Review and answer 23 questions about the article and the article supplement. Be very detail with each answers

20200428202831article_supp1.pdf

Home >Business & Finance homework help >Management homework help >Review and answer 23 questions about the article and the article supplement. Be very detail with each answers

HPV Vaccination Guideline Update:

American Cancer Society Guideline Endorsement

Supplemental Evidence Review

July 2016

Introduction

The 2007 American Cancer Society (ACS) guideline for use of human papillomavirus

(HPV) vaccine to prevent cervical cancer and its precursors recommended routine vaccination of

females aged 11-12 (with permissive vaccination of females as young as age 9); vaccination for

females 13-18 years to catch up missed vaccines (i.e. those not vaccinated at the recommended

routine age) or complete the vaccination series; and informed decision-making for females aged

19-26 years (based on the likely diminished benefit associated with previous exposure to HPV).

At the time of the release of the ACS 2007 guideline, no HPV vaccine was licensed for use in

males; additionally, new vaccine formulations have been approved and recommended. This

review and update of the 2007 ACS guideline is intended to address these changes. Because the

recommendations of the Advisory Committee on Immunization Practices (ACIP) serve as the

principal source of guidance on U.S. immunization policy, the ACS chose to consider

endorsement of the current ACIP recommendations for HPV vaccination.

Based on the previous ACS recommendations, a supplemental review of the evidence

was designed and performed to address three key questions:

1. Should HPV “catch-up” or late vaccination be recommended for females aged 19 through 26 years who have not been vaccinated previously?

2. Should HPV vaccination be recommended for males aged 9 through 26 years? 3. Should 9-valent HPV vaccination be recommended for males and/or females?

This review was restricted to the key questions above and did not revisit the question of

female vaccination in early adolescence. No new studies have been reported in recent years to

warrant reconsideration of the 2007 ACS recommendation for routine and late vaccination of

females up to age 19. However, many of the studies on late vaccination included in this

supplemental review did compare outcomes in women vaccinated at earlier ages with those

vaccinated after age 19.

While the ACIP recommendations were evidence-based, no formal systematic review

was conducted. Rather, the ACIP recommendations primarily were based on results from

randomized controlled trials (RCTs) conducted by the vaccine manufacturers measuring vaccine

efficacy, i.e., the percent reduction in disease incidence in a vaccinated group compared with an

unvaccinated control group under experimental conditions. Because HPV vaccination prevents

only disease resulting from infections with the HPV subtypes targeted by the vaccines, but offers

no protection against disease resulting from previous exposure to these HPV types, it also is

important to consider data from ecological studies measuring vaccine effectiveness, i.e.,

reduction in disease outcomes in a “real world” setting. This is especially relevant when

evaluating recommendations for late vaccination among females and males who are more likely

to have been sexually active and thus more likely to have had previous or current HPV

infections.

Methods

On July 16, 2014, a PubMed search was conducted using the following search terms:

(((((((human papillomavirus vaccine effectiveness) OR HPV vaccine effectiveness) OR human

papillomavirus vaccine efficacy) OR HPV vaccine efficacy) OR human papillomavirus vaccine

prevention) OR HPV vaccine prevention) OR human papillomavirus vaccine immunogenicity)

OR HPV vaccine immunogenicity). An updated search was completed on October 8, 2015, using

the same search terms.

Articles that addressed efficacy or effectiveness of the 9-valent, quadrivalent or bivalent

HPV vaccine in males or females were included. Articles that did not have abstracts, were not in

English, or did not address efficacy or effectiveness were excluded. Additionally, studies

reporting outcomes only for females vaccinated through age 18 were not included. Review

articles were included in the first round of review and were used to identify any additional

articles.

Table 1 describes outcomes of HPV vaccination that were considered. Critical outcomes

included prevention of advanced precancerous lesions, which is an accepted surrogate for cancer.

While prevention of oropharyngeal cancer is an important outcome, there are no known

detectable precancerous lesions, and no data are available yet on prevention of these cancers.

Adverse events (i.e. “harms”) potentially associated with vaccination of both females and

males have been included as outcomes of interest when reported in studies included in this

supplemental review, though adverse events were not included in the search terms. The Centers

for Disease Control and Prevention (CDC) and the ACIP sponsor an extensive ongoing

surveillance and safety monitoring program related to vaccination, and updated results are

publicly reported.1 CDC and ACIP regularly monitor post-licensure safety data through several

systems in the U.S. as well as reports from other countries. Studies from the U.S. and Europe, for

example, have shown no causal association of HPV vaccination and autoimmune disease, stroke,

Guillain-Barré syndrome, venous thromboembolism, seizures, connective tissue disorders, or

allergic disorders.1 The World Health Organization also monitors vaccine safety through its

Global Advisory Committee on Vaccine Safety (GACVS), which has published 6 reports on

HPV vaccines with the most recent report released in December, 2015.2

Table 1: Outcomes of Interest

Outcomes considered in the supplemental evidence review

Critical Important

Benefits: prevention of CIN2, CIN3, AIS

(F)

Benefits: prevention of penile (M) and

oropharyngeal cancer (M and F)

Benefits: prevention of VIN 2/3; VaIN 2/3

(F)

Benefits: prevention of GW (M and F)

