Review Article

The Potential Impact of Prophylactic Human Papillomavirus

Vaccination on Oropharyngeal Cancer
Theresa Guo, MD1; David W. Eisele, MD1; and Carole Fakhry, MD, MPH1,2

The incidence of oropharyngeal cancer (OPC) is significantly increasing in the United States. Given that these epidemiologic trends
are driven by human papillomavirus (HPV), the potential impact of prophylactic HPV vaccines on the prevention of OPC is of interest.
The primary evidence supporting the approval of current prophylactic HPV vaccines is from large phase 3 clinical trials focused on
the prevention of genital disease (cervical and anal cancer, as well as genital warts). These trials reported vaccine efficacy rates of
89% to 98% for the prevention of both premalignant lesions and persistent genital infections. However, these trials were designed
before the etiologic relationship between HPV and OPC was established. There are differences in the epidemiology of oral and genital
HPV infection, such as differences in age and sex distributions, which suggest that the vaccine efficacy observed in genital cancers
may not be directly translatable to the cancers of the oropharynx. Evaluation of vaccine efficacy is challenging in the oropharynx
because no premalignant lesion analogous to cervical intraepithelial neoplasia in cervical cancer has yet been identified. To truly
investigate the efficacy of these vaccines in the oropharynx, additional clinical trials with feasible endpoints are needed. Cancer
2016;000:000000. V C 2016 American Cancer Society.

KEYWORDS: cancer vaccines, human papillomavirus (HPV), human papillomavirus vaccines, oropharyngeal neoplasms, squamous cell
carcinoma of the head and neck.

INTRODUCTION
The incidence of head and neck squamous cell carcinoma (HNSCC), an entity historically caused by tobacco and alcohol
exposure, has decreased over the past 30 years.1 However, the incidence of oropharyngeal cancer (OPC), a subset of
HNSCC, has risen significantly.1-3 This dramatic increase in OPC is driven by human papillomavirus (HPV) infection.
Approximately 70% to 90% of newly diagnosed cases of OPC in the United States are caused by HPV.4 These HPV-
related cancers are often diagnosed in younger, healthier patients, many of whom are nonsmokers. In the face of this
changing epidemiology, there is increasing interest in the potential impact of HPV vaccines on the prevention of OPC.
To our knowledge, the 3 available prophylactic HPV vaccines have been rigorously evaluated to date only within the con-
text of anogenital HPV infection, premalignancy and malignancy. Therefore, the vaccines are approved by the United
States Food and Drug Administration (FDA) for the prevention of anogenital cancer, precancer, and warts, but not for
OPC. The current body of evidence is insufficient to determine the efficacy of these vaccines within the context of oral
HPV infection or OPC. This review provides an overview of the epidemiology of oral HPV infection and the potential
impact of the vaccine, and in addition discusses the limitations of our current understanding of oral HPV infection and
OPC within the context of vaccines.

Epidemiology of Oral HPV Infection

HPV infection, a sexually transmitted virus, is the primary cause of cervical and anal cancers, as well as a growing subset of
OPCs. HPV is the most common sexually transmitted infection,5 and a majority of the population will have evidence of
at least one infection in their lifetime.6 Oral HPV infection is associated with increased lifetime sexual exposure to the vi-
rus, a marker of which is increased number of lifetime oral or vaginal sexual partners.7 Based on prevalence data represen-
tative of the United States population, 6.9% of individuals have an oral HPV infection of any type detectable in the oral
cavity or oropharynx.7 HPV type 16 (HPV-16), which is responsible for the overwhelming majority of OPCs, is only
found in 1% of individuals in the United States.7

Corresponding author: Carole Fakhry, MD, MPH, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, 6210 JHOC, 601 N. Caroline
St, Baltimore, MD 21287-0910; Fax: (410) 614-8610; cfakhry@jhmi.edu
1
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland; 2Department of Epidemiology, Bloomberg
School of Public Health, Johns Hopkins Medical Institutions, Baltimore, Maryland

DOI: 10.1002/cncr.29992, Received: December 23, 2015; Revised: February 15, 2016; Accepted: February 17, 2016, Published online Month 00, 2016 in Wiley
Online Library (wileyonlinelibrary.com)

