Grading of Recommendations Assessment, Development and Evaluation (GRADE) for use of HPV vaccine in adults ages 27 through 45 years

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

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).123 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?"

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.gov. 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 publications45678910111213141516171819; personal communication from the vaccine manufacturer providing additional age-limited analyses for previously published studies20; and a June 2018 ACIP presentation on clinical data submitted to FDA supporting 9vHPV use in adults21. 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 trial22, an additional four studies reporting bridging immunogenicity and efficacy data from young adults23242526; two presentations on 9vHPV safety2324; and the updated FDA label for 9vHPV.1

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

Outcome Importance Included in evidence profile
Benefits
≥6-month persistent vaccine-type HPV infection Important Yes
Anogenital warts/condyloma/external genital lesions (EGL) Important Yes
Cervical or anal intraepithelial neoplasia (CIN or AIN) 1+ Important Yes
Cervical or anal intraepithelial neoplasia (CIN or AIN) 2+ Critical Yes
Combined endpoint: persistent infection, EGL, and/or CIN 1+ Important Yes
HPV-related cancer (anal, cervical, oropharyngeal, penile, and/or vaginal/vulvar) Critical No*
Immunogenicity (seropositivity and GMTs to vaccine types, early or late) Important Yes
Harms
Serious adverse events, any or vaccine-related Important Yes
Death, any or vaccine-related Critical Yes

Table 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

Table 2A: Characteristics of included studies

References in this table:456789101112131415161718192122

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
  • Harms
4vHPV 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
  • Harms
Wei,
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
  • Harms
Einstein,
2009[7]Einstein,
2014 [8]
NCT00423046 Observational trial in the USA Women age 18–45 years in the USA (N=1106) 60 months
  • Immunogenicity
  • Harms
Huang,
2018 [9]
NCT01427777 Observational trial in China Women age 9–45 years (N=468, including <250 age 27–45 years) 42 months
  • Immunogenicity
Giuliano,
2015 [10]
NCT01432574
(MAM)
Observational trial in the USA and Brazil Men 27–45 years (N=150) 7 months
  • Immunogenicity
  • Harms
Money,
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
  • Immunogenicity
Wilkin,
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)
  • Harms
2vHPV 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
  • Harms
Schwarz,
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
  • Harms
Einstein,
2009 [7]Einstein,
2014 [8]
NCT00423046 Observational trial in the United States Women age 18–45 years (N=1106) 24 months;
60 months
  • Immunogenicity
  • Harms
Zhu,
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
  • Harms

Table 2A Footnotes

* Age-restricted data obtained from Luxembourg, 201820

** Per-protocol results for benefits; intention-to-treat results for harms

Table 2B: Characteristics of included studies, supplemental

References in this table:21222324252627282930

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
  • Harms
4vHPV 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, harms
Arana [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, harms

Table 2B Footnotes

* Per-protocol results for benefits; intention-to-treat results for harms

Table 3A: Efficacy outcomes

References in this table:561421

Vaccine Reference Outcome
(number of months)
Vaccine group
N (%)
Placebo group
N (%)
Observed Efficacy**
(95% CI)
Persistent (≥6M) HPV infection
4vHPV 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/condyloma
4vHPV 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 EGL
4vHPV 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, 201820

