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Grading of Recommendations Assessment, Development and Evaluation (GRADE) for use of HPV vaccine in adults ages 27 through 45 years																									Related Pages
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			IntroductionMethodsResultsTablesSupplemental DataSummary
		
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Introduction
Three 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).[1-3] Until October 2018, all were licensed for use in persons aged 9 through 25 or 26 years. Since late 2016, only 9vHPV has been available in the United States. In October 2018, FDA approved an expansion of the age indication through age 45 years for 9vHPV. HPV vaccination of adults in the United States was considered using Grading of Recommendations Assessment, Development and Evaluation (GRADE). The main policy question was, “Should catch-up HPV vaccination be recommended for primary prevention of HPV infection and HPV-related disease for all persons aged 27 through 45 years?”
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Methods
The population of interest was adults aged 27 through 45 years at initiation of vaccination; intervention was catch-up vaccination with a complete 3-dose series of HPV vaccine (9vHPV, 4vHPV, or 2vHPV); comparison was persons through age 45 years with no catch-up HPV vaccination; and outcome was primary prevention of HPV infection and HPV-related disease.
Scientific literature was searched from January 1, 2006 through October 18, 2018 using five databases: Medline, Embase, CINAHL, Cochrane library, and ClinicalTrials.govexternal icon. Search terms used to identify clinical trials of efficacy for primary prevention of HPV-associated health outcomes and safety of 3 doses of any licensed HPV vaccine in adults (age 27–45 years at initiation of vaccination) are listed in the appendix. These searches identified 1,388 references.
Trials were excluded if they did not report original data on the relevant population, outcome, or intervention. Benefits were based on per-protocol analyses of HPV vaccine efficacy; immunogenicity data were also considered. Harms were any vaccine-related serious adverse events including deaths.
After reviewing titles and abstracts, we selected 100 references mentioning age 27 and older for detailed review. Of these, 16 publications were selected for inclusion, and 84 were excluded, 50 because they included duplicate data, and the others because they did not address the policy question: 15 did not report data on population of interest (not age-stratified), 11 did not report data on outcome of interest (not primary prevention), and 8 did not report data on intervention of interest (no HPV vaccination).
GRADE tables reference these 16 publications; [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] ; personal communication from the vaccine manufacturer providing additional age-limited analyses for previously published studies [20]; and a June 2018 ACIP presentation on clinical data submitted to FDA supporting 9vHPV use in adults [21]. In June 2019, GRADE tables were updated to include new results from a 9vHPV immunogenicity and safety trial in women age 16 through 45 years.[22]
Supplemental data may not directly address the policy question, and is not included in the formal GRADE scoring, but may be helpful for decision making. Supplemental GRADE tables include data from the 9vHPV trial [22], an additional four studies reporting bridging immunogenicity and efficacy data from young adults; [23] [24] [25] [26] two presentations on 9vHPV safety [23] [24]; and the updated FDA label for 9vHPV.[1]
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Results
Outcomes of interest included individual benefits and harms. Benefits of interest were per-protocol analyses of HPV vaccine efficacy against persistent HPV infections; anogenital warts; HPV-related precancers including cervical or anal intraepithelial neoplasias (CIN or AIN); or HPV-related cancers including cervical, anal, penile, vaginal, vulvar, and/or oropharyngeal cancers. Immunogenicity to HPV vaccine types was also considered. Harms of interest were vaccine-related serious adverse events including deaths. (Table 1)
Included trials involved 9vHPV, 4vHPV, or 2vHPV (Table 2A), as well as supplemental immunobridging data (Table 2B). For 9vHPV, there was 1 included observational trial. For 4vHPV, there were 7 included trials: 3 randomized placebo-controlled trials, and 4 observational trials. For 2vHPV, there were 4 included trials: 2 randomized placebo-controlled trials, and 2 observational trials. Supplemental data included 4 trials providing bridging immunogenicity data, and 2 surveillance reports of post-licensure safety data for 9vHPV in the United States.
In per-protocol analyses, HPV vaccines showed significant efficacy against a combined endpoint of persistent vaccine-type HPV infections, anogenital warts, and/or cervical intraepithelial neoplasia (CIN) grade 1 or worse (Table 3A). For immunogenicity, post-vaccination seroconversion rates were high, and antibody geometric mean titers (GMTs) tended to be higher than those after natural infection. Seropositivity rates were still high at 3 to 10 years post-initial vaccination, although noticeably lower for HPV type 18 (Table 3B).
For serious adverse events, numbers were comparable among the vaccine group and the placebo group across 8 studies; there were no vaccine-related deaths (Table 3C).
GRADE was used to evaluate evidence for use of 9vHPV in adults. Initial evidence level was 1 for each outcome based on data from randomized controlled trials (Table 4). All were downgraded for indirectness since no randomized placebo-controlled trials were conducted on use of 9vHPV in this age range, and extrapolation from 4vHPV efficacy was based on immunobridging data. Outcomes for which the 95% confidence interval crossed 1 were further downgraded for imprecision. For men, evidence type for each outcome could be further downgraded for indirectness, since most trials enrolled women only.
In summary, evidence level for efficacy is 2 in women and 3 in men, and evidence level for immunogenicity is 2. Overall evidence type for benefits is level 2 (Table 5A). Overall evidence type for harms is also level 2 (Table 5B).
