1 Memo DATE March 25, 2020 TO BA 105W Stu

1
Memo
DATE: March 25, 2020
TO: BA 105W Students
FROM: Deborah Hart
SUBJECT: Screencast presentation assignment
SUMMARY
Students will be graded on their delivery of a simple, narrated
screencast of slides on an
approved topic. The screencast should be
-based, objective, and purposeful.
speaking, wearing business casual attire.
yet professional.
The screencast is worth 80 points, or 8 percent of your final

course grade.
WHAT TO DO
This assignment asks that you to record a narrated slideshow
presentation (MS PowerPoint,
Google Slides, or the equivalent) on an approved topic using a
simple, free screen recorder like
Screencast-o-matic (https://screencast-o-matic.com).
Screen recorders can capture whatever is on your device’s
screen. They can also simultaneously
record audio (using built-in or external microphones) or video
(using a device’s camera or
webcam).
In the narrated screen recording of your slideshow, begin with a
webcam view of you
introducing yourself and your topic. Additional webcam shots
showing you speaking are
optional. For example, you may choose to include video in the
corner of your screen that shows
you narrating throughout the entire video. All webcam shots of
you should include at least your
upper torso and head. For best appearance, choose a neutral,
non-distracting background and use
good, natural lighting behind the camera (facing you). Out of
respect for your audience (and

yourself), please wear business casual attire in the webcam
view, at least from the waist up.
Throughout the screencast, use a simple, natural spoken style to
present each slide. Do not
simply read every slide title and bullet word-for-word. You may
follow a script that you prepare,
but try to sound like you’re speaking extemporaneously or
conversationally rather than reading.
Limit your presentation length to four to six minutes and your
completed media file to less than
500 MB. To submit, upload to Canvas assignment.
https://screencast-o-matic.com/
2
The following definitions may help you reflect on this
assignment:
ing to inform; providing or disclosing
information; instructive.
-based: Relies on accurate data from credible sources.

manipulation through use of skewed
visuals or coverage.
eful: Having a clear goal; answering the audience’s
unspoken question, “Why do I
need to know this?”
presentation, usually without reading
word-for-word. For this assignment, make your script sound
natural, conversational.
using language appropriate
for business contexts (think “Ted talk”).
Your completed screencast video will be uploaded to the Canvas
assignment and shared with
peer reviewers.
The topic
Your informative, fact-based, objective presentation should
focus on one of the three speech
topics introduced below. Unacceptable approaches to the
assignment that will result in a failing
grade include
argumentative speech (often about a political,
social, or ethical issue).

e for professional
settings.
even if you record new audio
for it [also violates campus policy on cheating and plagiarism.]
HOW TO PREPARE
Organizing the presentation
Your presentation should begin with an introduction that gains
attention and previews the topic;
continue with a body that describes the research findings; and
end with a conclusion that
summarizes key points and offers a “takeaway” (followed by
recommendation(s), if any).
A good beginning “hooks” the audience. Include a title
visual/slide with your name. Follow
with a preview of topics to be covered.
Your data, covering no more than three key points, should
follow in a logical order. After the
two introductory slides, use as many slides as you need for the
body of your presentation. A
presentation seven minutes long or less usually needs less than
10 slides total. You should plan

things to say in transition from one point to the next.
For your conclusion, briefly summarize what you’ve discussed.
Good presentations come to an
obvious end (the audience knows you’re done) without the tags
“that’s all” or “the end.”
3
Selecting content
The best screencasts remained focused on the topic at hand.
Avoid tangents or anecdotal
interruptions. However, in addition to providing facts about
your topic, you can use humor,
questions, and stories to increase listener interest (such as by
gaining attention in the
introduction) and/or illustrate points. Especially with humor, be
careful to not to offend or
distract the audience.
Writing a script
Screencast narrators usually follow a script. However, your
reading of the script needs to sound
like conversational but professional spoken language. Avoid
adopting an obvious “reading

aloud” style. If reading a script makes you sound boring or
static, consider following an outline
and talking through your subtopics in a more extemporaneous
style without saying, “um” or
inserting other speech fillers (“like, you know). Script or no,
you should practice the entire
presentation aloud several times before recording. Be prepared
to do multiple takes if necessary.
Although the free version of Screencast-o-matic only allows you
to cut (edit) the beginning or
end of your recording, you will be able to complete an
appropriate screencast with this tool.
Designing graphics
Good visuals supplement/support presentations only. For some
tips on presentations and slides,
see “The 10/20/30 Rule of Powerpoint” in Chapter 14 of your
textbook. Some hints include (1)
limiting the number of words per slide; (2) choosing simple,
pleasing color schemes; (3) using
graphics like charts or pictures where appropriate. One short
video clip of 30 seconds or less in
length may be used to help illustrate a point. Additional
materials, such as handouts, are allowed
and can be used effectively.

ASSESSMENT
Presentations are assessed using the following categories:
organization, content, nonverbal skills,
voice, and use of visual aids. The instructor rubric and student
feedback sheet are posted on
Canvas. Note that you will lose points in the rubric is your
presentation is less than four minutes
or more than six minutes in duration.
4
WHAT TO PRESENT
Choose from the following options for your screencast topic. At
least one week before the
screencast’s due date, notify the instructor on Google
Classroom about the topic you’re going
to cover.
Your screencast should be informative. As noted above,
argumentative speeches (usually for or
against a political, social, or ethical issue), or presentations
based primarily on personal opinion

or religious belief, or a biased presentation concerned with
marketing or selling a product, or
presentations using language or graphics inappropriate for
professional settings, are not
acceptable for this assignment.
OPTION A: An instructional video
Prepare a screencast instructing your audience in how to
perform a complex task or complete a
project. Completion of this task or project should require taking
multiple steps in order. Include
adequate explanation and/or illustrations of each step. You
should also consider using verbs in
the imperative mood
(https://grammar.collinsdictionary.com/us/easy-learning/the-
imperative) in
your slides to emphasize the action to be taken in each step.
OPTION B: Your formal, written report topic
Share with your classmates the results of your research on the
report topic assigned. Your
presentation must include a summary of the report’s findings,
its conclusions, and any
recommendations. Given our time constraints, you may only be
able to cover a portion of your

