1 

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

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?” 

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 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] 

https://www.cdc.gov/vaccines/acip/recs/grade/HPV-adults-H.pdf 8/15/2019
2

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]

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). 
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
4

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

* 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 
5

TABLE 2A: 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

• Harms

4vHPV

Muñoz, 2009 [4]*

Castellsagué, 2011 [5]*

Luxembourg, 2018 [21]

NCT00090220 

(Future III)

Randomized, 

placebocontrolled 

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, 

placebocontrolled 

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
6

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, 

placebocontrolled 

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, 

placebocontrolled 

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]

NCT00196937;

NCT00947115

Observational 

trial in 

Women age 15–55 years 

(N=667, including 226 

women age 26–45 years)

1 month;

48 months;

• Immunogenicity

• Harms
7

Schwarz, 2017 [18] Germany and 

Poland

72 months;

120 months

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 HPV069)

Randomized, 

placebocontrolled 

trial in China

Women age 9–45 years 

(N=1962, including 1212 

women age 26-45 years)

7 months • Immunogenicity

• Harms

* Age-restricted data obtained from Luxembourg, 2018 [20]

** Per-protocol results for benefits; intention-to-treat results for harms
8

TABLE 2B: 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

• Harms

4vHPV

Hillman, 2012 [23]

Giuliano, 2011 [24]

Palefsky, 2011 [25]

NCT00090285 Randomized, 

placebocontrolled 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, 

placebocontrolled 

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, 

placebocontrolled 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)
9

Van Damme, 2016 [28] NCT02114385 Randomized, 

placebocontrolled trial

in Belgium,

Netherlands, 

and Germany

Men age 16–26 

years (N=500)

7 months • 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

* Per-protocol results for benefits; intention-to-treat results for harms
10

TABLE 3A: Efficacy outcomes

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) - -
11

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)

* Age-restricted data obtained fromLuxembourg, 2018 [20]

** Per-protocol results
12

TABLE 3B: 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/mL

anti-HPV11 447 99.8 454 (424—485) mMu/mL

anti-HPV16 448 100 2148 (2001–2305) mMu/mL

anti-HPV18 469 99.6 532 (492–576) mMu/mL

anti-HPV31 487 99.8 396 (367–427) mMu/mL

anti-HPV33 492 99.8 259 (243–276) mMu/mL

anti-HPV45 511 99.2 146 (134–158) mMu/mL

anti-HPV52 496 100 245 (229–261) mMu/mL

anti-HPV58 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 1083 97.9 538 (506–573) mMU/mL

anti-HPV16 1092 98.6 2212 (2076–2357) mMU/mL

anti-HPV18 1223 97.1 348 (326–372) mMU/mL

Einstein, 2009 [7] anti-HPV16 M7 186 100 20605 (16259–26112) ED50

anti-HPV18 212 100 9674 (7677–18194) ED50

Huang, 2018 [9] anti-HPV6 M7 98.1

anti-HPV11 100

anti-HPV16 100
13

anti-HPV18 99.2

Giuliano, 2015 [10] anti-HPV6 M7 145 100 365 mMU/mL

anti-HPV11 145 100 490 mMU/mL

anti-HPV16 145 100 2178 mMU/mL

anti-HPV18 145 100 296 mMU/mL

Money, 2016 [11] anti-HPV6 M7 61 99.0 426 (324–561) mMU/mL

anti-HPV11 98 98.7 540 (436–668) mMU/mL

anti-HPV16 66 98.1 1495 (1046–2137) mMU/mL

anti-HPV18 94 93.6 295 (223–391) mMU/mL

2vHPV

Skinner, 2014 [13] anti-HPV16 M7 406 100 5413 (4934–5938) EU/mL

anti-HPV18 405 100 2568 (2340–2818) EU/mL

Schwarz, 2009; [15] anti-HPV16 M7 164 100 4060 (3511–4695) EU/mL

anti-HPV18 185 100 1881 (1661–2130) EU/mL

Einstein, 2009 [7] anti-HPV16 M7 168 100 6296 (4906–8082) ED50

anti-HPV18 190/192 99.0 1241 (947–1626) ED50

Zhu, 2014 [19] anti-HPV16 M7 596 100 6440 (6040–6866) EU/mL

anti-HPV18 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 1007 91.8 64 (61–69) mMU/mL

anti-HPV16 1022 97.3 200 (186–214) mMU/mL

anti-HPV18 1132 47.5 23 (21–25) mMU/mL

Einstein, 2014 [8] anti-HPV16 M60 73/76 96.1 555 (341–904) ED50

anti-HPV18 60/87 69.0 89 (59–136) ED50

Huang, 2018 [9] anti-HPV6 M42 91.2
14

anti-HPV11 88.3

anti-HPV16 96.8

anti-HPV18 37.6

Money, 2016 [11] anti-HPV6 M24 53 129 (93–179) mMU/mL

anti-HPV11 78 125 (125–160) mMU/mL

anti-HPV16 54 459 (341–618) mMU/mL

anti-HPV18 72 54 (39–74) mMU/mL

2vHPV

Skinner, 2014 [13] anti-HPV16 M48 345/345 100 546 (490–608) EU/mL

anti-HPV18 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 133/142 93.7 115 (94-142) EU/mL

