Clinical trials of human papillomavirus vaccines

Authors
Philip E Castle, PhD, MPH
J Thomas Cox, MD
Joel M Palefsky, MD
Section Editor
Martin S Hirsch, MD
Deputy Editor
Allyson Bloom, MD
Disclosures: Philip E Castle, PhD, MPH Speakers Bureau: Roche Molecular Systems [cervical cancer (Cobas
HPV test)]; Cepheid [cervical cancer (GeneXpert HPV test)]. Consultant/Advisory Boards: Roche [HPV testing
(Cobas HPV test)]; Cepheid [cervical cancer (GeneXpert HPV test)]; Teva Pharmaceuticals [HPV therapeutics];
Genticel [HPV testing]; ClearPath [HPV testing]; Guided Therapeutics [HPV testing]; Hologic [HPV testing (Aptima
HPV Test)]; GE Healthcare [Sample prep (FTA Elute-specimen transport medium)]. Data and Safety Monitoring
Board: Merck [cervical cancer (Gardasil and Gardasil 9 HPV vaccines)]. J Thomas Cox, MD Speaker's Bureau:
Roche [HPV testing (HPV test)]; Hologic/Gen-Probe [HPV testing (HPV test)]. Consultant/Advisory Boards: Merck
[Data safety and monitoring board (Quadrivalent and nonavalent HPV vaccine)]; Roche [Advisory board (HPV test)];
Hologic/Gen-Probe [Advisory board (HPV test)]; Trovagene [Scientific advisory board (Urine HPV test)]; Zilico
[Advisory board (Optical spectroscopy as a colposcopy adjunct)]. Joel M Palefsky, MD Grant/Research/Clinical Trial
Support: Merck and Co [HPV infection (Quadrivalent and nonavalent HPV vaccines)]; Hologic [HPV infection (HPV
assay)]. Consultant/Advisory Boards: Merck [HPV infection (Quadrivalent and nonavalent HPV vaccines)]; TheVax
[HPV infection (therapeutic HPV vaccine)]; Hera Therapeutics [HPV infection (HPV therapeutics)]. Martin S Hirsch,
MD Nothing to disclose. Allyson Bloom, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: Sep 23, 2014.
INTRODUCTION Two vaccines have been developed against human papillomavirus (HPV)
infection. One is a quadrivalent vaccine (Gardasil) and the other is a bivalent vaccine (Cervarix).
Some of the major clinical trials that have been performed to date in males and females are
discussed in detail below. The natural history, epidemiology, and immunology of HPV and
indications for use of HPV vaccine in clinical practice are discussed elsewhere. (See "Epidemiology
of human papillomavirus infections" and"Recommendations for the use of human papillomavirus
vaccines" and "The life cycle, natural history, and immunology of human papillomaviruses".)
VACCINE DEVELOPMENT The HPV L1 major capsid protein, when recombinantly expressed
alone, can self-assemble into virus-like particles (VLPs) for each HPV type [1,2]. The HPV L1 VLPs
do not contain the HPV viral genome or any other genetic material and therefore are rendered noninfectious and non-carcinogenic. Preclinical research demonstrated that L1 is highly immunogenic
with and without an adjuvant [2,3].
The proof-of-concept vaccine trial with HPV 16 VLP [4] demonstrated that HPV 16 infection could
be effectively prevented. In follow-up studies of this population, women were nearly completely
protected against HPV 16 up to 8.5 years after HPV 16 vaccination [5].
Two vaccines were subsequently developed and tested in phase III efficacy trials for use:

An HPV vaccine that targets HPV 6, 11, 16, and 18 (quadrivalent HPV 6/11/16/18 VLP
vaccine) (Gardasil; Merck & Co, Inc, Whitehouse Station, New Jersey)
An HPV vaccine that targets HPV 16 and 18 (bivalent HPV 16/18 VLP vaccine) (Cervarix;
GlaxoSmithKline, Rixensart, Belgium)
TOOLS FOR ASSESSMENT OF VACCINE EFFICACY Vaccine efficacy is measured only by the
prevention of virologic infection or related clinical events. The immunogenicity of the HPV vaccines
is not equated with vaccine efficacy primarily because there is no established correlate between a
titer level and protection against HPV infection or the development of cervical intraepithelial
neoplasia (CIN) or cancer.