Supplemental immunobridging data showed non-inferior immunogenicity comparing HPV vaccination in mid-adults with HPV vaccination in young adults (Supplemental table 1), and comparing 9vHPV in young adults with 4vHPV in young adults (Supplemental table 2). Supplemental data on harms summarize U.S. postlicensure safety data for over 29 million doses of HPV vaccine (Supplemental table 3).
Abbreviations
HPV, human papillomavirus
2vHPV, bivalent HPV vaccine (Cervarix)
4vHPV, quadrivalent HPV vaccine (Gardasil)
9vHPV, 9-valent HPV vaccine (Gardasil 9)
EGL, external genital lesions
CIN, cervical intraepithelial neoplasia
AIN, anal intraepithelial neoplasia
CI, confidence interval
M, months
GMT, geometric mean titer
mMU/mL, milliMerck Units per milliliter
EU/mL, ELISA units per milliliter
ED50, effective dose producing 50% response
RCT, randomized controlled trial
Obs, observational trial
Tables
Table 1: Important and critical outcomes related to HPV vaccination
Important and critical outcomes related to HPV vaccination
Outcome
Importance
Included in evidence profileBenefits≥6-month persistent vaccine-type HPV infection
Important
YesAnogenital warts/condyloma/external genital lesions (EGL)
Important
YesCervical or anal intraepithelial neoplasia (CIN or AIN) 1+
Important
YesCervical or anal intraepithelial neoplasia (CIN or AIN) 2+
Critical
YesCombined endpoint: persistent infection, EGL, and/or CIN 1+
Important
YesHPV-related cancer (anal, cervical, oropharyngeal, penile, and/or vaginal/vulvar)
Critical
No*Immunogenicity (seropositivity and GMTs to vaccine types, early or late)
Important
YesHarmsSerious adverse events, any or vaccine-related
Important
YesDeath, any or vaccine-related
Critical
YesTable 1 Footnotes
* No HPV-related cancers were reported in per-protocol analyses from any of the studies reviewed; data on these outcomes not necessarily expected in clinical trials of current duration/size
**Top of PageTable 2A: Characteristics of included studies
Characteristics of included studies
Vaccine
Author,  year [reference]
Clinical trial
number (name)
Design
Participants
(N=total enrolled)
Follow-up time
Main outcomes
related to HPV vaccine types**9vHPV
Luxembourg,
2019 [22]
NCT03158220 (Protocol 004)
Observational trial in 6 countries
Women age 27–45 years (N=642)
7 months
Immunogenicity
Harms4vHPV
Muñoz,
2009 [4]*Castellsagué,
2011 [5]*Luxembourg,
2018 [21]
NCT00090220
(Future III)
Randomized, placebo-controlled trial in 7 countries (through M48);
observational trial in Colombia (through M120)
Women age 24–45 years (N=3819)
7 months;
48 months;
120 months
Immunogenicity
Persistent HPV infection
External genital lesions (warts)
CIN 1+, CIN 2+
Combined endpoint
HarmsWei,
2018 [6]*
NCT00834106
Randomized, placebo-controlled trial in China
Women age 20–45 years (N=3006, including 1166 women age 27–45 years)
78 months
Persistent HPV infection
External genital lesions (warts)
CIN 1+, CIN 2+
Combined endpoint
HarmsEinstein,
2009[7]Einstein,2014 [8]
NCT00423046
Observational trial in the USA
Women age 18–45 years in the USA (N=1106)
60 months
Immunogenicity
HarmsHuang,
2018 [9]
NCT01427777
Observational trial in China
Women age 9–45 years (N=468, including <250 age 27–45 years)
42 months
ImmunogenicityGiuliano,
2015 [10]
NCT01432574
(MAM)
Observational trial in the USA and Brazil
Men 27–45 years (N=150)
7 months
Immunogenicity
HarmsMoney,
2016 [11]
None
(CTN 236)
Observational trial in Canada
HIV+ women age 15–45 years (N=372, including 98 women age 24–45 years)
24 months
ImmunogenicityWilkin,
2018 [12]
NCT01461096
(ACTG A5298)
Randomized, placebo-controlled trial in the USA and Brazil
HIV+ people age ≥27 years (N=575, including 472 men and 103 women)
12 months (trial halted; no per-protocol analysis)
Harms2vHPV
Skinner,
2014 [13]Wheeler,
2016 [14]
NCT00294047
(VIVIANE)
Randomized, placebo-controlled trial in 12 countries
Women age ≥26 years (N=4407, including 3916 women age 26–45 years)
48 months;
84 months
Immunogenicity
Persistent HPV infection
CIN 1+
CIN 2+
Combined endpoint
HarmsSchwarz,
2009 [15]Schwarz,
2011 [16]Schwarz,
2015 [17]Schwarz,
2017 [18]
NCT00196937;
NCT00947115
Observational trial in Germany and Poland
Women age 15–55 years (N=667, including 226 women age 26–45 years)
1 month;
48 months;
72 months;
120 months
Immunogenicity
HarmsEinstein,
2009 [7]Einstein,
2014 [8]
NCT00423046
Observational trial in the United States
Women age 18–45 years (N=1106)
24 months;
60 months
Immunogenicity
HarmsZhu,
2014 [19]
NCT01277042 (protocol HPV-069)
Randomized, placebo-controlled trial in China
Women age 9–45 years (N=1962, including 1212 women age 26-45 years)
7 months
Immunogenicity
HarmsTable 2A Footnotes
* Age-restricted data obtained from Luxembourg, 2018 [20]
** Per-protocol results for benefits; intention-to-treat results for harmsTable 2B: Characteristics of included studies, supplemental
Characteristics of included studies, supplemental
Vaccine
Author, year [reference]
Clinical trial
number (name)
Design
Participants (N=total enrolled)
Follow-up time
Main outcomes
related to HPV vaccine types*9vHPV
Luxembourg,
2019 [22]
NCT03158220 (Protocol 004)
Observational trial in 6 countries
Women age 16–26 years (N=570)
7 months
Immunogenicity
Harms4vHPV
Hillman,
2012 [23]Giuliano,
2011 [24]Palefsky,
2011 [25]
NCT00090285
Randomized, placebo-controlled trial in 18 countries
Men age 16–26 years (N=4065)
7 months
Supplemental, immunogenicity (bridging of age groups: 4vHPV immunogenicity and clinical efficacy in young adult males)Luxembourg,
2018 [21]
NCT00092521(Future I);
NCT00092534 (Future II);
NCT00090220 (Future III)
Post hoc analysis of data from randomized, placebo-controlled trials
Women age 16–26 years
7 months
Supplemental, immunogenicity (bridging of age groups: 4vHPV immunogenicity in young adult females)9vHPV
Joura,
2015 [26]Huh,
2017 [27]
NCT00543543
Randomized, placebo-controlled trial in 18 countries
Women age 16–26 years (N=14215)
7 months;
42 months
Supplemental, immunogenicity (bridging of vaccines: 9vHPV in young adult females)Van Damme,
2016 [28]
NCT02114385
Randomized, placebo-controlled trial in Belgium, Netherlands, and Germany
Men age 16–26 years (N=500)