Cancer Month 00, 2016 1

Review Article
Figure 1. Human papillomavirus (HPV) infection prevalence in
oral (top) and cervical (bottom) samples by age. The preva-
lence of oral HPV infection was determined using data from
the National Health and Nutrition Examination Survey
(NHANES) for 2009 through 2012 on men and women aged
14 to 69 years.7 Cervical prevalence rates were adapted from
adjusted NHANES data from women aged 14 to 59 years
between 2003 and 2004.11
Demographic and behavioral factors found to be
associated with an increased prevalence of infection, albeit
at one time point, provide a glimpse into potential risk
factors for incidence and duration, which are the determi-
nants of prevalent infection. Oral HPV infection is 2.3
times more common in men compared with women, after
adjusting for other risk factors including age, race, smok-
ing, and lifetime number of sexual partners. These sex dif-
ferences could be attributed to a lower antibody response
to HPV in men,8 or higher transmissibility of infection
through oral sex performed on a woman, which is sug-
gested by studies that demonstrate higher oral infection
rates in heterosexual men compared with homosexual
men.9,10
In multiple studies, a bimodal age distribution of
oral HPV has been noted, with the first peak at ages 30 to
2 Cancer
34 years and a second peak at ages 60 to 64 years (Fig. 1
top).3,7,11 Explanations for the first peak include a surge
in oral HPV infection after sexual debut and at peak
sexual activity. The second peak may be attributed to
potential reactivation of dormant infections with immu-
nosenescence, increased HPV exposure in divorced or
widowed populations, and/or increased rates of persistent
infection that increase overall prevalence.12-14
In addition to age and sex, other risk factors associ-
ated with oral HPV infection are smoking, heavy alcohol
use, and sexual behaviors.7 The prevalence of oral HPV is
2 to 3 times higher in current smokers,7 with a significant
dose-response relationship.15 There is also a dose-
response relationship noted between an increasing num-
ber of lifetime sexual partners (oral and vaginal) and oral
HPV infection in adjusted models.7 Other risk factors
include immunosuppression (such as human immunode-
ficiency virus [HIV] infection), single status, and poten-
tially deep kissing. Consistent with prevalence data, risk
factors (in limited natural history studies) associated with
incident infections include smoking, single status,14 heter-
osexual orientation in males,10 performing oral sex, and
HIV infection.16
Unfortunately, to the best of our knowledge, natural
history data that would elucidate factors affecting the ac-
quisition, clearance, and/or persistence of oral HPV infec-
tion as well as virally mediated transformation of normal
epithelium to precancerous tissue currently are limited.
Evidence to date has suggested that the majority of indi-
viduals who do acquire an oral HPV infection generally
clear the infection within 6 to 12 months,16,17 and 80%
of individuals who acquire an oral HPV infection clear
the infection by 1 year, regardless of HPV type-specific
infection.16 However, some infections persist, for reasons
yet to be identified, which may lead to a higher risk of
oncologic disease.16 Male sex, older age, and current
smoking status have been found to be significantly associ-
ated with a higher risk of oral HPV persistence.17 Other
factors that may be associated with persistent infection
include high oral HPV viral load18 and concurrent persis-
tent cervical infection, although long-term natural history
data are not available.19
In comparison, the prevalence of any cervical HPV
infection in women in the United States is significantly
higher (26.8% for women aged 14-59 years), and 15.2%
of women have high-risk cervical HPV infections, with
the most common being HPV-16.11 The peak prevalence
of cervical HPV infection is 44.8% in women aged 20 to
24 years, which is a few years after sexual debut (Fig. 1
bottom). The age distribution does demonstrate a small
Month 00, 2016