Vaccine efficacy is defined for several natural history events that all serve as surrogate markers for
the development of cervical cancer:
Incident HPV infection
Persistent type-specific HPV infection (>6 or >12 months)
Abnormal cytology
Abnormal histological changes
Measures of HPV infection and cervical abnormalities after immunization give complementary
information. The best surrogate for cancer risk is histologically-confirmed cervical precancerous
lesions, CIN2/3. In contrast, abnormal cytology can be caused by many HPV genotypes [6] and
therefore is a relatively nonspecific endpoint for type-specific protection. In contrast, prevention of
incident HPV infections provides evidence of type-specific effects of the vaccine, although most
HPV infections will eventually clear in the immunocompetent host.
Importantly, efficacy should not be confused with effectiveness or public health benefit. Efficacy is
the reduction of endpoints in a selected trial population. A simple measure of public health benefit is
the expected number of events (disease endpoints) averted per woman in a whole population of
women (ie, "all-comers"). Unfortunately, the two metrics of vaccine impact are often (incorrectly)
used interchangeably. Incident HPV infections at any age have a low risk of developing into
clinically-relevant disease [7]; only prevalently-detected HPV infections, which are not impacted by
HPV vaccination [8-10], are more likely to persist in older versus younger women [11]. Thus, while
HPV vaccination in women over 26 is highly efficacious [12], it prevents relatively fewer HPV
infections and even fewer CIN2/3compared with younger populations; these observations suggest
that within this age group, HPV vaccination provides little (public health) benefit.
QUADRIVALENT HPV 6/11/16/18 L1 VIRUS-LIKE PARTICLE VACCINE Gardasil targets HPV
genotypes 16 and 18, which are associated with the majority of cervical cancers and precancerous
lesions (cervical intraepithelial neoplasia (CIN) grade 2 or 3) worldwide, and HPV genotypes 6 and
11, which are associated with the vast majority of genital warts. Gardasil has been evaluated in two
large, randomized clinical trials named FUTURE (Females United To Unilaterally
ReduceEndo/ectocervical disease) II and I.
Efficacy in females
The FUTURE II trial In a phase III, multi-national prospective, double-blind, placebo-controlled
trial (FUTURE II), more than 12,000 women, aged 15 to 26 years (mean age of 20 years), were
randomly assigned to receive a three-dose regimen of vaccine or placebo [8]. The majority of the

study participants were from Europe (65 percent) and Latin America (26 percent). Women with
greater than four lifetime sexual partners or a history of abnormal cytology were excluded from the
study. Evidence of past or current infections with HPV 16 and/or HPV 18 (as measured by serology
and DNA detection in cervical specimens) was found in approximately one-fourth of the women in
the vaccine and placebo arms (23 and 28 percent, respectively) through one month follow-up after
vaccination.
The primary efficacy analysis (According-To-Protocol [ATP] analysis) was performed in those
subjects who did not have evidence of either HPV 16 or 18 infection (by HPV DNA or HPV
serological testing) through one month after the third dose of vaccine; these patients were referred
to as "HPV-naive" as per protocol. The primary composite end point was the development of CIN 2
or 3, adenocarcinoma in situ, or cervical cancer related to HPV 16 or HPV 18 among the "HPVnaive" women. After a mean follow-up of three years, the following results were demonstrated:
Vaccine efficacy, for the prevention of the primary composite end point, was 98 percent in
study participants who were "HPV-naive".
Vaccine efficacy remained high (95 percent) in those HPV-negative participants who did not
receive all doses of vaccine according to protocol, suggesting some flexibility in the timing of
the vaccine schedule.
Seroconversion rates at 24 months among 1512 vaccinated women in the immunogenicity
sub-study were 96, 97, 99, and 68 percent for HPV types 6, 11, 16, and 18, respectively.
The vaccine was well tolerated; women who received the vaccine were more likely to have
an injection site event (eg, erythema, pain, pruritus, and/or swelling) than women receiving the
placebo. A full discussion of adverse events associated with immunization, including the
postmarketing experience, is found elsewhere. (See"Recommendations for the use of human
papillomavirus vaccines", section on 'Vaccine safety'.)
Importantly, the vaccine efficacy for the composite endpoint in the intention-to-treat (ITT) analysis,
which included participants with baseline or incident HPV infection by one month after the last dose
of vaccine, was significantly lower (44 percent) than in the according-to-protocol (ATP) analysis.