written report’s content.
Since you’re the one who conducted the research, you may
consider yourself a kind-of expert,
called in to explain your research to a group of interested
people. Note: Since your audience
already knows why the report was written, you don’t need to
cover this information (its problem
and scope) in the presentation.
OPTION C: Propose your own informative presentation topic
To select Option C, you must propose an alternate topic (e. g. a
project, an interest, an area of
skill) on Google Classroom and attach an outline of the
presentation on that topic one week
in advance of your assignment due date. Choose any topic about
which you want to inform your
audience. Preferably, it should be a topic of some interest to
you. For example, you could
provide information on a class project you have completed, a
job you’ve held, or on an area of
interest (such as a hobby or a skill). As with Option A and B
above, support your presentation
with appropriate visuals.
https://grammar.collinsdictionary.com/us/easy-learning/the-
imperative

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.
2
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

3
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)
4
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):

6
Articles included for key
question 2:
6
question 1:
17
question 3:
6
question 2 (males):
43
question 1
(late vaccination of females):
124

question 2:
6
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
5
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
6
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
7
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)
cervical/extra genital disease
associated with HPV
6/11/16/18
-related
CIN, AIS, or cervical CA
CA, or vaginal CA
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
AIS
- 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.
8
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
-grade
abnormality or abnormal
cytology not confirmed by
histology, n=10,887)
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.
9
Important Outcomes: Persistent HPV Infection and Genital
Warts
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
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;
NCT00128661)

RCT (Glaxo
Smith Kline
sponsored;
NCT00128661)
n=7,466, Females
aged 18-25
Costa Rica, 2004-
2005
n=7,466, Females
aged 18-25
Costa Rica, 2004-
2009
Bivalent
Bivalent
Persistent oncogenic HPV

infection
Oral and cervical HPV
infection (not age-
stratified)
VE decreased by age in both per-protocol and
ITT analysis. In ITT VE for females
vaccinated at 18-19 was 68.9% and for
females vaccinated at 24-25 was 21.8%.
VE against oral HPV 16/18 infections was
93.3%; VE against cervical infections was
72.0% (not age-stratified)
Lang Kuhs
et al. 201414
RCT
(Glaxo Smith

Kline-
sponsored;
NCT00128661)
1,044, F, 18-25,
Costa Rica, 2004-
2009
Bivalent 1-time detection vulvar &
cervical HPV 16/18
infection
In ITT, VE for vulvar infection was 54.1%;
cervical infection VE of 45.8%.
Drolet et al.
201510
Systematic
review and
meta-analysis
of ecological

studies
20 studies, 140
million person-years
follow-up, Females,
International (9 high-
income countries),
2007-2014
Quadrivalent
and bivalent
16/18 (7 studies)
-grade cervical
lesions (2 studies)—see
above
Prevalence of HPV 16/18 decreased 64% in
females aged 13-19 and 31% in females aged
20-24. GW decreased 31% in females aged
15-19 and 11% in females aged 20-39.

10
Read et al.
201116
and Males aged 12-
26, attending sexual
health center
Melbourne Australia,
2004-2011
(only females had
been vaccinated)
Quadrivalent Diagnosis of GW From 2007/08 - 2010/11, in
females aged
<21, GW declined from 18.6% to 1.9%; in
females aged 21-29, GW declined 10.8% to
3.7%; no significant change in females ≥30.

Note: vaccination rates of females aged 20-26
years (3 doses, 42%) was about half that of
females aged 12-13 (3 doses, 73%).
Ali et al.
201317
and Males aged 12-
26 attending sexual
health center,
Australia, 2004-2011
Quadrivalent Inpatient treatment of GW In females aged 15-24,
the number of GW
treatments declined by 85.3% from 2007 to
2011. No significant trend in pre-vaccine
period. In females aged 25-34, number of
GW treatments declined 33%.
No significant trend for women aged 35-44.

Bauer et al.
201218
Females aged 11-26,
California, 2007-
2010
Quadrivalent
and bivalent
GW incidence
In females aged <21, GW diagnoses declined
by 34.8% between 2007-2010. In females
aged 21-25 GW diagnoses declined 10.0%.
Among females aged 26-30 GW diagnoses
increased by 10.1%.
Flagg et al.
201319
Ecological n >13,000,000,

Females and Males
aged 10-39, United
States (Private
Insurance), 2003-
2010
Quadrivalent
and bivalent
GW prevalence In females aged 10-14, GW remained stable
at 0.2-0.3 per 1000 person-years pre- and
post-introduction of vaccination. In females
aged 15-19, GW decreased from 2.9 to 1.8. In
females aged 20-24, GW declined from 5.5 to
4.8. In females aged 25-29 GW declined from
4.1 to 3.7.
Nsouli-Maktabi
et al. 201320
Females and Males,

17-50+ (U.S. Military
encounters), 2000-
2012
Quadrivalent GW incidence From 2006-2012, in females aged
<21, GW
incident diagnoses decreased 40%, from 3576
per 100,000 person-years to 2143. In females
aged 21-24, GW incident diagnoses decreased
25%, from 2700 to 2027. In females 25-29,
GW diagnoses remained stable through 2010,
followed by a slight increase up to 2012.
11
Markowitz et
al. 201321
Ecological n= 8,403, Females
aged 14-59, U.S.,
2003-2010

Quadrivalent HPV prevalence In females aged 14–19, vaccine-
type HPV
prevalence decreased 56%,
from 11.5% in 2003–2006 to 5.1% in 2007–
2010. In females aged 20-24, prevalence
increased from 18.5% to 19.9%. In females
aged 25-29, prevalence increased from 11.8%
to 13.1%.
AIS-Adenocarcinoma in situ; CA-cancer; CIN-cervical
intraepithelial neoplasia; GW-genital warts; HPV-human
papillomavirus; ITT-intention
to treat; OR-odds ratio; PP-per protocol; RCT-randomized
controlled trial; VaIN-vaginal intraepithelial neoplasia; VE-
vaccine efficacy; VIN-
vulvar intraepithelial neoplasia.
12
Efficacy in Males
Six studies investigating HPV vaccine efficacy in males were
included in the review.