Figure 2. Distribution of type-specific human papillomavirus (HPV) infections found in oropharyngeal cancer (top) and cervical
cancer (bottom). Oropharyngeal cancer data were pooled from studies for which type-specific HPV detection was performed.2,32
For cervical cancer, data were adapted from Munoz et al33 for tumors with a single HPV infection.
peak in older populations,20 again around 60 to 65 years
of age, but this is significantly less prominent than
that observed in oral infections.3,7,11,21 The median
clearance time of cervical infections is approximately 9 to
12 months, with 90% to 95% of infections being cleared
by 2 years.21 In cervical infection, HPV-16 is associated
with increased persistence,22 although age, smoking sta-
tus, and HIV infection do not appear to affect
persistence.23
Oral HPV Infection and Head and Neck Cancer
The relationship between HPV and the upper aerodiges-
tive tract was first appreciated in juvenile respiratory pap-
illomatosis, a disease entity in which infants are exposed
to female genital infections during birth.24,25 Subsequent
investigations revealed the presence of HPV DNA
through polymerase chain reaction analysis in head and
neck tumors,26,27 especially those arising from Waldeyers
ring.24 The presence of a known oncogenic virus within
these tumors suggested an etiologic connection; however,
epidemiologic evidence of causation was not available
until 2000 to 2001.28,29 In 2001, a large nested case-
control study in the Netherlands suggested that HPV-
related tumors may be distinct from tobacco-related
tumors. Serum samples available from a mean of 9.4 years
before the diagnosis of head and neck cancer were com-
pared with matched controls, and HPV-16 seropositivity
was found to be 2-fold higher in patients with HNSCC.29
Cancer Month 00, 2016
Impact of Prophylactic HPV Vaccines on OPC/Guo et al
In subgroup analysis by anatomic site, HPV seropositivity
was most strongly associated with an increased odds of
OPC (odds ratio, 14.4; 95% confidence interval, 3.6-
58.1). This study also demonstrated that HPV-16 seropo-
sitivity to capsid proteins L1 and L2 detected 10 to 15
years before cancer diagnosis could be associated with dis-
ease risk. Another large nested case-control study sug-
gested that HPV-related tumors may be distinct from
tobacco-associated disease, with fewer TP53 mutations
and improved disease-specific survival.28 Most recently,
genomic analysis of prospectively collected oral rinse sam-
ples collected in a nested case-control study also demon-
strated a significant association between the presence of
oral HPV-16 infection and incident cases of OPC (odds
ratio, 22.4; 95% confidence interval, 1.8-276.7) at a me-
dian follow-up of 3.9 years.30
It is now accepted that HPV is etiologically responsi-
ble for a subset of HNSCC tumors.31 In OPC, HPV-16 is
the most common high-risk infection. HPV-16 accounts
for approximately 90% of HPV-related OPCs (Fig. 2
Top).2,32,33 Other HPV type-specific infections found in
OPCs include HPV-18, HPV-33, and HPV-35. These
tumors exhibit distinct clinical characteristics with
improved prognosis compared with tumors that are unre-
lated to HPV,32,34 and a unique genetic profile with lower
mutational burden.35 However, the progression from
persistent infection to invasive carcinoma remains
unknown for OPC, including the identification of a
3
Review Article
TABLE 1. US FDA-Approved HPV Vaccines
Vaccine HPV Type-Specific Infections Covered
Cervarix (bivalent) (GlaxoSmithKline) 16 and 18
Gardasil (quadrivalent) (Merck) 6, 11, 16, and 18
Gardasil-9 (9-valent) (Merck) 6, 11, 16, 18, 31, 33, 45, 52, 58
Abbreviations: FDA, Food and Drug Administration; HPV, human papillomavirus.
suitable precursor lesion. HPV infection has been
reported with some premalignant lesions of the oral cav-
ity36,37 and oropharynx.37 However, the reliable detection
of these premalignant lesions poses a significant chal-
lenge,38 perhaps because the majority of HPV-related
tumors arise from tonsillar crypts rather than surface
epithelium.39
In patients with cervical cancer, several studies have
established persistent HPV infection as a necessary step