Einstein, 2014 [8] anti-HPV16 M60 89 100 1855 (1267–2715) ED50

anti-HPV18 109 100 892 (759–1268) ED50

* Age-restricted data obtained fromLuxembourg, 2018 [20]

** Per-protocol results
15

TABLE 3C: Harms

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)
16

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; 

5/2870 (0.2)

Anaplastic astrocytoma; 

Cardiac valve disease and liver 

disorder; Cardiorespiratory 

arrest; Lower respiratory tract 
17

Pneumonia; Pulmonary embolism; 

Suicide (x3)

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)

* Age-restricted data obtained from Luxembourg, 2018 [20]

** Intention-to-treat results
18

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 HPVrelated 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
19

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

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
20

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 HPVrelated outcomes than 

no vaccination 

2

2

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

* 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

* Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very Low
21

SUPPLEMENTAL DATA

SUPPLEMENTAL TABLE 1: 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) Comparison

Seropositive 

n/N

Seropositive

%

GMTs (95% CI)

mMU/mL

Seropositive 

n/N

Seropositive

%

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 447/448 99.8 454 (424—485) 421/421 100 599 (559–642) Not done

anti-HPV16 448/448 100 2148 (2001–2305) 436/436 100 3076 (2863–3304) 0.7 (0.6–0.8)

anti-HPV18 469/471 99.6 532 (492–576) 421/421 100 745 (685–809) 0.7 (0.6–0.8)

anti-HPV31 487/488 99.8 396 (367–427) 447/447 100 596 (551–645) 0.7 (0.6–0.7)

anti-HPV33 492/493 99.8 259 (243–276) 457/457 100 355 (332–379) 0.7 (0.7–0.8)

anti-HPV45 511/515 99.2 146 (134–158) 468/470 99.6 215 (198–234) 0.7 (0.6–0.8)

anti-HPV52 496/496 100 245 (229–261) 456/456 100 347 (324–371) 0.7 (0.6–0.8)

anti-HPV58 477/478 99.8 296 (277–317) 451/451 100 428 (399–459) 0.7 (0.6–0.8)

4vHPV, 

female

s

Muñoz, 2009 

[4]; age 27–

45 years

anti-HPV6 M7 1083/ 98.2 412

anti-HPV11 1083/ 97.9 538

anti-HPV16 1092/ 98.6 2212

anti-HPV18 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 2824 754.3 0.7 (0.7–0.8)

anti-HPV16 2749 2297.6 1.0 (0.9–1.1)

anti-HPV18 3006 458.1 0.8 (0.7–0.8)

4vHPV, 

males

Giuliano, 

2015 [10]; 

anti-HPV6 M7 145/145 100 419 (363–484)

anti-HPV11 145/145 100 517 (455–587)

anti-HPV16 145/145 100 2229 (2004–2448)
22

age 27–45 

years

anti-HPV18 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 1083/1092 99.2 624 (594–655)

anti-HPV16 1121/1135 98.8 2404 (2272–2544)

anti-HPV18 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 0.8 (0.7–0.9)

anti-HPV16 0.9 (0.7–1.1)

anti-HPV18 0.7 (0.6–0.9)
23

SUPPLEMENTAL TABLE 2: Immunobridging comparing 9vHPV in young adults with 4vHPV in young adults

Vaccine Reference; 

population

Antibody Months Vaccination with 9vHPV Vaccination with 4vHPV Comparison

Seropositive 

n/N

Seropositive

%

GMTs (95% CI)

mMU/mL

Seropositive 

n/N

Seropositive

%

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) -
24

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) -
25

SUPPLEMENTAL TABLE 3: 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)

-

-
26

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 Update: Recommendations of the Advisory Committee on Immunization 

Practices (ACIP) for Human Papillomavirus (HPV) Vaccination of Adults.
27

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

8/6/2018 71

-11

duplicates 

=60 

unique 

items
28

(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 ;

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
29

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