Benefits: prevention of AIN 2/3 (M and F) Benefits: prevention of HPV

infection/persistent infection (M and F)

Harms: Adverse events specified or reported in RCT protocols and established safety

monitoring systems

Harms: SAEs (allergic reaction,

anaphylaxis, appendicitis, autoimmune

disorders including Multiple Sclerosis,

complex regional pain syndrome, Guillain-

Barre syndrome, neurologic disorders,

postural orthostatic tachycardia syndrome

(POTS), stroke, seizures, syncope,* venous

thromboembolism; pregnancy outcomes

including miscarriage)

Harms: non-serious adverse events

(including syncope, pain, swelling,

erythema, fever, headache, nausea )

AIN-anal intraepithelial neoplasia; AIS-adenocarcinoma in situ; CIN-cervical intraepithelial neoplasia; F-

female; GW-genital wart; HPV-human papillomavirus; M- male; RCT-randomized controlled trial; SAE-

serious adverse event; VaIN-vaginal intraepithelial neoplasia; VIN-vulvar intraepithelial neoplasia

*About 7% of syncope was coded as serious, e.g. syncope followed by a head injury

Results

The search returned a total of 4091 article titles from the initial and updated searches, of which

167 full-text articles were reviewed. (Figure 1)

Figure 1. Flowchart of literature search for key questions

# of unique articles identified

through database search:

4091

# of full-text articles assessed for eligibility:

167

Articles reviewed for key

question 3 (9-valent):

Articles included for key

question 2:

Articles included for key

question 1:

Articles included for key

question 3:

Articles reviewed for key

question 2 (males):

Articles reviewed for key

question 1

(late vaccination of females):

124

Articles included for key

question 2:

Articles excluded for key

question 1:

Ages vaccinated <21

Small sample size

Location (non-Western

country w/ potentially

different sexual norms)

Immunogenicity only

Lack of age stratification

Articles excluded for key

question 2: Cross-protection

Alternative dosing schedule

Special populations (excl. MSM)

Model assessing using different

vaccines for males and females

Analysis before recommendation

for males

Immunogenicity only

Review of immunogenicity

Efficacy and Effectiveness of Late Vaccination in Females

Critical Outcomes

We included a pooled analysis of manufacturer-sponsored phase II and III trials, 1 RCT,

1 case control study, and 3 ecological studies that addressed critical outcomes, primarily CIN2

and above, in women, stratified by age. (Table 2)

The pooled analysis and 1 RCT addressing vaccine efficacy against CIN2 or worse found

that efficacy decreased with age at vaccination.3, 4 A long-term follow-up international study of

bivalent HPV vaccine in females having no more than six lifetime sexual partners found vaccine

efficacy against CIN2 or worse caused by HPV types 16 and 18 decreased from 79.1% in

females ages 15-17 to 65.0% in females ages 18-20 and 26.4% (non-significant) in females

vaccinated at ages 21-25.4 A pooled analysis of the effects of quadrivalent HPV vaccine against

cervical and genital lesions in females with no more than four sexual partners also found vaccine

efficacy decreased with age, from 69.0% in females less than age 17 to 61.9% in females ages

18-20 and 31.1% in females ages 21-26 years; efficacy decreased as well as with the number of

lifetime sexual partners.3 Suggestions of similar declines (not statistically significant) in efficacy

were observed for high grade VIN and VaIN.3

Crowe et al5 conducted a case-control study using linked data from the Queensland,

Australia registry four years after vaccine introduction, limited to women who had been eligible

for HPV vaccination and were presenting for their first cervical Pap test between 2007 and 2011.

As the guideline for cervical screening in Australia was for initiation of screening between ages

18 and 20 for sexually active women or 1-2 years after the first sexual contact, whichever is

later, the assumption of the study design was that women presenting for their first Pap test were

sexually naive at the time of the HPV vaccine introduction. The study found vaccine

effectiveness against CIN2 or worse was 46% for all ages (in women who completed 3 doses

compared to no vaccine). The effectiveness of the vaccine against CIN 2+ measured by age at

the time of vaccine program initiation in 2007 was 29% for ages 11-14 years (not statistically

significant), 57% for ages 15-18, 53% for ages 19-22, and 5% for ages 23-27. A secondary

analysis among women who had one or more cervical screening tests before their abnormal

screening result found vaccine effectiveness was 23% for CIN2 or worse. Only small, non-

significant protective effects against high-grade cervical abnormalities were observed for women

vaccinated after age 22.5

The three ecological studies using high-grade cervical lesions as the outcome of interest

all provided evidence of decreased vaccine effectiveness in women at older ages (with age

groupings varying across studies).6-8 A study using registry data from Australia just three years

after introduction of vaccination found a decrease in high grade lesions from 0.80% in 2006 to

0.42% in 2009 among women screened at age <18, no significant change in incidence for women

aged 18-20, and a small increase in incidence for women aged 21 and older. The population

vaccination rate (having received three doses) based on self-reported surveys was estimated at

79% in first-year high school females and 56% for women aged 18-28 years.7 A second study

using the Victoria, Australia cytology registry to examine vaccine effectiveness 7 years after

vaccine introduction found rates of high-grade cervical abnormalities decreased by over half in

females younger than age 20 (from 10.9/1000 in 2006 to 5/1000 in 2013), and from 21.1/1000 in