(Table 3) Three studies were based on 1 international RCT,
with endpoints including anal
intraepithelial neoplasia (AIN), penile intraepithelial neoplasia
(PIN), external genital lesions,
persistent HPV infections, immunogenicity, and adverse
events.22-24 Another RCT25 reported the
important outcome of HPV infection as well as immunogenicity,
and two mathematical
modeling studies predicted disease outcomes.26, 27 Males
included in these studies were aged 9-
26 years at the time of vaccination. The RCTs provide evidence
of vaccine efficacy in
heterosexual and homosexual males; potential impact of male
vaccination on disease outcomes is
further elucidated by results of mathematical models.
Palefsy et al24 reported that vaccine efficacy for AIN
associated with HPV 6/11/16/18 in
men who have sex with men (MSM) was 50.3% in the intention
to treat population (ITT) and
77.5% in the per protocol population.24 Similarly, Goldstone et
al23 reported 50.3% vaccine
efficacy against HPV 6/11/16/18-related AIN in the MSM ITT
population and 89.6% in the per
protocol population.23 Guiliano et al22 reported vaccine

efficacy of 60.2% for all external genital
lesions, and 65.5% for lesions related to HPV 6/11/16/18 in the
ITT population. For persistent
infection related to HPV 6/11/16/18, the observed efficacy was
47.8% in the ITT population and
85.6% in the per protocol population.22 No vaccine-related
serious adverse events were reported,
and non-serious adverse events were similar to the placebo
group as well as to findings from
studies of female vaccination.22, 24
Two mathematical models addressing critical outcomes
associated with HPV vaccination
concluded that there is an incremental reduction in HPV
infections, genital warts, CIN2/3,
cancer, and cancer death when vaccinating boys.26, 27
Vaccination of girls has indirect effects in
reducing HPV prevalence in heterosexual males.26 However, in
their analyses, Bogaards et al26
found that a vaccine coverage rate of 90% in girls would be
needed to produce substantive
reduction (66%) in the burden of HPV-related cancers in men.
At the current level of 60%
vaccine uptake of girls in the Netherlands, they estimated a 37%
reduction in HPV-associated

cancers in heterosexual men.26
13
Table 3: Efficacy in Males
Critical Outcomes
Summary of Findings
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
vaccine-type PIN 1,
2-3
perineal cancer
– 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
-
related AIN or anal
cancer
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
-
related PIN
l
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%.
14
Elbasha and
Dasbach, 201027
Mathematical
model
Males aged 9-26,
U.S.

-type GW
papillomatosis
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
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
-term anti-HPV
6/11/16/18
serological levels.
-
related persistent
infection or disease
Immunogenicity in males was similar
to females.
Incidence of HPV infection or disease
was similar in males and females.
15
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
vaccine-type GW
vaccine-type
persistent infection
-3

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
idence of
vaccine-type
persistent anal
infection

—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

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

16
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
17
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 trial
Protocol 019;
NCT 00090220)
n=1106 HSM,
n=1101 Females,
n=313 MSM, aged
16-26,
International (17
countries), 2012-
2014
9-valent
response
Injection-site,
Systemic

GMTs for HSM were higher than in
females. Responses in MSM were 11%-
30% lower than in females and 25%-41%
lower than in HSM (similar to findings
with quadrivalent vaccine). Seroconversion
was 99.4%-100% for all 9 HPV types in
HSM, MSM, and females.
Adverse events were similar as for
quadrivalent vaccine and fewer in males
than in females.
There were no vaccine-related SAEs.
SAEs regardless of cause occurred in 2.4%
of females and 1.6% of males.
Joura et al.
201528
RCT
(Merck
sponsored trial

NCT00543543)
n=14,215,
Females aged 16-
26, International,
2011 with 4 years
follow up
Quadrivalent
and 9-valent
vulvar, vaginal
lesions
Injection-site,
Systemic
outcomes
Rate of high-grade (HG) cervical, vulvar or
vaginal disease overall for per protocol

population HPV: uninfected on day 1 of
0.1 per 1000 person-years in the 9-valent
group and 1.6 in the quadrivalent group.
Risk of HG cervical, vulvar, and vaginal
disease in ITT for HPV: uninfected
2.4/1000 for 9-valent and 4.2/1000 for
quadrivalent. VE against HG disease
caused by additional 5 vaccine types was
96.7% in per-protocol population. VE
against HG disease caused by HPV
6/11/16/18 was similar to quadrivalent
vaccine.
Injection-site and systemic AEs were
slightly more likely for 9-valent.
There were 2 vaccine-related SAEs in each
group (<0.1%).
18

There were no vaccine-related deaths in
either group.
Proportions of participants with live births,
difficulty of delivery, spontaneous abortion
and late fetal deaths were similar for 9-
valent and quadrivalent vaccines (1192
participants in 9vHPV and 1129 in
quadrivalent HPV groups).
Kosalaraksa et
al. 201532
RCT n=1054, Males
and Females aged
11-15,
International (6
countries), 2010-
2011
9- -conversion
for concomitant

administration
with Tdap and
Poliomyelitis
Injection-site,
Systemic
Non-inferiority of anti-HPV GMTs and
sero-conversion rates for all 9-valent
antigens when given concomitantly with
Diphtheria, Tetanus, Pertussis and
Poliomyelitis vaccines.
>99.8% seroconversion for all HPV types.
Injection-site and systemic AEs were
slightly more likely for concomitant
injections.
There were no vaccine-related SAEs.

Schilling et al.
201533
RCT
(Merck
sponsored
Protocol
V503-005;
NCT00988884)
n=1241, Males
and Females aged
11-15,
International (5
countries), 2009-
2011
9- -conversion
for concomitant
administration
with Tdap and
Menactra

Injection-site,
Systemic
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
response
Injection-site,
Systemic
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.
19
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
response
Injection-site,
Systemic
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.
20
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,
37
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

21
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.
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.