toward the development of cervical intraepithelial neopla-
sia (CIN), a precursor lesion to cervical cancer.40 In con-
trast to OPC, HPV-16 represents only 60% of type-
specific infections in cervical cancer, with HPV-18 being
the next most common type-specific infection (Fig. 2 Bot-
tom).2,32,33 Although cervical cancer has the benefit of
large natural history studies with long-term follow-up,
retrospective studies have also been used to demonstrate
that inadequately treated cases of advanced CIN (CIN of
type 3 [CIN3]) progress to invasive carcinoma in 30% to
50% of cases by 30 years, with a majority of these progres-
sions occurring within 10 years.41
Current Prophylactic HPV Vaccines
Currently, there are 3 FDA-approved prophylactic HPV
vaccines (Table 1). In 2006, Gardasil (Merck and Com-
pany Inc, Whitehouse Station, NJ) became the first pro-
phylactic vaccine to be approved by the FDA for females
aged 9 to 26 years for the prevention of cervical cancer
and genital warts. Later, approval was expanded to males
for the indications of genital warts (2009) and anal malig-
nancies (2010). Approval of Cervarix (GlaxoSmithKline,
Philadelphia, Pa) followed in 2009 for females. Most
recently, Gardasil-9 was approved in 2014 for both males
and females. All 3 vaccines are approved for a dosing
schedule of 3 doses over 6 months, although recent trials
have suggested potential evidence of noninferiority for
shorter dose schedules, which is the subject of new trials
currently under development.42,43
All vaccines currently use virus-like particles of the
HPV L1 protein. Although Cervarix is only designed to
protect against HPV-16 and HPV-18, there is some evi-
dence of cross-reactivity to other high-risk types.44
4 Cancer
Female Ages, Years Male Ages, Years
925 -
926 926
926 926
Biologic Efficacy of Vaccines in Cervical
Infections and Cancer
The biologic efficacy of HPV vaccines in the prevention of
cervical infections and cancer was established through large,
blinded, randomized phase 3 clinical trials performed in
women aged 15 to 26 years (Table 2).45-47 Females United
To Unilaterally Reduce Endo/Ectocervical Disease
(FUTURE) I/II studies evaluated the quadrivalent Garda-
sil,48 whereas the PATRICIA (PApilloma TRIal against
Cancer In young Adults)49 and Costa Rica HPV Vaccine
Trial (CVT)50,51 evaluated bivalent Cervarix.
The design of a primary endpoint for these studies
posed a challenge due to both practical and ethical barriers
for evaluating the main endpoint of interest: the preven-
tion of invasive cervical cancer.45 First, after cervical HPV
infection, the development of invasive cancer is a relatively
rare event that may take a decade or longer to occur.
Thus, the design of a clinical trial to evaluate this endpoint
requires vast enrollment, a long follow-up period, and sig-
nificant cost. Furthermore, because women enrolled in
these clinical trials would have regular follow-up, the iden-
tification of premalignant lesions (CIN) would require
intervention before disease progression to invasive cancer.
Given these concerns, regulatory agencies, including
the FDA advisory committee, recommended that the pre-
vention of premalignant lesions of CIN grade 2 or higher
(CIN21) could be used as a sufficient surrogate primary
endpoint to evaluate the efficacy of the vaccine in preventing
cancer.52 In addition, the CVT study also investigated the
vaccines efficacy for the prevention of persistent viral infec-
tion (at 6 months and 12 months) as a surrogate endpoint.
These studies uniformly established the high efficacy
of the vaccine (89.5%-98.2%) in the prevention of pre-
malignant cervical lesions (CIN21) associated with cervi-
cal HPV type-specific infections covered by the vaccine
for women who were previously unexposed to cervical
HPV (Table 2).45-47 Efficacy decreased in all studies when
women who had previous exposure to HPV infection
were included in analysis (efficacy rate of 54.8%-
60.7%).45 In addition, vaccine efficacy was notably
reduced when lesions associated with other HPV
type-specific infections, not just those covered by the
Month 00, 2016
 Impact of Prophylactic HPV Vaccines on OPC/Guo et al