2008 to 13.5/1000 in 2013 in females aged 20-24. This study reported a gradual increase in rates

of high-grade cervical abnormalities among women ages 25-29 over the same period.6 Although

a national vaccination program registry reported a vaccine coverage rate of 70% for three doses

for females aged 12-17, and 32% for aged 18-26 in the study area, the actual age at HPV

vaccination for the cervical screening population in the data analyses was not verified. Another

ecological study of women in Connecticut from a mandatory reporting surveillance system found

that the largest and only statistically significant decrease in CIN2 or worse was 18% observed

among women ages 21 to 24, while no significant declines in CIN2 or worse were observed in

women ages 25 and older.8 These results must be interpreted with caution because of changes in

national recommendations for less aggressive follow up for younger women (ages 20-24) after

cervical screening.9 Overall, while the reduction in screen-detected high grade cervical lesions,

particularly in younger age groups, is consistent across these studies, conclusions are limited by

reliance on trend analyses and ecological data.

Important Outcomes

Three RCTs and 6 ecological studies addressed important outcomes of HPV infection,

persistent infection, and genital warts. (Table 2) Also, the ecological studies were included in a

meta-analysis of ecological time-trend studies conducted by Drolet et al.10

The RCTs, which included women with a limited number of lifetime sexual partners,

showed some vaccine efficacy in females 18-25 years.11-14 Of these, 1 RCT reported outcomes

stratified by age. This study of HPV vaccine efficacy from a community-based clinical trial

reported 68.9% efficacy against persistent infection in females ages 18-19 and 21.8% in females

ages 24-25.13

In the meta-analysis by Drolet et al,10 the authors reported a 31% reduction in genital

warts diagnoses among females ages 15-19 years who had been previously vaccinated and an

11% decrease in females ages 20-39. The analysis also found that HPV infections decreased by

64% in females ages 13-19 and 31% in women ages 20-24.10

Safety Outcomes

Safety outcomes have been reviewed extensively by the CDC, ACIP, and the Global

Advisory Committee on Vaccine Safety (GACVS). Vichnin et al15 (including authors who were

current or former employees of the vaccine manufacturers) published a comprehensive overview

of safety studies from 2006-2015. These studies included the CDC Vaccine Safety Datalink

(VSD), three register-based safety studies in Denmark and Sweden, a case-control study from

Kaiser Permanente Southern California, and post-licensure safety studies sponsored by vaccine

manufacturers. Passive reporting systems for adverse events included the CDC’s Vaccine

Adverse Events Reporting System (VAERS), the Australian National Surveillance Program, and

a manufacturer-supported pregnancy registry. The reviewers concluded the safety profile was

favorable, based on experience with the vaccine in hundreds of thousands of recipients, and one

of the most extensive safety evaluations of any licensed vaccine.15

The most recent GACVS report added new findings related to reports of Chronic

Regional Pain Syndrome, Guillain-Barre syndrome, and postural orthostatic tachycardia

syndrome (POTS) in some geographic areas. The GACVS report did not identify any new safety

issues related to these syndromes that would alter its recommendations for the use of the HPV

vaccine.2

Table 2: Studies Addressing Efficacy and Effectiveness of Late Vaccination in Females

Critical Outcomes: CIN2+

Author/year Study Design Population Vaccine Primary Outcome Summary of Findings

Kjaer et al.

20093

Pooled analysis

of 3 RCTs

(Merck-

sponsored

protocols 007

and 013;

NCT00092521,

protocol #015;

NCT00092534)

International

n=18,174 (half

vaccinated against

HPV, half placebo),

Females aged 16-26

(4 or fewer lifetime

sex partners; 1% of

subjects had 4 or

more partners, no

prior HPV infection)

Quadrivalent  Persistent infection,

cervical/extra genital disease

associated with HPV

6/11/16/18

 HPV 6/11/16/18-related

CIN, AIS, or cervical CA

 GW, VIN, VaIN, vulvar

CA, or vaginal CA

 HPV 16/18 CIN2+ (CIN2/3,

AIS, or cervical CA)

Vaccine Efficacy (VE) in Intention to

Treat (ITT) against vaccine-type high-

grade cervical lesions was 51.5%

(compared to 98.2% in per-protocol);

VE decreased with age (69.0% ≤17,

61.9% 18-20, 31.1% ≥21); VE against

vaccine-type high-grade vulvar and

vaginal lesions was 79.0% in ITT

(compared to 100.0% in per-protocol);

time-to-event analysis in ITT showed

significantly lower incidence of HPV

16/18-related CIN2+ over time in

vaccinated females.

VE in females with 0 sexual partners

86.5%; VE in females with 3-4 lifetime

sexual partners 48.1%.

VE in ITT against vaccine-type high-

grade VIN and VaIN 98.9% for females

≤17, 86.2% for females 18-20, and

55.1% for females ≥21.

Lehtinen et al.