22
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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.
23

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.
24
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.

Human Papillomavirus Vaccination Guideline Update: American
Cancer Society Guideline Endorsement
Debbie Saslow, PhD1, Kimberly S. Andrews, BA2, Deana
Manassaram-Baptiste, PhD3,
Lacey Loomer, MSPH4, Kristina E. Lam, MD, MPH5, Marcie
Fisher-Borne, MPH, PhD6,
Robert A. Smith, PhD7, and Elizabeth T. H. Fontham, MPH,
DrPh8 on behalf of the American
Cancer Society Guideline Development Group
1Director, Cancer Control Intervention, Human Papillomavirus
and Women’s Cancers, American
Cancer Society, Atlanta, GA
2Director, Guideline Process, American Cancer Society,
Atlanta, GA
3Director, Guideline Process, American Cancer Society,
Atlanta, GA
4Graduate Student, Emory University Rollins School of Public
Health, Atlanta, GA
5Medical Epidemiologist, Georgia Department of Public Health,
Atlanta, GA
6Program Director, Human Papillomavirus Vaccination,
American Cancer Society, Atlanta, GA
7Vice President, Cancer Screening, American Cancer Society,
Atlanta, GA

8Founding Dean and Professor Emeritus, Louisiana State
University School of Public Health, New
Orleans, LA
Abstract
The American Cancer Society (ACS) reviewed and updated its
guideline on human papillomavirus
(HPV) vaccination based on a methodologic and content review
of the Advisory Committee on
Immunization Practices (ACIP) HPV vaccination
recommendations. A literature review was
performed to supplement the evidence considered by the ACIP
and to address new vaccine
formulations and recommendations as well as new data on
population outcomes since publication
of the 2007 ACS guideline. The ACS Guideline Development
Group determined that the evidence
Corresponding author: Debbie Saslow, PhD, Cancer Control
Department, American Cancer Society, 250 Williams St, Suite
600,
Atlanta, GA 30303; [email protected]
Additional supporting information may be found in the online
version of this article.
DISCLOSURES: The American Cancer Society (ACS)
supported the development of the guideline through the use of
general funds.
Outside the submitted work, the ACS is the recipient of 2

cooperative agreements from the Centers for Disease Control
and Prevention
(CDC), Prevention and Public Health Fund, that seek to increase
human papillomavirus (HPV) vaccination of girls and boys ages
11
to 12 years within the United States. Debbie Saslow reports
being Principal Investigator of both of those cooperative
agreements, and
Marcie Fisher-Borne reports being co-Principal Investigator and
receiving salary support through one of those cooperative
agreements.
All remaining authors report no conflicts of interest.
Author Contributions: Debbie Saslow: Conceptualization,
methodology, validation, formal analysis, investigation,
resources,
writing–original draft, writing–review and editing,
visualization, and project administration. Kimberly S. Andrews:
Methodology,
writing–original draft, writing–review and editing, and project
administration. Deana Manassaram-Baptiste: Investigation,
writing–
original draft, and writing–review and editing. Lacey Loomer:
Formal analysis and writing–review and editing. Kristina E.
Lam:
Investigation and writing–review and editing. Marcie Fisher-
Borne: Writing–review and editing. Robert A. Smith: Writing–
review
and editing, visualization, supervision, and project
administration. Elizabeth T. H. Fontham: Conceptualization,
validation, writing–
review and editing, and project administration.
HHS Public Access
Author manuscript
CA Cancer J Clin. Author manuscript; available in PMC 2017

August 14.
Published in final edited form as:
CA Cancer J Clin. 2016 September ; 66(5): 375–385.
doi:10.3322/caac.21355.
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supports ACS endorsement of the ACIP recommendations, with
one qualifying statement related
to late vaccination. The ACS recommends vaccination of all
children at ages 11 and 12 years to
protect against HPV infections that lead to several cancers and
precancers. Late vaccination for

those not vaccinated at the recommended ages should be
completed as soon as possible, and
individuals should be informed that vaccination may not be
effective at older ages.
Keywords
American Cancer Society; Advisory Committee on
Immunization Practices; guideline; human
papillomavirus (HPV); vaccine; cancer prevention
Introduction
The burden of human papillomavirus (HPV)-related diseases, an
understanding of the
association of HPV infection with several cancer types, and the
availability of vaccines
together present an unprecedented opportunity for cancer
prevention. Saraiya et al1
performed a recent study in which archival tissue from patients
with cancer in 7 population-
based cancer registries was tested for the presence of high-risk
HPV types. HPV infection
was associated with 91% of cervical cancers, 69% of vulvar
cancers, 75% of vaginal
cancers, 63% of penile cancers, 89% of anal cancers in males,
93% of anal cancers in

females, and 72% of oropharyngeal cancers in males and 63% of
oropharyngeal cancers in
females.1 The Centers for Disease Control and Prevention
(CDC) applied these proportions
to the most recently available registry data on HPV-associated
cancers to estimate the
number of cancers caused by HPV. They estimated that around
30,700 cancers (based on
2008–2012 data) probably attributable to HPV are diagnosed in
the United States each year:
19,200 in women and 11,600 in men.2 The incidence rates of
several of these cancers are
increasing, with striking socioeconomic disparities for several
HPV-associated cancers
among both men and women.3
Three HPV vaccines (the Cervarix [GlaxoSmithKline, London,
UK] bivalent vaccine
[2vHPV] and the Gardasil [Merck & Company, Kenilworth, NJ]
quadrivalent [4vHPV] and
9-valent [9vHPV] vaccines) are licensed in the United States
and around the world (Table
1).4–9 These vaccines protect against the HPV types that are
responsible for most cases of
HPV-associated cancers; the 4vHPV and 9vHPV vaccines also