Supplemental, immunogenicity (bridging of vaccines: 9vHPV in young adult males)Donahue [29]
N/A
Observational data from Vaccine Safety Datalink (VSD)
U.S. enrollees age 9–26 years

Supplemental, harmsArana [30]
N/A
Observational data from Vaccine Adverse Events Reporting System (VAERS)
Reports of potential adverse events following 9vHPV (N=8529 in the USA; n=73 age 26–45)

Supplemental, harmsTable 2B Footnotes
* Per-protocol results for benefits; intention-to-treat results for harmsTable 3A: Efficacy outcomes
Characteristics of included studies, supplemental
Vaccine
Reference
Outcome
(number of months)
Vaccine group
N (%)
Placebo group
N (%)
Observed Efficacy**
(95% CI)Persistent (≥6M) HPV infection4vHPV
Castellsagué,
2011 [5]*
6M-persistent cervical HPV 6/11/16/18 (M48)
8/1358 (0.6)
71/1372 (5.2)
88.8% (76.8–95.4)Wei,
2018 [6]*12M-persistent cervical HPV 6/11/16/18 (M78)
3/521 (0.6)
29/515 (5.6)
90.0% (67.6–98.0)2vHPV
Wheeler,
2016 [14]
6M-persistent cervical HPV 6/11 (M84)
6/1815 (0.06)
67/1786 (0.7)
91.4% (79.4–97.1)Anogenital warts/condyloma4vHPV
Castellsagué,
  2011 [5]*
  Luxembourg,
    2018 [21]
Condyloma (M48)
0/1376 (0.0)
5/1384 (0.4)
100% (-9.8–100)Condyloma (M120)
  0/527 (0.0)
  -
  -Wei,
2018 [6]*
Condyloma (M48)
0/521 (0.0)
0/516 (0.0)
-Cervical Intraepithelial Neoplasia (CIN), any grade (1+)4vHPV
Castellsagué,
  2011 [5]*
  Luxembourg,
    2018 [21]
CIN 1+ (M48)
1/1358 (0.0)
16/1370 (1.2)
93.7% (59.5–99.9)CIN 1+ (M120)
  0/527 (0.0)
  -
  -Wei,
2018 [6]*CIN 1+ (M78)
0/520 (0.0)
6/515 (1.2)
100% (15.5–100)2vHPV
Wheeler,
2016 [14]CIN 1+ (M84)
2/1852 (0.02)
12/1818 (0.1)
83.7% (21.9–98.5)Cervical Intraepithelial Neoplasia [CIN] 2+4vHPV
Castellsagué,
  2011 [5]*
  Luxembourg,
    2018 [21]
CIN 2+ (M48)
1/1358 (0.0)
5/1370 (0.4)
79.8% (-80.1–99.6)CIN 2+ (M120)
  0/527 (0.0)
  -
  -Wei,
2018 [6]*
CIN 2+ (M78)
0/520 (0.0)
4/515 (0.8)
100% (-51.0–100)2vHPV
Wheeler,
2016 [14]
CIN 2+ (M84)
1/1852 (0.01)
6/1818 (0.06)
83.7% (-46.5–99.7)Combined endpoint: persistent infection, CIN 1+, and/or EGL4vHPV
Castellsagué,
  2011 [5]*
  Luxembourg,
    2018 [21]
Combined endpoint: persistent infection,
CIN 1+, and/or EGL (M48)
9/1376 (0.7)
72/1384 (5.2)
87.7% (75.4–94.6)Combined endpoint: CIN or condyloma (M72–120)
  0/527 (0.0)
  -
  -Wei,
2018 [6]*
Combined endpoint: persistent infection,
CIN 1+, and/or EGL (M78)
3/521 (0.6)
31/516 (6.0)
90.6% (69.9–98.2)2vHPV
Wheeler,
2016 [14]
Combined endpoint: persistent infection,
CIN 1+ (M84)
7/1852 (0.07)
71/1818 (0.7)
90.5% (78.6–96.5)Table 3A Footnotes
* Age-restricted data obtained from Luxembourg, 2018 [20]
** Per-protocol resultsTable 3B: Immunogenicity outcomes
Immunogenicity outcomes
Vaccine
Reference
Antibody
Months
Post-vaccination**Seropositive

n
Seropositive

%
GMTs (95% CI)Immunogenicity, early (7 months post first vaccination dose)9vHPV
Luxembourg,
2019 [22]
anti-HPV6
M7
448
100
638 (595–685) mMu/mLanti-HPV11
  M7
  447
  99.8
  454 (424–485) mMu/mLanti-HPV16
  M7
  448
  100
  2148 (2001–2305) mMu/mLanti-HPV18
  M7
  469
  99.6
  532 (492–576) mMu/mLanti-HPV31
  M7
  487
  99.8
  396 (367–427) mMu/mLanti-HPV33
  M7
  492
  99.8
  259 (243–276) mMu/mLanti-HPV45
  M7
  511
  99.2
  146 (134–158) mMu/mLanti-HPV52
  M7
  496
  100
  245 (229–261) mMu/mLanti-HPV58
  M7
  477
  99.8
  296 (277–317) mMu/mL4vHPV
Muñoz,
2009 [4]*
anti-HPV6
M7
1083
98.2
412 (386–440) mMU/mLanti-HPV11
  M7
  1083
  97.9
  538 (506–573) mMU/mLanti-HPV16
  M7
  1092
  98.6
  2212 (2076–2357) mMU/mLanti-HPV18
  M7
  1223
  97.1
  348 (326–372) mMU/mLEinstein,
2009 [7]
anti-HPV16
M7
186
100
20605 (16259–26112) ED50anti-HPV18
  M7
  212
  100
  9674 (7677–18194) ED50Huang,
2018 [9]
anti-HPV6
M7