20124

RCT n=18,644 (half

vaccinated against

HPV, half control),

Females aged 15-25

(no more than six

sexual partners),

International (14

countries in Asia

Pacific, Europe,

Latin America, and

North America),

2004-2009

Bivalent  CIN1+, CIN2+, CIN3+, and

AIS

 6- and 12-months persistent

infection

For cervical lesions caused by HPV 16

or 18 in ITT, VE for CIN2+ 79.1% for

females 15-17, 65.0% for females 18-20,

and 26.4% (not statistically significant)

for females 21-25.

For cervical lesions caused by any HPV

type in ITT, VE for CIN2+ 44.0% for

females 15-17, 40.6% for females 18-20,

and 8.9% (not statistically significant)

for females 21-25.

Crowe et al.

20145

Case-Control

(Linked

administrative

health datasets)

n=108,353, Females

aged 12-26 in 2007

eligible for

vaccination program

and attending first

Pap screening 2007-

2011, Queensland,

Australia

Quadrivalent

 CIN2 or worse (n=1062)

 Other (low-grade

abnormality or abnormal

cytology not confirmed by

histology, n=10,887)

 96,404 controls (negative

cytology result)

For females with 3 doses who were ages

11-14 in 2007, adjusted OR for CIN2+

0.71 (not statistically significant);

females aged 15-18, OR 0.43; females

aged 19-22, OR 0.47; females aged 23-

27, OR 0.95.

Brotherton et

al. 20117

Ecological n=1,718,494,

Females aged 18-26,

Victoria, Australia

registry data, 2007-

2011

(vaccination program

for all women aged

12-26 was introduced

2007-2009)

Quadrivalent High-grade cervical lesions

(CIN2+/AIS) and low-grade

cervical lesions

A significant difference of 0.38% in

incidence of high-grade cervical lesions

in girls receiving Pap screening at age

<18 years.

No change in females screened at ages

18-20.

18% increase in females screened at ages

21-25.

Niccolai et al.

20138

Ecological n=411,624, Females

aged 21-39,

Connecticut registry

data, 2008-2011

Quadrivalent High-grade cervical lesions

(CIN2+/AIS)

No significant change in high-grade

cervical lesions in females aged >25.

Statistically significant decrease among

females aged 21–24 years, from 834 in

2008 to 688 in 2011 per 100,000 women.

Note: U.S. HPV vaccination rates

increased from 25% to 53% for 1+ doses

for females 13-17 (and from 45% to 61%

in CT) and from 11% to 21% for females

19-26 during this time period. Also,

screening recommendations changed in

2009.

Brotherton et

al. 20156

Ecological

(time- and age-

group specific

trends)

n=8,130,567 Pap test

records from

Australia Cervical

Cytology Registry,

Victoria, 2000 to

2013

Quadrivalent CIN2 or worse Significant decrease in women screened

at age <20 (10.9 to 5 per 1,000) and in

women aged 20-24 (16.1 to 13.5 per

1,000); increase in women aged 25-29

(15.8 to 17.7 per 1,000), from 2006 to

2013.

Important Outcomes: Persistent HPV Infection and Genital Warts

Author/year Study Design Population Vaccine Primary Outcome Summary of Findings

Castellsague

et al. 201111

RCT

(Merck-

sponsored

Protocol 019;

NCT00090220)

n=3,819, Females

aged 24-45 with no

history of cervical

disease or GW in past

5 years, International

(7 countries), 2004-

2005 with 4 years

follow up

Quadrivalent  Persistent infection

 CIN/GW related to

HPV 6/11/16/18

VE against the combined incidence of

persistent infection, CIN, or GW vaccine-type

HPV in ITT was 47.2% (compared to 88.7%

in per-protocol); VE against HPV 16/18

persistent infection, CIN, or GW was 41.6%

in ITT (compared to 84.7%); VE against HPV

6/11 was 61.3% in ITT (compared to 94.8%).

There was no significant difference in VE

between the 25-34 and 35-45 age groups.

Herrero et al.

201113

Herrero et al.

201312

RCT

(Glaxo Smith

Kline-

sponsored

Protocol 20;

NCT00090285)

n=3,463 HSM aged

16-23; n=602 MSM

aged 16-26,

International (18

countries), 2004-2011

Quadrivalent  Incidence of

vaccine-type PIN 1,

2-3

 Penile, perianal, or

perineal cancer

 SAEs

 GW – see below

VE against PIN was not observed in

ITT.

VE was 100% in per-protocol based on

3 cases of PIN in controls (placebo).

No vaccine-related SAEs.

Palefsky et al.

201124

RCT (Merck-

sponsored

Protocol 20;

NCT00090285)

n=598 MSM

aged 16-26,

International (7

countries), 2004-2011

Quadrivalent  HPV 6/11/16/18-

related AIN or anal

cancer

 SAEs

VE against AIN was 50.3% in ITT and

77.5% in per-protocol (PP). VE for

AIN2/3 was 54.2% in ITT and 74.9%

in PP.

No vaccine-related SAEs.

Goldstone et al.

201323

RCT (Merck-

sponsored

Protocol 20;

NCT00090285)

n=3,463 HSM aged

16-23; n=602 MSM

aged 16-26,

International (18

countries), 2004-2011

Quadrivalent  HPV 6/11/16/18-

related PIN

 AIN in MSM only

 Outcomes for all

HPV types EGL

VE was 50.3% against vaccine-type

AIN in ITT MSM and 89.6% in PP.