protect against nearly all
cases of genital warts. The CDC, the American Cancer Society
(ACS), and many provider
groups recommend giving the 3-dose series of the HPV vaccine
to children at ages 11 to 12
years (Table 1).4–9
2007 ACS Guideline for HPV Vaccine Use
The ACS first published a guideline for the use of prophylactic
HPV vaccines for the
prevention of cervical intraepithelial neoplasia (CIN) and
cervical cancer in 2007,10
recommending routine vaccination for females ages 11 to 12
years (with vaccination
permitted in children as young as 9 years) and vaccination for
females ages 13 to 18 years to
catch up on a missed vaccine or to complete the vaccination
series. The ACS concluded that
there were insufficient data to recommend for or against routine
universal vaccination of
Saslow et al. Page 2
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females ages 19 to 26 years; instead, the ACS recommended
informed decision making for
vaccination in this population.10
The 2007 ACS guideline has been important in making clear the
significance of the HPV
vaccine as a cancer-prevention intervention. However, since
publication of the guideline,
there have been additional studies, new vaccine formulations
licensed for use in the United
States, and new immunization recommendati ons.5–9 The 2007

ACS guideline does not
address use of the vaccine in males or use of the most recently
available 9-valent vaccine
formulation; nor does it reflect recent evidence on the
effectiveness of late vaccination, eg, at
ages 19 to 26 years.
The ACS Consideration of Endorsement of Recommendations of
the
Advisory Committee on Immunization Practices
The recommendations for vaccines developed by the Advisory
Committee on Immunization
Practices (ACIP) serve as the principal source of guidance on
US immunization policy; the
ACS has been represented on the ACIP HPV Vaccine Work
Group since 2005. The ACIP
recommendations for HPV vaccination, as for other vaccines in
children and adolescents, are
harmonized with recommendations made by the American
Academy of Pediatrics, the
American Academy of Family Physicians, and the American
College of Obstetricians and
Gynecologists. Recognizing the need to update the ACS HPV
vaccine use guideline and the

value in consistency across organizations in HPV immunization
efforts as a primary cancer-
prevention strategy, the ACS chose to consider endorsement of
the HPV vaccine
recommendations of the ACIP.
HPV vaccination protects against infection with the targeted
HPV types and subsequent
related disease; however, it does not protect against disease
resulting from previous exposure
to these HPV types. The 2007 ACS guideline and the ACIP
recommendations from 2006
through 2015 were primarily based on randomized controlled
trial (RCT) evidence of
vaccine efficacy, ie, the percentage reduction in disease
incidence in a vaccinated group
compared with the incidence in an unvaccinated control group
under optimal conditions, and
noninferior immunogenicity findings in females and males ages
9 to 15 years.4–9 Thus, it is
also important to consider observational data, such as results
from ecological studies
measuring vaccine effectiveness, ie, reduction in disease
outcomes in a “real-world” setting.
This is especially relevant when evaluating recommendations

for vaccination among older
females and males, who are more likely to have been sexually
active and thus more likely to
have had previous HPV exposure. Hence, the association
between vaccine effectiveness and
age and the implications for late vaccination recommendations
were a major focus of this
update.
ACIP Recommendations
The ACIP and the CDC first issued recommendations for
routine HPV vaccination of
females ages 11 to 12 years and catch-up vaccination for
females ages 13 to 26 years with
the quadrivalent HPV (4vHPV) vaccine in 2006.4 An ACIP
work group reviewed published
and unpublished clinical trial data on vaccine efficacy against
persistent HPV infections,
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cervical disease, and external genital warts; immunogenicity;
and safety and adverse events.
Data on the epidemiology and natural history of HPV, vaccine
acceptability, and cost
effectiveness were also considered. The recommendation for
catch-up vaccination of
females who were not previously vaccinated was based in part
on a review of data from
efficacy clinical trials that included females ages 16 to 23 years
or 16 to 26 years and the
recognition that, when HPV vaccination was first introduced,
females older than 12 years

would not have had the opportunity to receive the vaccine. The
ACIP report noted that
overall vaccine effectiveness would be lower in a population of
females who are sexually
active; thus, effectiveness would decrease with increasing age,
increasing number of sexual
partners, and greater likelihood of HPV exposure. They
concluded, however, that the
majority of females in this age group would derive at least
partial benefit from vaccination.4
In 2009, the ACIP updated its recommendation for females to
include use of the bivalent
(2vHPV) vaccine and provided guidance that 4vHPV may be
given to males ages 9 through
26 years.5,6 The ACIP recommended routine vaccination of
males in 2011 based on a review
of data on vaccine efficacy against anal cancer precursors and
genital warts, vaccine safety,
disease burden, cost effectiveness, and programmatic
considerations.7 For the
recommendations on male vaccination, the ACIP adopted the
Grading of Recommendation
Assessment Development and Evaluation (GRADE)
methodology to evaluate evidence and

develop recommendations.11 Routine vaccination of males ages
11 or 12 years was a
category A recommendation, indicating that it applies to all
persons in an age or risk-based
group. Vaccination was also recommended for males ages 13 to
21 years who have not been
vaccinated previously or who have not completed the 3-dose
series. The ACIP stated that
“males ages 22 through 26 years may be vaccinated.”7
In 2015, the ACIP updated their recommendations to include the
9-valent vaccine (9vHPV)
based on data from 9vHPV prelicensure clinical trials as well as
efficacy trials from the
4vHPV vaccine program.9 The noninferior immunogenicity of
9vHPV compared with
4vHPV and in males compared with females was used to
conclude its efficacy for HPV type
6 (HPV6), HPV11, HPV16, and HPV18. The safety of 9vHPV
was evaluated based on 6
phase 3 studies in the clinical development program. All data
came from RCTs conducted
by the vaccine manufacturer.9
The current ACIP recommendations also address special
populations, including men who