** Per-protocol results

Table 3B: Immunogenicity outcomes

References in this table:4578910111315181922

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/mL
anti-HPV11 M7 447 99.8 454 (424–485) mMu/mL
anti-HPV16 M7 448 100 2148 (2001–2305) mMu/mL
anti-HPV18 M7 469 99.6 532 (492–576) mMu/mL
anti-HPV31 M7 487 99.8 396 (367–427) mMu/mL
anti-HPV33 M7 492 99.8 259 (243–276) mMu/mL
anti-HPV45 M7 511 99.2 146 (134–158) mMu/mL
anti-HPV52 M7 496 100 245 (229–261) mMu/mL
anti-HPV58 M7 477 99.8 296 (277–317) mMu/mL
4vHPV Muñoz,
2009 [4]*
anti-HPV6 M7 1083 98.2 412 (386–440) mMU/mL
anti-HPV11 M7 1083 97.9 538 (506–573) mMU/mL
anti-HPV16 M7 1092 98.6 2212 (2076–2357) mMU/mL
anti-HPV18 M7 1223 97.1 348 (326–372) mMU/mL
Einstein,
2009 [7]
anti-HPV16 M7 186 100 20605 (16259–26112) ED50
anti-HPV18 M7 212 100 9674 (7677–18194) ED50
Huang,
2018 [9]
anti-HPV6 M7 98.1
anti-HPV11 M7 100
anti-HPV16 M7 100
anti-HPV18 M7 99.2
Giuliano,
2015 [10]
anti-HPV6 M7 145 100 365 mMU/mL
anti-HPV11 M7 145 100 490 mMU/mL
anti-HPV16 M7 145 100 2178 mMU/mL
anti-HPV18 M7 145 100 296 mMU/mL
Money,
2016 [11]
anti-HPV6 M7 61 99.0 426 (324–561) mMU/mL
anti-HPV11 M7 98 98.7 540 (436–668) mMU/mL
anti-HPV16 M7 66 98.1 1495 (1046–2137) mMU/mL
anti-HPV18 M7 94 93.6 295 (223–391) mMU/mL
2vHPV Skinner,
2014 [13]
anti-HPV16 M7 406 100 5413 (4934–5938) EU/mL
anti-HPV18 M7 405 100 2568 (2340–2818) EU/mL
Schwarz,
2009; [15]
anti-HPV16 M7 164 100 4060 (3511–4695) EU/mL
anti-HPV18 M7 185 100 1881 (1661–2130) EU/mL
Einstein,
2009 [7]
anti-HPV16 M7 168 100 6296 (4906–8082) ED50
anti-HPV18 M7 190/192 99.0 1241 (947–1626) ED50
Zhu,
2014 [19]
anti-HPV16 M7 596 100 6440 (6040–6866) EU/mL
anti-HPV18 M7 363/365 99.5 3563 (3310–3836) EU/mL
Immunogenicity, later (up to 120 months post first vaccination dose)
4vHPV Castellsagué,
2011 [5]*
anti-HPV6 M48 1007 85.3 61 (57–65) mMU/mL
anti-HPV11 M48 1007 91.8 64 (61–69) mMU/mL
anti-HPV16 M48 1022 97.3 200 (186–214) mMU/mL
anti-HPV18 M48 1132 47.5 23 (21–25) mMU/mL
Einstein,
2014 [8]
anti-HPV16 M60 73/76 96.1 555 (341–904) ED50
anti-HPV18 M60 60/87 69.0 89 (59–136) ED50
Huang,
2018 [9]
anti-HPV6 M42 91.2
anti-HPV11 M42 88.3
anti-HPV16 M42 96.8
anti-HPV18 M42 37.6
Money,
2016 [11]
anti-HPV6 M24 53 129 (93–179) mMU/mL
anti-HPV11 M24 78 125 (125–160) mMU/mL
anti-HPV16 M24 54 459 (341–618) mMU/mL
anti-HPV18 M24 72 54 (39–74) mMU/mL
2vHPV Skinner,
2014 [13]
anti-HPV16 M48 345/345 100 546 (490–608) EU/mL
anti-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/mL
anti-HPV18 M120 133/142 93.7 115 (94-142) EU/mL
Einstein,
2014 [8]
anti-HPV16 M60 89 100 1855 (1267–2715) ED50
anti-HPV18 M60 109 100 892 (759–1268) ED50

Table 3B Footnotes

* Age-restricted data obtained from Luxembourg, 201820

** Per-protocol results

Table 3C: Harms

References in this table:568101214181922

Vaccine Reference Outcome** Months Vaccine group
n/N (%)
Placebo group
n/N (%)
Serious adverse events, any
9vHPV 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 group
2vHPV Einstein,
2014 [8]
Serious adverse events M60 37/553 (6.7) No placebo group
Wheeler,
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 group
Vaccine-related serious adverse events
9vHPV 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 group
2vHPV 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 group
Zhu,
2014 [19]
Vaccine-related serious adverse events M12 0/606 (0.0) 0/606 (0.0)
Deaths, any
9vHPV 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 embolism

Wei,
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 group
Giuliano,
2015 [10]
Death M7 0/150 (0.0) No placebo group
Wilkin,
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 cancer

Schwarz,
2017 [18]
Death M48 2/226 (0.9)

Chronic lymphocytic leukemia; Lung cancer

No placebo group
Vaccine-related deaths
9vHPV 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 group
Giuliano,
2015 [10]
Death, vaccine-related M7 0/150 (0.0) No placebo group
Wilkin,
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 group
Zhu,
2014 [19]
Death, vaccine-related M12 0/606 (0.0) 0/606 (0.0)

Table 3C Footnotes

* Age-restricted data obtained from Luxembourg, 201820

** Intention-to-treat results

Table 4: Evidence for use of 9vHPV in adults ages 27 through 45 years

Outcome Finding Design (number of studies) Initial evidence level* Risk of bias Inconsistency Indirectness Imprecision Other considerations** Evidence type*
9vHPV Benefits
Persistent 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 Harms
Serious 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 1

Table 5A: Summary of evidence for benefits

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 2
Immunogenicity RCTs (3), Obs (6) 9vHPV is immunogenic 2

Table 5A Footnotes

* Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very Low

Table 5B: Summary of evidence for harms

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 2

Table 5B Footnotes

* Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very Low

Supplemental Data

Supplemental Table 1: Immunobridging comparing HPV vaccination in mid-adults with HPV vaccination in young adults

References in this table:410212223

Group Reference; population Antibody Months Mid-adult vaccination (27–45 years) Young adult vaccination (16–26 years) Comparison
Sero-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 done
anti-HPV11 M7 447/448 99.8 454 (424—485) 421/421 100 599 (559–642) Not done
anti-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/ 98.2 412
anti-HPV11 M7 1083/ 97.9 538
anti-HPV16 M7 1092/ 98.6 2212
anti-HPV18 M7 1223/ 97.1 348
Luxembourg,
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

References in this table:262728

Vaccine Reference; population Antibody Months Vaccination with 9vHPV Vaccination with 4vHPV Comparison
Sero-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

References in this table:2324

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
Medline

(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 798
Embase

(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 items

CINAHL

(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 items

Cochrane 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 items

Clinicaltrials.gov Interventional Studies | “human papillomavirus vaccine” OR “human papilloma virus vaccine” OR “HPV vaccine” OR Gardasil OR Cervarix OR silgard | Adult 8/6/2018 128

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