For all HPV types VE was 25.7% and

54.9%.

VE against PIN was 100% in PP (3

cases in controls; 2 of the 3 cases were

PIN2/3).

VE against AIN1 in HPV naïve MSM

93.1%; for all HPV types 67.2%.

Elbasha and

Dasbach, 201027

Mathematical

model

Males aged 9-26,

U.S.

Quadrivalent  Vaccine-type GW

 Respiratory

papillomatosis

 CIN; cervical,

vulvar, vaginal,

penile, anal,

head/neck cancer

Mathematical model predicting

additional reduction of GW, CIN2/3,

cancer, and cancer death when boys

and men are vaccinated compared to

vaccinating girls and women only:

Vaccinating boys and men decreased

the respective mean cumulative

number of GW cases, CIN 2/3 cases,

cancer cases, and cancer deaths among

women by 1,849,000, 708,000, 45,000,

and 15,000, respectively, within 100

years following the introduction of the

vaccine. The mean cumulative number

of GW cases, cancer cases, and cancer

deaths among men prevented after 100

years of vaccination were 3,297,000,

71,000, and 25,000, respectively.

Bogaards et al.

201526

Mathematical

model

Males aged 12 years,

Netherlands

Vaccination

against HPV

16 and 18

Burden of anal, penile,

and oropharyngeal

carcinoma among

HSM and MSM.

Burden of HPV-associated cancers in

males could be reduced by 37%, given

the level of 60% vaccine uptake of

girls; Estimated 66% reduction in

burden of HPV related-cancer in men

if vaccine uptake among girls increase

to 90%.

Important Outcomes

Author/year Study Design Population Vaccine Primary Outcome Summary of Findings

Ferris et al. 201425 RCT (Long

term follow up

Protocol V501-

108)

n=1781, Males and

Females aged 9-15,

(Sexually naïve

boys), International,

2003-2013

Quadrivalent  Long-term anti-HPV

6/11/16/18

serological levels.

 HPV 6/11/16/18-

related persistent

infection or disease

Immunogenicity in males was similar

to females.

Incidence of HPV infection or disease

was similar in males and females.

Giuliano et al. 201122

RCT (Merck-

sponsored

Protocol 20;

NCT00090285)

n=3,463 HSM aged

16-23; n=602 MSM

aged 16-26,

International (18

countries), 2004-2011

Quadrivalent  Incidence of

vaccine-type GW

 Incidence of

vaccine-type

persistent infection

 AEs; PIN 1, 2-3

 Penile, perianal, or

perineal cancer—see

above

VE was 65.5% for GW in ITT in HSM

and MSM for lesions related to HPV

6/11/16/18. VE was 63.7% in HSM

and 70.2% in MSM.

Palefsky et al. 201124 RCT (Merck-

sponsored

Protocol 20;

NCT00090285)

n=598 MSM aged

16-26, International

(7 countries), 2004-

2011

Quadrivalent  Incidence of

vaccine-type

persistent anal

infection

 AEs

 AIN—see above

VE against vaccine-type persistent

infection was 47.8% in ITT and 85.6%

in PP.

Significant increase in reports of

injection site pain compared to

placebo; other AEs similar to placebo

Goldstone et al.

201323

RCT (Merck-

sponsored

Protocol 20;

NCT00090285)

n=3,463 HSM aged

16-23; n=602 MSM

aged 16-26,

International (18

countries), 2004-2011

Quadrivalent HPV 6/11/16/18-

related EGL

PIN; AIN in MSM

only—see above

VE was 66.7% against vaccine-type

EGLs in ITT population and 90.8% in

PP.

VE was 59.3% in ITT and 81.5% in PP

for all HPV types.

AEs similar to placebo.

AE-adverse event; AIN-anal intraepithelial neoplasia; CIN-cervical intraepithelial neoplasia; EGL-external genital lesions; GW-genital warts;

HPV-human papillomavirus; HSM-heterosexual male; ITT-intention to treat; MSM-men who have sex with men; PIN-penile intraepithelial

neoplasia; PP-per protocol; RCT-randomized controlled trial; SAE-serious adverse event; VE-vaccine efficacy

Efficacy of 9-valent HPV Vaccine in Males and Females

There are limited data reporting our specified critical and important outcomes. The 9-

valent vaccine was licensed by the FDA in December 2014 and recommended by ACIP in

February 2015. ACIP recommendations for use of the 9-valent vaccine, targeting HPV types 31,

33, 45, 52, and 58, in addition to the types included in the quadrivalent vaccine, were based

largely on inference of efficacy from non-inferiority findings of studies of immunogenicity.