have sex with men; persons who are immunocompromised
because of transplantation,
medications, or human immunodeficiency virus (HIV); and
children with a history of sexual
assault or abuse.8,9
Methods: ACS Guideline Endorsement
The ACS instituted a Guideline Development Group (GDG) (a
volunteer group of clinicians,
methodologists, and public health practitioners) in 2012.12 To
update the ACS
recommendations for HPV vaccination, a guideline endorsement
process was implemented
similar to the American Society of Clinical Oncology (ASCO)
model for endorsing another
organization’s guidelines.13 This model includes a
methodologic review using the Appraisal
of Guidelines for Research and Evaluation II (AGREE II)
instrument,14 a search for new
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evidence published since completio n of a guideline under
consideration, and a content
review.13
Following this approach, the ACS endorsement process for the
HPV vaccine update
included: 1) a methodologic assessment of the ACIP
recommendations, 2) a supplemental
evidence review, 3) a content review of the ACIP
recommendations by the ACS GDG, 4)
development and approval of endorsement statements, 5) a
review of the evidence report and

endorsement paper by expert advisors, and 6) approval of
endorsement statements by the
ACS Board of Directors.
The methodologic assessment of the ACIP recommendations for
HPV vaccination was
completed by 4 ACS guideline staff members working
independently, using the AGREE II
instrument.14 A written summary of this assessment was
provided to the ACS GDG.
A supplemental evidence review was conducted by ACS staff to
identify any new data since
the release of the ACIP recommendations (see online supporting
information). The scope of
the review also included male vaccination and the new vaccine
formulation not covered in
the 2007 ACS guideline, as well as continuing questions about
the effectiveness of
vaccination at older ages. This supplemental evidence review
was designed to address 3 key
questions:
1. Should HPV “catch-up” or “late” vaccination be
recommended for females ages
19 to 26 years who have not been vaccinated previously?

2. Should HPV vaccination be recommended for males ages 9 to
26 years?
and females?
Methodologic details of the evidence review are described in
the online supporting
information. The evidence review report was reviewed by
external advisors with expertise in
epidemiology, HPV, HPV vaccines, cervical cancer screening,
management and treatment,
adolescent health, and gynecology. Reviewer comments,
including those addressing
interpretation of the literature, were incorporated into the final
version.
The ACS GDG performed a content review of the ACIP HPV
vaccination recommendations
(consistent with its prior adoption of GRADE15) to assess: 1)
whether the recommendations
were adequately supported by the evidence, 2) whether there
was confidence in the
magnitude of estimates of effects on important outcomes, and 3)
whether there was a
favorable balance between desirable and undesirable outcomes.
On the basis of the evidence

considered by the ACIP, results of the ACS supplemental
evidence review, and comments
from expert advisors, the GDG voted on whether to endorse the
ACIP recommendations
either as stated or with commentary and qualifying statements
when necessary for
clarification or when the GDG judgments on the evidence and
recommendations differed
from those of the ACIP.
The draft endorsement statements were reviewed by the expert
advisors and submitted with
a draft supplemental evidence review report to the ACS Mission
Outcomes Committee and
Board of Directors for approval.
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ACS Guidelines and Conflicts of Interest
All participants in the guideline development process were
required to submit disclosures of
all financial and nonfinancial (personal, intellectual, and
practice-related) relationships and
activities that might be perceived as posing a conflict of interest
in development of the HPV
vaccination guideline. The chairperson of the ACS GDG had the
responsibility to ensure that
balanced perspectives were taken into account in deliberations
and decision making.
Results of the ACS Methodologic Assessment
The overall score (the average of the 4 reviewers) of the ACIP
recommendations on HPV
vaccination using the AGREE II instrument was 75%. Particular

attention was given to the
Rigour of Development subscale, which is designed to assess
the quality of the processes
used, evidence synthesis, and the methods used to formulate the
guideline recommendation
statements. A slightly lower appraisal rating (69%) was given
on this subscale, although the
reviewers noted that some domains of the AGREE II instrument
may not be suitable for
evaluating a vaccine use guideline.
The conclusion of the methodologic assessment was that,
overall, ACIP recommendations
are well written and presented, with suitable methods of
development. Although extensive
evidence to support the recommendation statements was
presented and evidence tables were
provided for the 2011 and 2015 updates, documentation was not
provided that a systematic
evidence review was performed for any of the ACIP guideline
iterations, and data search
strategies were not clearly described. There also was heavy
reliance on data from RCTs
sponsored by the vaccine manufacturers as well as unpublished
data provided by the

manufacturer. The possible limitations of such data were not
clearly described or
acknowledged in the recommendation statements.
Detailed epidemiologic, efficacy, harms, and vaccine safety
information was presented with
the ACIP recommendations. However, the recommendation
statements did not address the
benefit of specific catch-up ages (eg, ages 21–26 years) for
females or provide a rationale for
the difference in their recommended ages for males (ie, ages
13–21 years) and females (ages
13–26 years). Furthermore, while the ACIP has updated their
recommendations several
times and considered new data on efficacy and immunogenicity
as well as adverse events, it
is not clear what level of consideration was given to
effectiveness data from countries with
high vaccination rates or to evidence on vaccine effectiveness
stratified by age.
Despite the aforementioned limitations, the ACIP
recommendations are evidence based,
with extensive summaries of the epidemiology of HPV and
associated diseases as well as

efficacy and immunogenicity findings for the vaccines
presented. The licensed HPV
vaccines are well described, and extensive updated information
is provided on vaccine safety
from clinical trials and postlicensure studies and monitoring.
ACS Supplemental Evidence Review
In addition to the methodological review, the ACS conducted a
supplemental evidence
review to identify relevant data published since the most recent
ACIP recommendations
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were released as well as relevant data that were not included by
the ACIP. The report on this
evidence review is provided online (see online supporting
information).
A PubMed search updated through October 8, 2015, yielded
4091 articles, of which 338
were potentially relevant based on title; among these, 167 were
selected for full review based
on examination of the abstract and 29 articles were included in
this review. The included
articles address the critical outcomes of HPV vaccine
effectiveness against the development
of precancerous lesions and the important outcomes of HPV
vaccine effectiveness against
genital warts and persistent infection. There were 17 studies on
late vaccination in females
(ages 18–26 years), 6 on males (ages 9–26 years), and 6 that
addressed use of the 9vHPV
vaccine. Given the limited number and size of studies of
efficacy for critical and important