98.1anti-HPV11
  M7
  
  100anti-HPV16
  M7
  
  100anti-HPV18
  M7
  
  99.2Giuliano,
2015 [10]
anti-HPV6
M7
145
100
365 mMU/mLanti-HPV11
  M7
  145
  100
  490 mMU/mLanti-HPV16
  M7
  145
  100
  2178 mMU/mLanti-HPV18
  M7
  145
  100
  296 mMU/mLMoney,
2016 [11]
anti-HPV6
M7
61
99.0
426 (324–561) mMU/mLanti-HPV11
  M7
  98
  98.7
  540 (436–668) mMU/mLanti-HPV16
  M7
  66
  98.1
  1495 (1046–2137) mMU/mLanti-HPV18
  M7
  94
  93.6
  295 (223–391) mMU/mL2vHPV
Skinner,
2014 [13]
anti-HPV16
M7
406
100
5413 (4934–5938) EU/mLanti-HPV18
  M7
  405
  100
  2568 (2340–2818) EU/mLSchwarz,
2009; [15]
anti-HPV16
M7
164
100
4060 (3511–4695) EU/mLanti-HPV18
  M7
  185
  100
  1881 (1661–2130) EU/mLEinstein,
2009 [7]
anti-HPV16
M7
168
100
6296 (4906–8082) ED50anti-HPV18
  M7
  190/192
  99.0
  1241 (947–1626) ED50Zhu,
2014 [19]
anti-HPV16
M7
596
100
6440 (6040–6866) EU/mLanti-HPV18
  M7
  363/365
  99.5
  3563 (3310–3836) EU/mLImmunogenicity, later (up to 120 months post first vaccination dose)4vHPV
Castellsagué,
2011 [5]*
anti-HPV6
M48
1007
85.3
61 (57–65) mMU/mLanti-HPV11
  M48
  1007
  91.8
  64 (61–69) mMU/mLanti-HPV16
  M48
  1022
  97.3
  200 (186–214) mMU/mLanti-HPV18
  M48
  1132
  47.5
  23 (21–25) mMU/mLEinstein,
2014 [8]
anti-HPV16
M60
73/76
96.1
555 (341–904) ED50anti-HPV18
  M60
  60/87
  69.0
  89 (59–136) ED50Huang,
2018 [9]
anti-HPV6
M42