Three RCTs found the antibody response of the 9-valent vaccine for HPV types

6/11/16/18 to be non-inferior to that of the quadrivalent vaccine, with a similar safety profile.28-30

Joura et al28 conducted an international RCT with four years of follow-up and found similar

protection against disease caused by the HPV types included in the quadrivalent vaccine and

96.7% efficacy in the per-protocol population against high-grade disease caused by the

additional HPV types. Additionally, the authors found a lower overall rate of high-grade cervical,

vulvar, and vaginal disease in the 9-valent group compared to the quadrivalent group. All cases

of high-grade disease occurred in participants who had an HPV infection at baseline.28

Immunogenicity and safety were also compared across age groups and gender. One study

found that the antibody responses in girls and boys ages 9-15 were non-inferior to the responses

in women ages 16-26 years.29 Vesikari et al30 found a higher antibody response for all 9 HPV

types in females ages 9-12 years compared to females vaccinated at ages 13-15 years. Another

study found antibody response for heterosexual males (HSM) was non-inferior to that in women

ages 16-26 years, but antibody response for men who have sex with men (MSM) was lower than

in HSM.31 Adverse events were similar compared with the quadrivalent vaccine and fewer in

males than in females.28, 30, 31 Injection-site adverse events were less common in males and

females ages 9-15 than in ages 16-26.29

Two studies assessed the immunogenicity and safety of the 9-valent vaccine when given

concomitantly with Diphtheria, Tetanus, Pertussis and either Poliomyelitis or Menactra vaccines

and found no difference in antibody response and similar safety profiles.32, 33

Table 4: Studies Addressing Efficacy of 9-valent Vaccine

Efficacy of 9-valent Vaccine

Author/year Study Design Population Vaccine Primary

Outcome

Summary of Findings

Castellsague

et al. 201531

RCT

(Merck

sponsored

Protocol

V503-005;

NCT00988884)

n=1241, Males

and Females aged

11-15,

International (5

countries), 2009-

2011

9-valent  Sero-conversion for concomitant

administration

with Tdap and

Menactra

 Adverse events:

Injection-site,

Systemic

 SAEs

No difference in antibody response to any

of the vaccines; 100% seroconversion to

all 9 HPV types.

Increased reports of swelling in the

concomitant group; other injection-site and

systemic AEs similar across groups.

No vaccine-related SAEs reported.

Van Damme et

al. 201529

RCT

(Merck-

sponsored

protocol V503-

002;

NCT00943722)

n=3074 Males

aged 9-15,

Females aged 9-26

(n=1875 Females

9-15, n=647 Males

9-15, n=444

Quadrivalent,

9-valent  Antibody

response

 Adverse events: Injection-site,

Systemic

 SAEs

Seroconversion was 99.5%-100% for all 9

HPV types. Antibody responses were

similar for males and females. Responses

persisted for 2.5 years in >90% males and

females aged 9-15.

Females 16-26),

International (17

countries), 2009-

2013

Injection-site AEs were lower in males and

females aged 9-15 compared to females

aged 16-26.

There were 2 reported vaccine-related

SAEs (<0.2%).

Vesikari et al.

201530

RCT n=600, Females

aged 9-15,

International (6

countries), 2011

Quadrivalent,

9-valent  Antibody

response

 Adverse events: Injection-site,

Systemic

 SAEs

Anti HPV 31/33/45/52/58 GMTs were

greater by 1-2 orders of magnitude in the

9-valent group compared to the

quadrivalent and similar for HPV

6/11/16/18. Response was higher for all 9

HPV types in females aged 9-12 compared

to females aged 13-15.

AEs similar for the two vaccines although

more participants reported swelling after

receiving the 9-valent vaccine.

No vaccine-related SAEs were reported.

AE-adverse event; GMT-geometric mean titer; HG-high grade; HPV-human papillomavirus; HSM-heterosexual male; ITT-intention to treat; MSM-men who have sex with men; RCT-randomized controlled trial; SAE-serious adverse event; Tdap-tetanus, diphtheria, and acellular

pertussis vaccine; VE-vaccine efficacy.

Discussion

We performed a supplemental evidence review to support an update to the 2007 ACS

guideline and consideration of endorsement of the current ACIP recommendations. ACIP

primarily focused on RCTs, which demonstrated high efficacy and acceptable safety (with

predominantly non-serious side effects). Additionally, CDC and other agencies monitor

extensive safety data beyond the published literature, with frequent updates.1

This review was guided by three questions. To address question 1, we first examined

available effectiveness data related to the question of late vaccination, including results from

time-trend and registry linkage ecological studies, as well as modeling studies that applied trial

findings to predict long-term disease outcomes in the population. Data on the second question,

which pertained to male vaccination, derive from RCTs and modeling studies. For the third

question related to use of the recently licensed and recommended 9-valent vaccine, it was

necessary to rely largely on RCTs with non-inferiority and immunogenicity outcomes.

1. Should late (“catch-up”) HPV vaccination be recommended for females aged 19 through 26 years who have not been vaccinated previously?

The RCTs showed that vaccine efficacy decreases with age. The CDC and ACIP have

acknowledged that “although overall vaccine effectiveness would be lower when

administered to a population of females who are sexually active, and would decrease with

older age and likelihood of HPV exposure with increasing number of sex partners, the

majority of females in this age group will derive at least partial benefit from vaccination,”34

and that, in males, “the population level benefits decrease with increasing age at vaccination,

especially after age 21 years.”35

Data from ecological studies support the conclusion from RCTs that effectiveness is

reduced with vaccination at older ages. These decreases are challenging to measure for

several reasons. Few ecological studies have been conducted, and these are mostly

population-based rather than based on linked data, i.e. data from individual screening results

linked to vaccination status including age at vaccination. Most ecological studies did not

measure age at vaccination specifically, but reported age at screening or diagnosis. In these

studies, the age at vaccination has to be extrapolated. Further, vaccination rates are lower in

older females in all countries where late vaccination is available. Measures of long-term

effectiveness are also limited. It should be noted, however, that two studies published after

completion of this supplemental evidence review provide individual-level data on outcomes

by age and report greater effectiveness in girls who were younger at vaccination initiation.36,