outcomes, the additional outcome of immunogenicity was
considered for 9vHPV. The major
findings of these studies are described in the online supporting
information and summarized
for each key question below.
Although not included in the search terms for this review,
reported adverse events potentially
associated with vaccination were included as outcomes of
interest (see online supporting
information). The CDC and the ACIP sponsor an extensive,
ongoing surveillance and safety
monitoring program related to vaccination, and updated results
are publicly reported.16 The
CDC and ACIP regularly monitor postlicensure safety data
through several systems in the
United States as well as reports from other countries. Studies
from the United States and
Europe, for example, have shown no causal association of HPV
vaccination and autoimmune
disease, stroke, Guillain-Barre syndrome, venous
thromboembolism, seizures, connective
tissue disorders, or allergic disorders.16 The World Health
Organization also monitors

vaccine safety through its Global Advisory Committee on
Vaccine Safety, which has
published 6 reports on HPV vaccines, with the most recent
report released in December
2015.17 Adverse events associated with the vaccination of
males and with the 9vHPV
vaccine were included when they were reported as outcomes in
the studies included in the
current supplemental review.
Results of the ACS Supplemental Evidence Review
1. Should HPV “late” vaccination be recommended for females
ages 19 to 26
years who have not been vaccinated previously?—Although, in
general, the data
show efficacy across all age groups included in the RCTs, there
is consistency in the
findings from RCTs and observational studies that vaccine
effectiveness is highest in
preteens and early teens, lower in middle to late teen age
groups, and lowest in young adult
age groups (ie, ages 20 years and older) (see online supporting
information). Results from a
pooled analysis of 3 RCTs showed that estimates of benefits
against high-grade cervical
lesions are substantially reduced when vaccination occurs after

age 21 years compared with
vaccination before age 19 years.18 The results from
observational data (3 ecological studies
and 1 case-control study using linked data) provide additional
evidence of reduced
vaccination effectiveness at older ages, with greater decline in
high-grade cervical lesions
among females younger than 19 years after the introduction of
vaccination compared with
older age groups.19–22
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Estimates of the effectiveness of HPV vaccine by age must be
regarded with caution. Most
ecological studies did not specifically measure age at
vaccination. The majority of these
studies examined population outcomes after the introduction of
vaccination and were not
based on linked vaccination and screening data. Conclusions
from the included
observational studies are also limited by the time-frame since
vaccine introduction and
adoption.
2. Should HPV vaccination be recommended for males ages 9 to
26 years?—
The manufacturer-sponsored RCTs have demonstrated vaccine
efficacy, high levels of
immunogenicity, and safety in males comparable to those in
females. The evaluations of
cancer precursor outcomes are limited by a small number of
cases, particularly in
heterosexual males.23,24 Vaccine efficacy for the important

outcomes of persistent infection
and genital warts was demonstrated in all men included in the
RCTs, and efficacy against
anal intraepithelial neoplasia was demonstrated in men who
have sex with men. Modeling
studies also suggest reductions in critical and important
outcomes and in HPV-associated
cancer cases and deaths.25,26 None of the studies reported
outcomes stratified by age at
vaccination.
3. Should 9vHPV vaccination be recommended for males and
females?—The
available data on the 9vHPV vaccine are limited but show
efficacy, immunogenicity, and
safety comparable to those demonstrated for the quadrivalent
vaccine.
Although several RCTs reported on antibody response and
seroconversion rates of the
9vHPV vaccine formulation,27–31 only one reported data on
our critical and important
outcomes.32 On the basis of an RCT with 4 years of follow-up,
Joura et al found similar
protection against cervical, vulvar, and vaginal lesions caused
by the HPV types included in

the 4vHPV vaccine and a lower overall rate of high-grade
lesions in the 9vHPV group
compared with the 4vHPV group.32
Given the limited direct evidence of efficacy of the recently
approved 9vHPV vaccine
formulation against disease outcomes, data on the endpoints of
immunogenicity and
noninferiority have been included, consistent with international
recommendations on the use
of surrogate trial endpoints.33 Three RCTs found that the
antibody response of the 9vHPV
vaccine for HPV6, HPV11, HPV16, and HPV18 was noninferior
to that of the 4vHPV
vaccine, and both had similar safety profiles.30–32
ACS Content Review
The GDG conducted a content review of the ACIP HPV vaccine
use recommendations as
part of the ACS endorsement process. The objective of the
content review was to assess the
specific recommendations made and the extent to which the
available evidence supports
each recommendation.
In the evaluation of the content and evidence presented in the

ACIP recommendations, the
GDG members considered these questions:
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• Were the results of the studies supporting these
recommendations interpreted and
applied according to the GDG’s judgements about the data?
• Is the evidence presented in support of each recommendation

sufficient?
• Are the recommendations in the guideline clear, and will they
be easily
understood by the intended audience?
• Is there agreement with the judgement of the balance of
benefits and harms
reflected in the recommendations, and is there confidence in the
estimates of
effects?
• Do the recommendations adequately take into consideration
patient values and
preferences?
Upon completion of the content review, the GDG selected
among options of full
endorsement, endorsement with qualifying statements or
exceptions, or rejection for each
ACIP recommendation (Table 2). The GDG determined that the
benefits of HPV vaccination
for prevention of cancer incidence, mortality, and morbidity in
both males and females
outweigh the limited, predominantly nonserious side effects.
The available evidence strongly
supports an update to the ACS recommendation for HPV
vaccination related to the
vaccination of males and the use of the 9vHPV vaccine

formulation. The benefits are
reduced at older ages at vaccination, supporting the
recommendation for routine vaccination
at ages 11 to 12 years or as soon thereafter as possible.
Providers should inform individuals
aged 22 to 26 years who have not been previously vaccinated or
who have not completed the
series that vaccination at older ages is less effective in lowering
cancer risk.
The ACS Mission Outcomes Committee and Board of Directors
then approved the
endorsement and ACS guideline update as recommended by the
GDG.
Discussion
Since release of the 2007 ACS guideline for HPV vaccine use to
prevent cervical cancer and
its precursors,10 additional evidence has accumulated, and new
immunization
recommendations addressing additional populations and new
vaccine formulations have
been issued. The ACS conducted a supplemental evidence
review and a methodologic
assessment and content review of the current ACIP
recommendations.4–9 This update of the