TABLE 2. Summary of HPV Vaccine Clinical Trials Performed in Cervical Cancer Populations

Persistent Viral
Infection Efficacy Disease Efficacy
Trial Cohort Vaccine Control Follow-Up (!6 Months) (CIN21)

FUTURE I/II Women aged 1526 y Gardasil (quadrivalent) Placebo 4y Not evaluated 98.2%
(Merck) N 5 7865
N 5 7864
PATRICIA Women aged 1525 y Cervarix (bivalent) Hepatitis A vaccine 4y 91.4%-94.3% 92.9%
(GlaxoSmithKline) N 5 7305
N 5 7338
CVT Women aged 1825 y Cervarix Hepatitis A vaccine 4y 90.2%-93.1% 89.5%
N 5 2643 N 5 2697
9-Valent Trial Women aged 1626 y Gardasil-9 (9-valent) Gardasil (quadrivalent) 4y Risk reduction: Risk reduction:
N 5 5948 N 5 5943 96.0%a 96.3%-96.7%a

Abbreviations: CIN21, cervical intraepithelial neoplasia, grade 2 or higher; CVT, Costa Rica HPV Vaccine Trial; HPV, human papillomavirus; PATRICIA, PApil-
loma TRIal against Cancer In young Adults.
Vaccine efficacy is summarized for the prevention of persistent infection and disease (CIN21) for each study. Efficacy data shown are limited to participants
who received all 3 scheduled doses and demonstrated no evidence of HPV exposure prior to vaccination.
a
For the 9-Valent Trial, risk reduction for disease or infection associated with HPV type-specifc infections 31, 33, 45, 52, and 58 (types added to the 9-valent
vaccine) is shown rather than absolute efficacy.45-47

vaccine, were included (efficacy of 42.9%-64.9%).45
These data provided a rationale for the development of
the 9-valent vaccine (Gardasil-9; Merck), which recently
demonstrated high efficacy in the prevention of CIN21
lesions and persistent infections associated with HPV-31,
HPV-33, HPV-45, HPV-52, and HPV-58 compared
with the quadrivalent vaccine (Table 2).45-47
Follow-up studies from these trials have used immu-
nogenicity to gauge antibody response and the stability of
immune response to the vaccine. Antibody titers obtained 1
month after vaccine administration have been noted to rise
to levels that are 100 times higher than those after natural
infection.45 After this peak, titers generally decline over 2
years before stabilizing, but remain at least 10 times higher
than levels after natural infection.44 Both bivalent and quad-
rivalent vaccines have shown sustained immunogenicity for
up to 8 years after the initial vaccination.43,53-55 When
comparing both vaccines, Cervarix induces substantially
higher titer responses, particularly in younger patients.44
Although higher antibody responses would appear to be
optimal, to the best of our knowledge, the minimum
threshold required to achieve vaccine protection against
genital infection is unknown.45 The range of immunogenic-
ity with known vaccine efficacy against both persistent
infection and precancerous cervical disease has served as a
basis for subsequent studies to establish noninferiority for
new vaccines,46 populations,56-58 and dosing schedules.42,43
Studies in Other Populations
Men
Although the majority of HPV vaccine studies were per-
formed in women, studies in men may provide important
insight because OPCs now account for 78.2% of newly
diagnosed HPV-related tumors in men (14.4% anal and
7.4% penile).59 In addition, approximately 80% to 85%
of OPCs are diagnosed in men.3,34 In a randomized trial,
the quadrivalent vaccine demonstrated 90.4% vaccine ef-
ficacy for the prevention of external genital lesions in men
(including penile, perianal, or perineal intraepithelial neo-
plasia or cancer) for covered HPV type-specific infections
in HPV-naive subjects.60 For persistent infection (!6
months), the observed efficacy rate was 78.7% for HPV-
16 and 96% for HPV-18.60 Similar to studies in women,
efficacy was lower when subjects with prior HPV expo-
sure were included. A subanalysis of men who have sex
with men determined the vaccine efficacy for the preven-
tion of anal intraepithelial neoplasia and anal infection to
be 77.5% and 93.8% to 100%, respectively.61 The
results of these studies led to FDA approval of Gardasil
for males.
Older women
Studies in older women may provide evidence of age-
related immunogenic changes after vaccination. The age
of these study populations approaches the median age of
individuals at the time of diagnosis of OPC (58 years).62
One study evaluated Gardasil in women aged "45 years
and found the vaccine efficacy for persistent infection to
be 91.8% for women aged 24 to 34 years and 88.6% for
women aged 35 to 45 years without prior exposure to
HPV.63 In immunogenicity studies for Cervarix, although
antibody titers were found to be slightly lower in women
aged 45 to 55 years compared with females aged 15 to 25
years, the peak titers were still 57 to 84 times higher than
those elicited by natural infection and plateau levels at 2