91.2anti-HPV11
  M42
  
  88.3anti-HPV16
  M42
  
  96.8anti-HPV18
  M42
  
  37.6Money,
2016 [11]anti-HPV6
M24
53

129 (93–179) mMU/mLanti-HPV11
  M24
  78
  
  125 (125–160) mMU/mLanti-HPV16
  M24
  54
  
  459 (341–618) mMU/mLanti-HPV18
  M24
  72
  
  54 (39–74) mMU/mL2vHPV
Skinner,
2014 [13]anti-HPV16
M48
345/345
100
546 (490–608) EU/mLanti-HPV18
  M48
  336/338
  99.4
  228 (202–259 EU/mL)Schwarz,
2017 [18]
anti-HPV16
M120
120/121
99.2
334 (270-414) EU/mLanti-HPV18
  M120
  133/142
  93.7
  115 (94-142) EU/mLEinstein,
2014 [8]
anti-HPV16
M60
89
100
1855 (1267–2715) ED50anti-HPV18
  M60
  109
  100
  892 (759–1268) ED50Table 3B Footnotes
* Age-restricted data obtained from Luxembourg, 2018 [20]
** Per-protocol resultsTable 3C: Harms
Harms
Vaccine
Reference
Outcome**
Months
Vaccine group
n/N (%)
Placebo group
n/N (%)Serious adverse events, any9vHPV
Luxembourg,
2019 [22]
Serious adverse events
M7
8/640 (0.1)
6/570 (0.1)4vHPV
Castellsagué,
2011 [5]*
Serious adverse events
M48
14/1908 (0.7)
16/1902 (0.8)Wei,
2018[6]*
Serious adverse events
M78
20/580 (3.4)
23/586 (3.9)Einstein,
2014 [8]
Serious adverse events
M60
44/553 (8.0)
No placebo group2vHPV
Einstein,
2014 [8]
Serious adverse events
M60
37/553 (6.7)
No placebo groupWheeler,
2016 [14]
Serious adverse events
M48
286/2877 (9.9)
266/2870 (9.3)Schwarz,
2017 [18]
Serious adverse events
M48
8/226 (3.5)
No placebo groupVaccine-related serious adverse events9vHPV
Luxembourg,
2019 [22]
Vaccine-related serious adverse events
M7
0/640 (0.0)
0/570 (0.0)4vHPV
Castellsagué,
2011 [5]*
Vaccine-related serious adverse events
M48
0/1908 (0.0)
0/1902 (0.0)Wei,
2018 [6]*
Vaccine-related serious adverse events
M78
0/580 (0.0)
1/586 (0.2)Giuliano,
2015 [10]
Vaccine-related serious adverse events (grade 3+)
M7
1/150 (0.7)
No placebo group2vHPV
Wheeler,
2016 [14]
Vaccine-related serious adverse events
M84
5/2877 (0.2)
8/2870 (0.3)Schwarz,
2017 [18]
Vaccine-related serious adverse events
M48
1/226 (0.4)
Cervical dysplasia (resolved)
No placebo groupZhu,
2014 [19]
Vaccine-related serious adverse events
M12
0/606 (0.0)
0/606 (0.0)Deaths, any9vHPV
Luxembourg,
2019 [22]
Death
M7
0/640 (0.0)
0/570 (0.0)4vHPV
Castellsagué,
2011 [5]*
Death
M48
7/1908 (0.4)
Acute liver disease secondary to nasopharyngeal cancer; Breast cancer; Cardiac arrest secondary to breast cancer metastasis; Cardiac arrest secondary to cerebrovascular accident; Pulmonary embolism; Pericarditis; Tuberculosis
1/1902 (0.1)
Pulmonary embolismWei,
2018 [6]*
Death
M78
2/580 (0.3)
Ovarian cancer; Road traffic crash
0/586 (0.0)Einstein,
2014 [8]
Death
M60
1/553 (0.2)
Metastatic renal cell carcinoma
No placebo groupGiuliano,
2015 [10]
Death
M7
0/150 (0.0)
No placebo groupWilkin,
2018 [12]
Death
M12
3/276 (1.1)
6/277 (2.2)2vHPV
Wheeler,
2016 [14]
Death
M84
13/2877 (0.5)
Acute myocardial infarction; Acute renal failure; Breast cancer; Cervix cancer; Glioblastoma multiforme; Homicide; Interstitial lung disease; Lung cancer; Pneumonia; Pulmonary embolism; Suicide (x3)
5/2870 (0.2)
Anaplastic astrocytoma; Cardiac valve disease and liver disorder; Cardiorespiratory arrest; Lower respiratory tract infection and sepsis; Nasopharyngeal cancerSchwarz,
2017 [18]
Death
M48
2/226 (0.9)
Chronic lymphocytic leukemia; Lung cancer
No placebo groupVaccine-related deaths9vHPV
Luxembourg,
2019 [22]
Death, vaccine-related
M7
0/640 (0.0)
0/570 (0.0)4vHPV
Castellsagué,
2011 [5]*
Death, vaccine-related
M48
0/1908 (0.0)
0/1902 (0.0)Wei,
2018 [6]*
Death, vaccine-related
M78
0/580 (0.0)
0/586 (0.0)Einstein,
2014 [8]
Death, vaccine-related
M60
0/553 (0.0)
No placebo groupGiuliano,
2015 [10]
Death, vaccine-related
M7
0/150 (0.0)
No placebo groupWilkin,
2018 [12]
Death, vaccine-related
M12
0/276 (0.0)
0/277 (0.0)2vHPV
Wheeler,
2016 [14]
Death, vaccine-related
M84
0/2877 (0.0)
0/2870 (0.0)Schwarz,
2017 [18]
Death, vaccine-related
M48
0/226 (0.0)
No placebo groupZhu,
2014 [19
Death, vaccine-related
M12
0/606 (0.0)
0/606 (0.0)Table 3C Footnotes
* Age-restricted data obtained from Luxembourg, 2018 [20]
** Intention-to-treat resultsTable 4: Evidence for use of 9vHPV in adults ages 27 through 45 years
Evidence for use of 9vHPV in mid-adult age group
Outcome
Finding
Design (number of studies)
Initial evidence level*
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations**
Evidence type*9vHPV BenefitsPersistent HPV infection
Prevents
≥6M-persistent
HPV infection
RCTs (3)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**Anogenital warts
Prevents anogenital warts
RCTs (2)
+ supplemental
1
Not serious
Not serious
Serious1
Serious2
None
**3**CIN 1+
Prevents CIN 1+
RCTs (3)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**CIN 2+
Prevents CIN 2+
RCTs (3)
+ supplemental
1
Not serious
Not serious
Serious1
Serious2
None
**3**Combined endpoint
Prevents the above HPV-related outcomes
RCTs (3)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**Immunogenicity
Immunogenic
RCTs (3), Obs (6)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**9vHPV HarmsSerious Adverse Events
Similar numbers of  serious adverse events with 9vHPV vs placebo
RCTs (3), Obs (3)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**Vaccine-related Serious Adverse Events
Few vaccine-related serious adverse events
RCTs (4), Obs (3)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**Death
Similar numbers of deaths with 9vHPV vs placebo
RCTs (4), Obs (4)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**Vaccine-related Death
No vaccine-related deaths
RCTs (5), Obs (4)
+ supplemental
1
Not serious
Not serious
Serious1
Not serious
None
**2**
Table 4 Footnotes
RCT, randomized controlled trial; Obs, observational study
* Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very Low
** Strength of association, dose-response, plausible residual confounding, publication bias
1 Downgraded for indirectness since no randomized placebo-controlled trials were conducted on use of 9vHPV in adults aged 27 through 45 years, and there are no 4vHPV efficacy trials in males aged 27 through 45 years; extrapolation of efficacy from 4vHPV across age and genders is based on supplemental bridging immunogenicity data
2 Downgraded for imprecision since 95% confidence interval for efficacy includes 1Table 5A: Summary of evidence for benefits
Summary of evidence for benefits, 9vHPV use in adults age >26 years
Comparison
Outcome
Design (number of studies)
Findings
Evidence type
Overall evidence type*HPV vaccination
(adults age 27–45 years) versus no HPV vaccination
Efficacy
RCTs (3)
9vHPV is more efficacious against HPV-related outcomes than no vaccination
2
2Immunogenicity
RCTs (3), Obs (6)
9vHPV is immunogenic
2Table 5A Footnotes
* Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very Low
Table 5B: Summary of evidence for harms
Summary of evidence for harms, 9vHPV use in adults age >26 years
Comparison
Outcome
Design (number of studies)
Findings
Evidence type
Overall evidence type*HPV vaccination
(adults age 27–45 years) versus no HPV vaccination
Harms, any
RCTs (4), Obs (4)
Similar adverse events among participants  receiving placebo versus 9vHPV
2
**2**Vaccine-related harms
RCTs (5), Obs (4)
Few vaccine-related serious adverse events, and no vaccine-related deaths
2Table 5B Footnotes
* Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very LowSupplemental Data
Supplemental Table 1: Immunobridging comparing HPV vaccination in mid-adults with HPV vaccination in young adults
Immunobridging comparing HPV vaccination in mid-adults with HPV vaccination in young adults
Group
Reference; population
Antibody
Months
Mid-adult vaccination (27–45 years)
Young adult vaccination (16–26 years)
ComparisonSero-positive

n/N
Sero-positive

%
GMTs (95% CI)

mMU/mL
Sero-positive

n/N
Sero-positive

%
GMTs (95% CI)