For these and other reasons, caution must be exercised in drawing conclusions from

observational and ecological studies, due to risk of bias and confounding, although Drolet et

al10 in their systematic review point out that identified confounding factors would likely lead

to underestimation of vaccination benefits. There are also questions of generalizability, since

study subjects sought care in the health care system. Finally, these results are based on a

relatively short time period following the introduction of vaccination in the studied

populations. However, the RCT findings of vaccination efficacy provide a strong foundation

for confidence that vaccination confers population benefits and long-term potential for

disease prevention. Drolet et al10 also emphasize that the magnitude of effects and dose-

response associations in these studies, as well as consistency of results with findings from

RCTs and modeling, lend credibility to the strong estimates of effect. Although there are

limited data for estimating age-specific benefits, the available evidence suggests that efficacy

and effectiveness are maximized when vaccination occurs at the recommended ages for both

females and males, compared to vaccination at older ages.

2. Should HPV vaccination be recommended for males aged 9 through 26 years? There are fewer studies of HPV vaccination of males, and those that exist are limited by

small study sizes and small numbers of pre-cancer outcomes, compared with studies of

females. At this time, there is a lack of evidence of vaccine efficacy for cancer or pre-cancer

prevention in average-risk men, and age-stratified data are very limited for males. The

available studies have shown that vaccine efficacy, immunogenicity, and safety are similar in

males compared to females.

Vaccination of males as well as females should lead to greater protection against HPV-

associated cancers diagnosed in men, including oropharyngeal cancers. Men who have sex

with men have a particularly high burden of HPV-associated cancers. Across studies,

reductions in occurrence of persistent infection and anogenital warts were reported. Though

genital warts are non-life threatening, they are often resistant to treatment and have high rates

of recurrence, contributing to significant declines in quality of life.

Modeling studies, though valuable in permitting an examination of population effects

based on data from other study types, are dependent in part on unverified assumptions.

Modeling results suggest that vaccination of males may, through herd immunity, provide

additional protection to females in addition to providing protection to males.

3. Should 9-valent HPV vaccination be recommended for males and/or females? The available data on the 9-valent HPV vaccine, approved by the FDA and recommended

by the ACIP in 2015, showed comparable efficacy, immunogenicity, and safety with the

quadrivalent vaccine. There are limited data on our specified critical outcomes. Conclusions

about effectiveness are largely based on surrogate endpoints (immunogenicity and non-

inferiority). These endpoints, though, have been judged to be appropriate and acceptable by

an international panel.38

The scope of this supplemental review is limited. We did not re-examine the RCT evidence on

vaccine efficacy in adolescent girls; nor did we search the literature for supplemental evidence

on adverse events and vaccine safety. On the three questions we addressed, there is consistency

in the direction and magnitude of effect of the available vaccine formulations, across study types,

for efficacy and effectiveness outcomes in females and males. Though there is decreased benefit

at older ages, overall, HPV vaccination of men and women as recommended has been

demonstrated to provide a level of protection against HPV-related disease.

References

1. Stokley S, Jeyarajah J, Yankey D, et al. Human papillomavirus vaccination coverage among adolescents, 2007-

2013, and postlicensure vaccine safety monitoring, 2006-2014--United States. MMWR Morb Mortal Wkly Rep.

2014;63: 620-624.

2. World Health Organization Global Advisory Committee on Vaccine Safety (GACVS). Statement on Safety of

HPV Vaccines. Available at:

http://www.who.int/vaccine_safety/committee/topics/hpv/statement_Dec_2015/en/. Last accessed June 20,

2016

3. Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent

human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions.

Cancer Prev Res (Phila). 2009;2: 868-878.

4. Lehtinen M, Paavonen J, Wheeler CM, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against

grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-

blind PATRICIA trial. Lancet Oncol. 2012;13: 89-99.

5. Crowe E, Pandeya N, Brotherton JM, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the

prevention of cervical abnormalities: case-control study nested within a population based screening programme

in Australia. BMJ. 2014;348:g1458.

6. Brotherton J, Saville A, May C, Chappell G, Gertig D. Human papillomavirus vaccination is changing the

epidemiology of high-grade cervical lesions in Australia. Cancer Causes & Control. 2015;26: 953-954.

7. Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination

programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet. 2011;377: 2085-2092.

8. Niccolai LM, Julian PJ, Meek JI, McBride V, Hadler JL, Sosa LE. Declining rates of high-grade cervical

lesions in young women in Connecticut, 2008-2011. Cancer Epidemiol Biomarkers Prev. 2013;22: 1446-1450.

9. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal

cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013;121: 829-846.

10. Drolet M, Benard E, Boily MC, et al. Population-level impact and herd effects following human papillomavirus

vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis. 2015;15:565-580.

11. Castellsague X, Munoz N, Pitisuttithum P, 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. Br J Cancer.

2011;105:28-37.

12. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years

after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8: e68329.