Cancer Month 00, 2016 5

Review Article
years remained 8-fold to 16-fold higher than those after
natural infection.55
Children
Immunogenicity studies have allowed for
immunobridging, which uses measurement of immune
response to vaccines (through anti-HPV antibody levels)
to establish noninferiority of vaccine efficacy.47 This
allows for the bridging of vaccines to populations for
whom evaluating primary disease endpoints is not feasi-
ble, such as children who are the target recipients of these
vaccines (to provide the vaccine to a fully HPV-naive pop-
ulation). Ethical considerations are significantly greater
when designing clinical trials that include minors, and
therefore shorter trials with minimal intervention are
desired. In addition, children are unlikely to acquire other
primary endpoints (ie, HPV infection or precancerous
lesions) until they reach adulthood. These studies estab-
lished safety in pediatric populations and demonstrated
that immune responses were robust in boys and girls aged
10 to 15 years, with antibody titers that were 1.7 to 2.7
times higher when compared with those in young
adults.56-58 In addition, antibody titers are reported to
remain stable for up to 8 years in pediatric populations.54
As we think about establishing vaccine efficacy for oral
HPV infection and OPC, the determination of immuno-
genicity levels that can protect against oral HPV infection
may permit immunobridging and defining efficacy in pe-
diatric populations.
What Do We Know About HPV Vaccines in
Relation to OPC?
To the best of our knowledge, few studies to date have
been conducted to evaluate the impact of the HPV vac-
cine on oral HPV infection or OPC. The convergence of
our relatively new understanding of the etiologic connec-
tion between HPV and OPC, the sample size considera-
tions, and consequent cost implications means that
clinical trials were not previously designed for the study of
oral HPV infection within the context of vaccines.
Additional data collected from the CVT study
cohort has provided some indirect evidence of the poten-
tial efficacy of the vaccine in preventing oral infec-
tion.64,65 At the 4-year follow-up after vaccination, oral
rinses were obtained and demonstrated that the preva-
lence of oral HPV overall (0.7% vs 1.3%) and oral HPV-
16/18 (0.03% vs 0.5%) were lower in the vaccinated
group compared with the control group, with an esti-
mated vaccine efficacy of 93.3% for HPV-16/18 infec-
tion.64 Because the study was not originally designed to
6 Cancer
evaluate vaccine efficacy in oral HPV infection, no base-
line oral HPV infection data were available. Furthermore,
there were few prevalent or incident oral HPV infections
noted within the cohort. The study was conducted only in
women, whereas oral HPV infection and OPC are more
common in men.66 Last, the CVT study provided point
prevalence data, but because it had only one time point it
was not able to evaluate vaccine efficacy for the prevention
of persistent infection, which is the recommended end-
point by the World Heath Organization International
Agency for Research on Cancer (WHO IARC).47
Although only limited epidemiologic data currently
are available regarding vaccine efficacy for oral HPV infec-
tion, there is some promising biologic evidence. In animal
studies, both vaccination and passive antibody transfer
were found to provide protection against oral infection
and the development of oral lesions from canine oral pap-
illomavirus.67 The efficacy of passive immunity demon-
strates the important role of immunoglobulins (Ig), such
as IgG neutralizing antibodies in providing protection
against oral infection,68 and oral mucosal IgG, which is
largely derived from the serum.69 Oral mucosal IgG
against HPV is detectable, although at a lower rate, in
individuals who are seropositive for HPV70,71 as well as
vaccinated individuals.72 In addition to IgG, the other
main mucosal antibody present in the oral cavity is secre-
tory IgA,73 and a high prevalence of oral IgA has been
observed in women with a history of CIN.74 Given the ro-
bust serum immunogenic response to the vaccine noted in
multiple populations,56-58 the presence of oral IgG and se-
cretory IgA and subsequent protection against oral infec-
tion is likely. However, to the best of our knowledge, few
data are currently available to evaluate oral mucosal anti-
body response to vaccination and its correlation with vac-
cine efficacy.
Other studies have used predictive modeling to
understand the potential benefit of HPV vaccination
within the context of OPC. One such modeling study
demonstrated that even with 50% vaccine uptake and
50% vaccine efficacy, vaccinating young boys specifically
for the prevention of OPC would be cost-effective.75
Studies in cervical cancer have projected that given estab-
lished trends and efficacy, significant decreases in inci-
dence and mortality from cervical cancer would be
observed by 2050.76 Given the higher median age at the
time of the diagnosis of OPC compared with cervical can-
cer (58 years vs 48 years),62 a reduction in incidence and
mortality rates for OPC would not likely be observed
until at least 2060.3 In addition to assumptions regarding
vaccine efficacy and vaccine uptake, this projection also
Month 00, 2016