mMU/mL
GMT ratio
(95% CI)9vHPV
Luxembourg,
2019 [22];age 16–26 and 27–45 years
anti-HPV6
M7
448/448
100
638 (595–685)
420/421
99.8
788 (733–847)
Not doneanti-HPV11
  M7
  447/448
  99.8
  454 (424—485)
  421/421
  100
  599 (559–642)
  Not doneanti-HPV16
  M7
  448/448
  100
  2148 (2001–2305)
  436/436
  100
  3076 (2863–3304)
  0.7 (0.6–0.8)anti-HPV18
  M7
  469/471
  99.6
  532 (492–576)
  421/421
  100
  745 (685–809)
  0.7 (0.6–0.8)anti-HPV31
  M7
  487/488
  99.8
  396 (367–427)
  447/447
  100
  596 (551–645)
  0.7 (0.6–0.7)anti-HPV33
  M7
  492/493
  99.8
  259 (243–276)
  457/457
  100
  355 (332–379)
  0.7 (0.7–0.8)anti-HPV45
  M7
  511/515
  99.2
  146 (134–158)
  468/470
  99.6
  215 (198–234)
  0.7 (0.6–0.8)anti-HPV52
  M7
  496/496
  100
  245 (229–261)
)
  456/456
  100
  347 (324–371)
  0.7 (0.6–0.8)anti-HPV58
  M7
  477/478
  99.8
  296 (277–317
  451/451
  100
  428 (399–459)
  0.7 (0.6–0.8)4vHPV, females
Muñoz,
2009 [4];age 27–45 years
anti-HPV6
M7
1083/
98.2
412anti-HPV11
  M7
  1083/
  97.9
  538anti-HPV16
  M7
  1092/
  98.6
  2212anti-HPV18
  M7
  1223/
  97.1
  348Luxembourg,
2018 [21];
age 16–26 years
anti-HPV6
M7



2800

536.2
0.8 (0.7–0.8)anti-HPV11
  M7
  
  
  
  2824
  
  754.3
  0.7 (0.7–0.8)anti-HPV16
  M7
  
  
  
  2749
  
  2297.6
  1.0 (0.9–1.1)anti-HPV18
  M7
  
  
  
  3006
  
  458.1
  0.8 (0.7–0.8)4vHPV, males
Giuliano,
2015 [10];
age 27–45 years
anti-HPV6
M7
145/145
100
419 (363–484)anti-HPV11
  M7
  145/145
  100
  517 (455–587)anti-HPV16
  M7
  145/145
  100
  2229 (2004–2448)anti-HPV18
  M7
  145/145
  100
  300 (259–347)Hillman,
2012 [23];
age 16–26 years
anti-HPV6
M7



1080/1092
98.9
448 (423–474)anti-HPV11
  M7
  
  
  
  1083/1092
  99.2
  624 (594–655)anti-HPV16
  M7
  
  
  
  1121/1135
  98.8
  2404 (2272–2544)anti-HPV18
  M7
  
  
  
  1143/1174
  97.4
  402 (380–426)Luxembourg,
2018 [21];
age 27–45 years
anti-HPV6
M7






0.8 (0.6–1.0)anti-HPV11
  M7
  
  
  
  
  
  
  0.8 (0.7–0.9)anti-HPV16
  M7
  
  
  
  
  
  
  0.9 (0.7–1.1)anti-HPV18
  M7
  
  
  
  
  
  
  0.7 (0.6–0.9)Supplemental Table 2: Immunobridging comparing 9vHPV in young adults with 4vHPV in young adults
Immunobridging comparing 9vHPV in young adults with 4vHPV in young adults
Vaccine
Reference; population
Antibody
Months
Vaccination with 9vHPV
Vaccination with 4vHPV
ComparisonSero-positive

n/N
Sero-positive

%
GMTs (95% CI)

mMU/mL
Sero-positive

n/N
Sero-positive

%
GMTs (95% CI)

mMU/mL
GMT ratio
(95% CI)9vHPV
Joura [26]; females age 16–26 years
anti-HPV6
M7
3985/3993
99.8
893
3969/3975
99.8
875
1.0 (0.9–1.1)anti-HPV11
  
  3994/3995
  100
  666
  3980/3982
  99.9
  830
  0.8 (0.8–0.8)anti-HPV16
  
  4031/4032
  100
  3131
  4060/4062
  100
  3157
  1.0 (1.0–1.0)anti-HPV18
  
  4532/4539
  99.8
  805
  4528/4541
  99.7
  679
  1.2 (1.1–1.2)Huh [27]; females age 16–26 years
anti-HPV6
M42
692
95.5
147 (137-158)
675
94.5
144 (134–155)
1.0 (0.9–1.1)anti-HPV11
  
  696
  95.4
  85 (79-91)
  677
  96.8
  104 (97–112)
  0.8 (0.7–0.9)anti-HPV16
  
  709
  98.4
  347 (319-377)
  690
  98.6
  363 (334–395)
  1.0 (0.8–1.1)anti-HPV18
  
  806
  81.6
  71 (65-77)
  770
  77.0
  60 (55–66)
  1.2 (1.0–1.3)anti-HPV31
  
  783
  93.6
  70 (65-76)
  730
  13.0
  <4
  -anti-HPV33
  
  835
  94.6
  44 (42-47)
  789
  7.6
  <4
  -anti-HPV45
  
  846
  78.8
  21 (20-23)
  802
  1.2
  <3
  -anti-HPV52
  
  791
  95.2
  43 (41-46)
  735
  5.6
  <3
  -anti-HPV58
  
  784
  94.4
  52 (49-56)
  756
  5.6
  <4
  -Van Damme [28]; males age 16–26 years
anti-HPV6
M7
224/228
98.2
758 (666–863)
223/226
98.7
618 (554–690)
1.2 (1.0–1.5)anti-HPV11
  
  228/228
  100
  682 (609–763)
  226/226
  100
  769 (683–865)
  0.9 (0.8–1.0)anti-HPV16
  
  234/234
  100
  3924 (3514–4382)
  237/237
  100
  3788 (3378–4247)
  1.0 (0.9–1.2)anti-HPV18
  
  233/234
  99.6
  884 (766–1020)
  235/236
  99.6
  791 (683–916)
  1.1 (0.9–1.4)anti-HPV31
  