13. Herrero R, Wacholder S, Rodriguez AC, et al. Prevention of persistent human papillomavirus infection by an

HPV16/18 vaccine: a community-based randomized clinical trial in Guanacaste, Costa Rica. Cancer Discov.

2011;1: 408-419.

14. Lang Kuhs KA, Gonzalez P, Rodriguez AC, et al. Reduced prevalence of vulvar HPV16/18 infection among

women who received the HPV16/18 bivalent vaccine: a nested analysis within the Costa Rica Vaccine Trial.

J Infect Dis. 2014;210: 1890-1899.

15. Vichnin M, Bonanni P, Klein NP, et al. An Overview of Quadrivalent Human Papillomavirus Vaccine Safety -

2006 to 2015. Pediatr Infect Dis J. 2015; 34:983–991.

16. Read TR, Hocking JS, Chen MY, Donovan B, Bradshaw CS, Fairley CK. The near disappearance of genital

warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination

programme. Sex Transm Infect. 2011;87:544-547.

17. Ali H, Guy RJ, Wand H, et al. Decline in in-patient treatments of genital warts among young Australians

following the national HPV vaccination program. BMC Infect Dis. 2013;13:140.

18. Bauer HM, Wright G, Chow J. Evidence of human papillomavirus vaccine effectiveness in reducing genital

warts: an analysis of California public family planning administrative claims data, 2007-2010. Am J Public

Health. 2012;102: 833-835.

19. Flagg EW, Schwartz R, Weinstock H. Prevalence of anogenital warts among participants in private health plans

in the United States, 2003-2010: potential impact of human papillomavirus vaccination. Am J Public Health.

2013;103: 1428-1435.

20. Nsouli-Maktabi H, Ludwig SL, Yerubandi UD, Gaydos JC. Incidence of genital warts among U.S. service

members before and after the introduction of the quadrivalent human papillomavirus vaccine. MSMR. 2013;20:

17-20.

21. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young

women following HPV vaccine introduction in the United States, National Health and Nutrition Examination

Surveys, 2003-2010. J Infect Dis. 2013;208: 385-393.

22. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and

disease in males. N Engl J Med. 2011;364:401-411.

23. Goldstone SE, Jessen H, Palefsky JM, et al. Quadrivalent HPV vaccine efficacy against disease related to

vaccine and non-vaccine HPV types in males. Vaccine. 2013;31:3849-3855.

24. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial

neoplasia. N Engl J Med. 2011;365:1576-1585.

25. Ferris D, Samakoses R, Block SL, et al. Long-term study of a quadrivalent human papillomavirus vaccine.

Pediatrics. 2014;134: e657-665.

26. Bogaards JA, Wallinga J, Brakenhoff RH, Meijer CJ, Berkhof J. Direct benefit of vaccinating boys along with

girls against oncogenic human papillomavirus: bayesian evidence synthesis. BMJ. 2015;350: h2016.

27. Elbasha EH, Dasbach EJ. Impact of vaccinating boys and men against HPV in the United States. Vaccine.

2010;28: 6858-6867.

28. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial

neoplasia in women. N Engl J Med. 2015;372:711-723.

29. Van Damme P, Olsson SE, Block S, et al. Immunogenicity and Safety of a 9-Valent HPV Vaccine. Pediatrics.

2015;136:e28-39.

30. Vesikari T, Brodszki N, van Damme P, et al. A Randomized, Double-Blind, Phase III Study of the

Immunogenicity and Safety of a 9-Valent Human Papillomavirus L1 Virus-Like Particle Vaccine (V503)

Versus Gardasil(R)in 9-15-Year-Old Girls. Pediatr Infect Dis J. 2015;34:992–998.

31. Castellsague X, Giuliano AR, Goldstone S, et al. Immunogenicity and safety of the 9-valent HPV vaccine in

men. Vaccine. 2015;33:6892-6901.

32. Kosalaraksa P, Mehlsen J, Vesikari T, et al. An open-label, randomized study of a 9-valent human

papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to

healthy adolescents 11-15 years of age. Pediatr Infect Dis J. 2015;34: 627-634.

33. Schilling A, Parra MM, Gutierrez M, et al. Coadministration of a 9-Valent Human Papillomavirus Vaccine

With Meningococcal and Tdap Vaccines. Pediatrics. 2015;136: e563-572.

34. Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent Human

Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP).

MMWR Recomm Rep. 2007;56:1-24.

35. Recommendations on the use of quadrivalent human papillomavirus vaccine in males--Advisory Committee on

Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60:1705-1708.

36. Cameron RL, Kavanagh K, Pan J, et al. Human Papillomavirus Prevalence and Herd Immunity after

Introduction of Vaccination Program, Scotland, 2009-2013. Emerg Infect Dis. 2016;22:56-64.

37. Herweijer E, Sundstrom K, Ploner A, Uhnoo I, Sparen P, Arnheim-Dahlstrom L. Quadrivalent HPV vaccine

effectiveness against high-grade cervical lesions by age at vaccination: A population-based study. Int J Cancer.

2016;138:2867-2874.

38. International Agency for Research on Cancer HPV Working Group. Primary End-points for Prophylactic HPV

Vaccine Trials. Lyon (FR): International Agency for Research on Cancer(c), 2014.