Obs (3)e No cases 2

Table 20 Footnotes
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

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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 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 cases 2
Anaphylaxis 9vHPV Randomized (1), Obs (2)c No vaccine-related cases 2

Table 21 Footnotes
a Data from Protocols 020
b Supportive data from Protocols 001, 003
c Data from Protocols 001, 002, 003

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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 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)
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 2
Anaphylaxis Randomized (1), Obs (3)c No cases 2

Table 22 Footnotes
a Data from Protocol 020
b Supportive data from Protocols 001, 002
c Data from Protocols 002, 005, 007, 009

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Table 23: Considerations for formulating recommendations for 9vHPV

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

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References

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  3. 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.
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