  234/234
  100
  794 (694–909)
  146/237
  61.6
  15 (12–18)
  -anti-HPV33
  
  236/236
  100
  460 (411–516)
  40/236
  16.9
  3 (3–4)
  -anti-HPV45
  
  232/232
  100
  263 (226–306)
  22/236
  9.3
  2 (2–3)
  -anti-HPV52
  
  235/235
  100
  431 (378–491)
  6/236
  2.5
  2 (2–2)
  -anti-HPV58
  
  232/232
  100
  691 (615–777)
  84/233
  36.1
  6 (5–7)
  -Supplemental Table 3: 9vHPV post-licensure safety data
9vHPV post-licensure safety data
Vaccine
Reference
Outcome
Months
Vaccine group
n/N (%)
Placebo group
n/N (%)9vHPV
Donahue,
2018 [23],
Vaccine Safety Datalink
Pre-specified adverse events
Any
Signal detected: Syncope, injection site reactions
Signal not confirmed: Allergic reactions, appendicitis (no increased risk in further analysis)
No signal detected: Anaphylaxis, Guillain-Barré syndrome, pancreatitis, seizures, stroke, venous thromboembolism, chronic inflammatory demyelinating polyneuropathy
–Arana,
2018 [24],*
Vaccine Adverse Event Reporting System
Serious adverse events
Deaths
Any
Any
3/73 (4.1)
0/73 (0.0)
–
–Summary
After reviewing the available data including the GRADE analysis, in June 2019, ACIP recommended catch-up HPV vaccination for all adults through age 26 years. ACIP did not recommend catch-up vaccination of adults aged 27–45 years, but recognized that some adults who are not previously vaccinated may be at risk for new HPV infection and might benefit from vaccination in this age range; therefore, ACIP recommended shared clinical decision making regarding potential HPV vaccination for these individuals. See 2019 policy note Updated Recommendations of the Advisory Committee on Immunization Practices for Human Papillomavirus Vaccination of Adults.Appendix: Search Methods
Database, Strategy, run date, records
Database
Strategy
Run Date
RecordsMedline
(OVID)
1946-
*Papillomavirus Vaccines/ OR Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 / OR (human papillomavirus ADJ2 vaccin*) OR (human papillomavirus ADJ2 immunization*) OR (human papillomavirus ADJ2 immunisation*) OR (human papilloma virus ADJ2 vaccin*) OR (human papilloma virus ADJ2 immunization*) OR (human papilloma virus ADJ2 immunisation*) OR (HPV ADJ2 vaccin*) OR (HPV ADJ2 immunization*) OR (HPV ADJ2 immunisation*) OR Gardasil OR Cervarix OR silgard
AND
Adult/ OR (older ADJ2 26) OR 27 years OR >26 OR =>27 OR age 27 OR aged 27 OR ages 27* OR mid-adult OR older women OR older men
AND
((randomized controlled trial.pt. or controlled clinical trial.pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not (exp animals/ not humans.sh.))
Limit 2006- ;
8/6/2018
798Embase
(OVID)
1947-
*Wart virus vaccine/ OR (human papillomavirus ADJ2 vaccin*) OR (human papillomavirus ADJ2 immunization*) OR (human papillomavirus ADJ2 immunisation*) OR (human papilloma virus ADJ2 vaccin*) OR (human papilloma virus ADJ2 immunization*) OR (human papilloma virus ADJ2 immunisation*) OR (HPV ADJ2 vaccin*) OR (HPV ADJ2 immunization*) OR (HPV ADJ2 immunisation*) OR Gardasil OR Cervarix OR silgard
AND
Adult/ OR (older ADJ2 26) OR 27 years OR >26 OR =>27 OR age 27 OR aged 27 OR ages 27* OR mid-adult OR older women OR older men
AND
crossover procedure.sh. OR double-blind procedure.sh. OR randomized controlled trial.sh. OR single-blind procedure.sh. OR (random* OR  factorial* OR crossover* OR (cross ADJ1 over*) OR placebo* OR (doubl* ADJ1 blind*) OR (singl* ADJ1 blind*) OR assign* OR allocat* OR volunteer*).sh,ab,ti.
Limit 2006- ; not pubmed/medline ;
8/6/2018
611
-285
duplicates
=327
unique itemsCINAHL
(Ebsco)
(MM “Papillomavirus Vaccine”) OR (“human papillomavirus” N2 vaccin*) OR (“human papillomavirus” N2 immunization*) OR (“human papillomavirus” N2 immunisation*) OR (“human papilloma virus” N2 vaccin*) OR (“human papilloma virus” N2 immunization*) OR (“human papilloma virus” N2 immunisation*) OR (HPV N2 vaccin*) OR (HPV N2 immunization*) OR (HPV N2 immunisation*) OR Gardasil OR Cervarix OR silgard
AND
(MH “Adult”) OR (older N2 26) OR 27 years OR >26 OR =>27 OR “age 27” OR “aged 27” OR “ages 27*” OR mid-adult OR “older women” OR “older men”
AND
(TX allocat* random*) OR (MH “Quantitative Studies”) OR (MH “Placebos”) OR (TX placebo*) OR (TX random* allocat*) OR (MH “Random Assignment”) OR (TX randomi* control* trial*) OR (TX ( (singl* N1 blind*) OR (singl* N1 mask*) )) OR (TX ( (doubl* N1 blind*) OR (doubl* N1 mask*) )) OR (TX ( (tripl* N1 blind*) OR (tripl* N1 mask*) )) OR (TX ( (trebl* N1 blind*) OR (trebl* N1 mask*) )) OR (TX clinic* N1 trial*) OR (PT “Clinical trial”) OR (MH “Clinical Trials+”)
Limit 2006- ; exclude Medline records ;
8/6/2018
71
-11
duplicates
=60
unique itemsCochrane Library
[mh “Papillomavirus Vaccine”] OR ((“human papillomavirus” NEAR/2 vaccin*) OR (“human papillomavirus” NEAR/2 immunization*) OR (“human papillomavirus” NEAR/2 immunisation*) OR (“human papilloma virus” NEAR/2 vaccin*) OR (“human papilloma virus” NEAR/2 immunization*) OR (“human papilloma virus” NEAR/2 immunisation*) OR (HPV NEAR/2 vaccin*) OR (HPV NEAR/2 immunization*) OR (HPV NEAR/2 immunisation*) OR Gardasil OR Cervarix OR silgard):ti,ab
AND
[mh “Adult”] OR ((older NEAR/2 26) OR 27 years OR >26 OR =>27 OR “age 27” OR “aged 27” OR “ages 27*” OR mid-adult OR “older women” OR “older men”):ti,ab
Limit to database *Central Register of Controlled Trials*
8/6/2018
148
-110
duplicates
=38
unique itemsClinicaltrials.gov
Interventional Studies | “human papillomavirus vaccine” OR “human papilloma virus vaccine” OR “HPV vaccine” OR Gardasil OR Cervarix OR silgard | Adult
8/6/2018
128References