assumes sustained vaccine protection and no contribution
of the second peak of oral HPV infection noted in older
populations.3
What Questions Should We Be Asking Next?
How much do the differences between oral and genital
HPV infection matter in relation to vaccine efficacy? If a
higher level of immunogenicity is required for protection
against oral HPV infection, this may inform recommen-
dations for dosing schedules, particularly in men. If the
increased incidence of oral HPV infection at an older age
is related to immunosenescence, would a vaccine booster
be needed at an older age? Should type-specific HPV
infections unique to OPC tumors be considered in future
vaccine development?
Many questions remain, but an important issue to
address is how to investigate and establish the efficacy of
vaccines in the oropharynx. What is a feasible primary
endpoint for such a study? How closely can we establish
the relationship between persistent infection and invasive
cancer? Is prevention of persistent infection an adequate
surrogate endpoint, given that no precursor lesion can
currently be identified?
Primary Endpoints for Trial Design in Oral HPV
The WHO IARC and National Cancer Institute recently
convened to discuss acceptable primary endpoints for the
future evaluation of prophylactic HPV vaccines.47,77 A
decade ago, CIN21 was recommended as the primary
endpoint with which to establish the efficacy of disease
prevention.52 However, the body of knowledge has grown
significantly since this time. Another challenge of trial
design is that given the established efficacy of the vaccine,
randomized placebo controlled trials can no longer be
ethically performed.47
The main primary endpoints for vaccine trial design
are: 1) disease endpoint (prevention of precancerous or
invasive cancer); 2) viral endpoint (prevention of persis-
tent infection); and 3) immunogenicity (comparison of
immunologic response). Disease endpoints are the gold
standard because the primary goal of HPV vaccine is not
the prevention of infection but the prevention of disease.
Although the ideal trial design would evaluate vaccine effi-
cacy for the prevention of invasive cancer, the time
between oral HPV infection and cancer progression is
likely to be prohibitively long. Unfortunately, to the best
of our knowledge, no suitable premalignant lesion, such
as CIN, that could serve as a surrogate disease endpoint is
currently appreciated in the oropharynx.3 Even malignant
tumors can be a diagnostic challenge, and HPV-related
Cancer Month 00, 2016
Impact of Prophylactic HPV Vaccines on OPC/Guo et al
OPCs are often diagnosed at a late stage with frequent
lymph node metastasis.78
A viral endpoint (ie, the prevention of persistent
infection) may be ideal because it has several advantages.
Persistent infection is a more common event and can be
determined objectively within a shorter time frame; this
allows for significantly smaller and shorter trials to estab-
lish efficacy.47 However, the validity of a viral endpoint is
contingent on a strong etiologic connection between per-
sistent infection and disease, and therefore its ability to
predict disease efficacy.
In cervical cancer, significant evidence collected
through prospective natural history studies have strongly
established persistent HPV infection as an essential step in
the development of CIN31.79 In addition, vaccine effi-
cacy for persistent infection was nearly equivalent to effi-
cacy for the prevention of disease in both the PATRICIA
and CVT trials (Table 2).45-47 In OPC however, evidence
establishing this etiologic connection between persistent
infection and disease remains elusive, and, definitive stud-
ies have been limited by the lack of a precursor lesion.77
Nevertheless, the WHO IARC recommended that the
prevention of persistent oral HPV-16 and/or HPV-18
infection would be an acceptable surrogate endpoint for
the evaluation of vaccine efficacy.77 Persistent oral HPV
infection is currently being evaluated using oral rinses,64
which have been optimized80 and demonstrate high con-
cordance with HPV infection detected by tonsillar brush
biopsy.38 In regard to immunogenicity endpoints, as dis-
cussed earlier, it is unknown what level of immunogenic-
ity is sufficient for protection against oral HPV infection.
Furthermore, would immunogenicity be best evaluated
with serum or oral antibody measures? After vaccine effi-
cacy against oral HPV infection is established, immuno-
bridging trials could be used to establish vaccine efficacy
for oral infections and disease in pediatric populations,
new vaccines, or new dosing schedules, as has been done
in cervical cancer. For the oropharynx, a viral primary
endpoint represents the most feasible option for trial
designs, and data concerning immunogenicity should be
collected to inform future studies (Fig. 3).41,62,81
Conclusions: What Does the Landscape Ahead
Look Like?
As of 2014, it has been estimated that 21% of eligible
teenage boys and 40% of girls have received 3 doses of the
HPV vaccine.82 Although knowledge and acceptance
regarding the HPV vaccine continue to grow, vaccine
uptake still lags significantly behind the goal of 80% by
2020 set by the Department of Health and Human
7
Review Article