ACS guideline addresses changes since 2007 and endorses
current ACIP recommendations
for HPV vaccination, with the addition of one qualifying
statement about decreased
effectiveness of the vaccine in persons ages 22 years and older.
The original recommendations for routine vaccination at age 11
or 12 years were based on
considerations of immunogenicity in this age group, including
higher antibody titers
compared with older age groups; data on age of initiation of
sexual activity; and, for
programmatic purposes, the established young adolescent health
care visit at age 11 or 12
years.4,10 This review did not revisit the age for routine
vaccination (ie, at ages 11–12 years).
This update and endorsement process focused on 3 key
questions. The 2007 ACS guideline
agreed with the recommendations of the ACIP and other
organizations in recommending
August 14.
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routine vaccination for females ages 11 to 12 years and catch-up
vaccination for females
ages 13 to 18 years but it differed in recommending informed
decision making rather than
routine vaccination for females ages 19 to 26 years. There was a
lack of efficacy data for the
prevention of HPV16/HPV18–related CIN2 or CIN3 in women
who have had more than 4
lifetime sexual partners because of inclusion criteria for the
clinical trials. National survey

data showed that half of females over age 19 years had 4 or
more lifetime sexual partners.34
The ACS therefore selected a cutoff of age 18 years and
recommended an informed
discussion between a woman and her health care provider
regarding her risk of previous
HPV exposure and potential benefit from vaccination for women
ages 19 to 26 years. An
additional consideration supporting this cutoff was that the
federally funded Vaccines for
Children program provides free vaccination for uninsured and
underinsured children,
covering approximately one-half of the US population, through
age 18 years.35
There is consistency in findings from the RCTs of greater
efficacy among the per-protocol
group (no evidence of current or past infection) compared with
the intention-to-treat group
(see online supporting information). The evidence for vaccine
efficacy in preventing
precancerous lesions is based primarily on data from RCTs that
included women ages 15 to
26 years who had a limited number of lifetime sexual partners.
Ecological studies examining

trends in disease outcomes since the introduction of vaccination
show either significantly
reduced effectiveness or no effectiveness in older age
groups.20–22 These findings suggest
that the “real-world” effectiveness of HPV vaccination in
women (and men) older than age
21 years is likely to be lower than that in younger populations.
Two studies that were published after the completion of our
supplemental evidence review
provide individual-level data on outcomes by age. By using
linkage data from Scotland
measuring HPV prevalence in a population of women who had
been eligible for the catch-up
vaccination program and who presented for their first screening
at age 20 or 21 years,
Cameron et al36 reported that the odds of testing positive for
HPV16 or HPV18 were 7.7%
for women who were vaccinated at age 15 or 16 years, 12.5%
for those vaccinated at age 17
years, 16.6% for those vaccinated at age 18 years, and 30.3%
for those vaccinated at ages 19
to 21 years, with an odds ratio of 5.31 when the age at
vaccination was from 19 to 21 years
compared with 15 to 16 years.36 In a nationwide study that

included the entire female
population of Sweden ages 13 to 29 years,37 Herweijer et al
used national register-based
data to measure the effectiveness of HPV vaccination stratified
by age at vaccination. In
their study, vaccine effectiveness against CIN2 or greater was
75% for individuals who were
vaccinated before age 17 years, 46% for those vaccinated at
ages 17 to 19 years, and 22%
for those vaccinated at age 20 years or older. When the results
were restricted to individuals
in the organized cervical screening program (ie, women ages
23–29 years who had recently
been screened), the authors found a strong protective effect of
vaccination for women who
were vaccinated before age 20 years and a much smaller level of
protection that was not
statistically significant for those vaccinated at age 20 years or
older.37
Although some women (and, by inference, men) ages 22 to 26
years will benefit from HPV
vaccination, and vaccination is both licensed and safe for this
age group, the efficacy and
effectiveness for preventing precancerous lesions are reduced

compared with vaccination at
a younger age (see online supporting information). In 2007, the
ACIP report acknowledged
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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.”4 Similarly, the ACIP
2011 report on male vaccination reported that, “the population
level benefits decrease with
increasing age at vaccination, especially after age 21 years.”7
The supplemental evidence review included articles that
stratified outcomes by age, with
most studies reporting outcomes for females younger than 18 to
20 years compared with
females older than 19 or 20 years. There are limited data on
precise age distinctions. In
considering endorsement, the ACS qualified the ACIP
recommendation for late vaccination
of individuals older than 21 years based on: 1) evidence of
greater benefit for females
vaccinated at ages 18 to 20 years compared with 21 to 26 years,
2) opportunities for young
women and men to get vaccinated at college, 3) opportunities
for young women and men to
access vaccination without parental consent, and 4) consistency
with the ACIP

recommendation for males.
On the basis of the available evidence, the ACS endorses the
ACIP recommendations for late
vaccination with the caveat that providers should inform
individuals aged 22 to 26 years who
have not been previously vaccinated or who have not completed
the series that vaccination at
older ages is less effective in lowering cancer risk. Adherence
to routine vaccination at age
11 or 12 years should be emphasized, and vaccination should
not be deferred with the
expectation that later vaccination will be similarly effective.
The second key question addressed in this update is whether
males as well as females should
be vaccinated. The 2007 ACS guideline was developed before
the availability of data from
studies of male vaccination and before US Food and Drug
Administration review and
approval for this indication. Evidence published since 2007 has
shown vaccine efficacy and
immunogenicity in males and safety comparable to that in
females. For average-risk men
(excluding men who have sex with men and

1 Memo DATE March 25, 2020 TO BA 105W Stu

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