Food and Drug Administration. Prescribing information [Package insert]external icon. Gardasil 9 [Human Papillomavirus 9-valent Vaccine, Recombinant], Merck & Co., Inc.
Food and Drug Administration. Prescribing information [Package insert]external icon. Gardasil [Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant], Merck & Co., Inc.
Food and Drug Administration. Prescribing information [Package insert]external icon. Cervarix [human papillomavirus bivalent (types 16, 18) vaccine, recombinant], GlaxoSmithKline.
Muñoz N, Manalastas R, Jr., Pitisuttithum P, Tresukosol D, Monsonego J, Ault K, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. *Lancet*. 2009;373:1949-57.
Castellsagué X, Muñoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K, et al. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age. *British journal of cancer*. 2011;105:28-37.
Wei L, Xie X, Liu J, Zhao Y, Chen W, Zhao C, et al. Efficacy of quadrivalent human papillomavirus vaccine against persistent infection and genital disease in Chinese women: A randomized, placebo-controlled trial with 78-month follow-up. *Vaccine*. 2018.
Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. *Human Vaccines*. 2009;5:705-19.
Einstein MH, Takacs P, Chatterjee A, Sperling RS, Chakhtoura N, Blatter MM, et al. Comparison of long-term immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: end-of-study analysis of a Phase III randomized trial. *Human vaccines & Immunotherapeutics*. 2014;10:3435-45.
Huang T, Liu Y, Li Y, Liao Y, Shou Q, Zheng M, et al. Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: Up to 3.5years of follow-up. *Vaccine*. 2018;36:1368-74.
Giuliano AR, Isaacs-Soriano K, Torres BN, Abrahamsen M, Ingles DJ, Sirak BA, et al. Immunogenicity and safety of Gardasil among mid-adult aged men (27-45 years)–The MAM Study. *Vaccine*. 2015;33:5640-6.
Money DM, Moses E, Blitz S, Vandriel SM, Lipsky N, Walmsley SL, et al. HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine. *Vaccine*. 2016;34:4799-806.
Wilkin TJ, Chen H, Cespedes MS, Leon-Cruz JT, Godfrey C, Chiao EY, et al. A randomized, placebo-controlled trial of the quadrivalent HPV vaccine in HIV-infected adults age 27 years or older: AIDS Clinical Trials Group protocol A5298. *Clinical Infectious Diseases*. 2018;05:05.
Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmeron J, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. *Lancet*. 2014;384:2213-27.
Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM, Chatterjee A, Lazcano-Ponce E, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. *Lancet Infect Dis*. 2016;16:1154-68.
Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Schulze K, et al. Persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in women aged 15-55 years. *Human Vaccines*. 2011;7:958-65.
Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Perona P, et al. Immunogenicity and tolerability of an HPV-16/18 AS04-adjuvanted prophylactic cervical cancer vaccine in women aged 15-55 years. *Vaccine*. 2009;27:581-7.
Schwarz T, Spaczynski M, Kaufmann A, Wysocki J, Galaj A, Schulze K, et al. Persistence of immune responses to the HPV-16/18 AS04-adjuvanted vaccine in women aged 15-55 years and first-time modelling of antibody responses in mature women: results from an open-label 6-year follow-up study. *BJOG: An International Journal of Obstetrics & Gynaecology*. 2015;122:107-18.
Schwarz TF, Galaj A, Spaczynski M, Wysocki J, Kaufmann AM, Poncelet S, et al. Ten-year immune persistence and safety of the HPV-16/18 AS04-adjuvanted vaccine in females vaccinated at 15-55 years of age. *Cancer Medicine*. 2017;6:2723-31.
Zhu F, Li J, Hu Y, Zhang X, Yang X, Zhao H, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years. *Human vaccines & Immunotherapeutics*. 2014;10:1795-806.
Luxembourg A, Merck & Co., Inc. Personal communication. September 17-October 18, 2018.
Luxembourg A. 9vHPV Vaccine for Mid-Adult Persons (27-45 yo) Results from Clinical Studies.  Advisory Committee on Immunization Practices (ACIP). Atlanta, GA.June 20, 2018.
Luxembourg A. 9vHPV immunogenicity and safety trial in mid-adult females.  Advisory Committee on Immunization Practices (ACIP). Atlanta, GA.June 26, 2019.
Hillman RJ, Giuliano AR, Palefsky JM, Goldstone S, Moreira ED, Jr., Vardas E, et al. Immunogenicity of the quadrivalent human papillomavirus (type 6/11/16/18) vaccine in males 16 to 26 years old. *Clin Vaccine Immunol*. 2012;19:261-7.
Giuliano AR, Palefsky JM, Goldstone S, Moreira ED, Jr., Penny ME, Aranda C, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. *N Engl J Med*. 2011;364:401-11.
Palefsky JM, Giuliano AR, Goldstone S, Moreira ED, Jr., Aranda C, Jessen H, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. *N Engl J Med*. 2011;365:1576-85.
Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. *N Engl J Med*. 2015;372:711-23.
Huh WK, Joura EA, Giuliano AR, Iversen OE, de Andrade RP, Ault KA, et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial. *Lancet*. 2017;390:2143-59.
Van Damme P, Meijer C, Kieninger D, Schuyleman A, Thomas S, Luxembourg A, et al. A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men. *Vaccine*. 2016;34:4205-12.
Donahue J. Rapid Cycle Analysis of the 9-valent Human Papillomavirus Vaccine (9vHPV) in the Vaccine Safety Datalink.  Advisory Committee on Immunization Practices (ACIP). Atlanta, GA.February 21, 2018.
Arana J. Adverse events following 9-valent human papillomavirus vaccine (9vHPV) reported to the Vaccine Adverse Event Reporting System (VAERS).  Advisory Committee on Immunization Practices (ACIP). Atlanta, GA.February 21, 2018.Top of Page
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