Figure 3. Schematic diagram for comparison of known and unknown vaccination-related endpoints for the progression from
human papillomavirus (HPV) infection to malignancy in the cervix and oropharynx. After vaccination, the first potential endpoint
would be antibody response. Antibody titers necessary for the prevention of cervical HPV infection have been established, but
remain unknown in the oropharynx. In the cervix, the peak age of HPV infection is earlier (aged 20-24 years). The average age at
the time of diagnosis of cervical intraepithelial neoplasia of type 2 or higher (CIN21), the precancer disease surrogate endpoint
used in vaccine trials in the cervix, is approximately 10 years later, at a median age of 34 years.81 The progression from CIN21 to
invasive cancer occurs in 30% to 50% of cases.41 The median age at the time of diagnosis of invasive cervical cancer is 48
years,76 with a latency of >10 years from CIN21.41 In comparison, oral HPV infection has a bimodal age distribution. The first
peak is at 30 to 34 years of age and the second peak is at 60 to 64 years of age. Although persistent oral HPV infection has not
been established as a viral endpoint predating oropharyngeal cancer (OPC), it is expected to have an analogous role as in the
model of cervical HPV to cervical cancer progression. No precursor lesion has been identified to date, but the median age at the
time of diagnosis of OPC is later than that of cervical cancer at 58 years.76 Based on current knowledge, potential vaccination-
related endpoints for oral HPV infection and OPC include antibody response (immunogenicity endpoint), persistent HPV infection
(viral endpoint), precancer (disease surrogate endpoint), and invasive cancer (disease endpoint). Unknowns are depicted in gray.

Services Healthy People 2020 objectives.83 In other coun-
tries, vaccine uptake for at least 2 doses has been able to
reach approximately 70% in school-aged girls in both the
United Kingdom84 and Australia.85 Improved public
knowledge regarding the etiologic connection between
HPV and OPC may increase vaccine uptake in men
because a key barrier to HPV vaccination among males
has been a reported lack of perceived benefit by both
parents83 and health care providers.86 Even if vaccine effi-
cacy against oral infection or vaccine uptake in men is
minimal, herd immunity is likely to play a role in decreas-
ing the overall prevalence of HPV in the general popula-
tion, although these effects are difficult to estimate.76 In
this changing landscape, there are new challenges to

8 Cancer Month 00, 2016


evaluating vaccine efficacy. Although placebo-controlled
trials can no longer be performed ethically, observed
changes in current OPC incidence trends can provide
indirect evidence of the potential impact of HPV vaccines
in OPC.
FUNDING SUPPORT
Supported by grants P50DE019032 and 2T32DC000027-26 and
the Oral Cancer Foundation.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
AUTHOR CONTRIBUTIONS
Theresa Guo: Conceptualization, investigation, resources, data
curation, writingoriginal draft, writingreview and editing, and
visualization. David W. Eisele: Writingreview and editing and
supervision. Carole Fakhry: Conceptualization, methodology,
investigation, writingreview and editing, supervision, and project
administration.
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