Vaccine efficacy for CIN 2 or 3 disease due to all HPV types was also low (17 percent) in the overall
population of women who had undergone randomization. These results suggest limited crossreactivity of protection and the importance of early vaccination before infection.
The FUTURE 1 trial A similarly designed phase III placebo-controlled trial was conducted in
5455 women aged 16 to 24 years to assess the efficacy of quadrivalent vaccine to prevent HPVrelated anogenital disease (FUTURE I) [9]. The majority of the study participants were from Latin
America (41 percent) or North America (29 percent). Women with greater than four lifetime sexual
partners or a history of any genital warts or abnormal cytology were excluded from the study.
Evidence of past or current infection with one or more of the vaccine genotypes (HPV 6, 11,
16 and/or 18) as measured by serology and DNA detection in cervical specimens was found among
women in the vaccine and placebo arms (38 and 42 percent, respectively) through one month
follow-up after vaccination.
The primary aim of the trial was to determine vaccine efficacy in reducing the combined endpoint of
incidence of anogenital warts, vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial
neoplasia (VAIN) grades 1 to 3 or cancer associated with HPV 6, 11, 16, or 18. A secondary aim
was to observe whether the administration of vaccine reduced the combined incidence of CIN

grades 1 to 3, adenocarcinoma in situ, or cancer associated with vaccine-type HPV. After a mean
follow-up of three years, the following results were demonstrated:
The vaccine was 100 percent effective in preventing anogenital disease in women who were
"HPV-naive" (ie, no cases were identified in the vaccine group versus 60 cases in the placebo
group).
Vaccine efficacy was 100 percent in preventing CIN grades 1 to 3 or adenocarcinoma in situ
caused by the vaccine-type HPVs in those women who were "HPV-naive" (ie, no cases were
diagnosed in the vaccine group, whereas 65 cases were diagnosed in placebo group).
The vaccine was well tolerated. However, women who received the vaccine were 10 percent
more likely to experience an injection site event (erythema, pain, pruritus, and/or swelling) and
3 percent more likely to experience an injection-related event (eg, fever) than women receiving
the placebo. A full discussion of adverse events associated with immunization, including the
postmarketing experience, is found elsewhere. (See "Recommendations for the use of human
papillomavirus vaccines", section on 'Vaccine safety'.)
As noted in the FUTURE II trial, vaccine efficacy in preventing cervical disease among the intentionto-treat group, which included participants with baseline HPV infection prior to vaccination, was
lower (55 percent) compared with the according-to-protocol analysis in FUTURE I. Vaccine efficacy
against lesions associated with any HPV genotype for all cervical lesions was 20 percent.
A summary of the efficacy data from four placebo-controlled, double-blind, randomized Phase II and
III clinical studies of the quadrivalent vaccine may also be viewed on the website for the US Food
and Drug Administration (www.fda.gov).
Prevention of subsequent disease A post-hoc subgroup analysis of pooled data from the two
FUTURE trials evaluated the effect of the quadrivalent HPV vaccine on rates of HPV-related
disease in women who developed genital disease despite vaccination. Among women who
underwent cervical surgery for HPV-related disease, the incidence of subsequent CIN grade 2 or
worse related to any HPV type was lower in the 474 who had received the vaccine compared with
the 592 placebo recipients (1.1 versus 3.1 cases per 100 person years) [13]. Among women who
had been treated for genital warts, or vaginal or vulvar intraepithelial neoplasia, vaccine recipients
had lower rates of subsequent genital warts but the same rates of vulvar, vaginal, or CIN grade 2 or
worse as placebo recipients. This study had several notable limitations. The mean follow-up was
short (1.2 years), and there were few overall events. Furthermore, the retrospective analysis could
not ensure that all events were new episodes as opposed to residual disease. Nevertheless, these
results suggest that the vaccine may reduce the risk of subsequent HPV-related cervical disease in
women with a history of CIN grade 2 or worse. Although the study demonstrated efficacy, there are
no data on the population effectiveness or cost effectiveness to support vaccination of this
subgroup.
Cross-protection Secondary combined analyses of data from the FUTURE I and II trials
demonstrated partial protection against acquisition of the nonvaccine HPV types
(HPV 31/33/45/52/58) that cause approximately 20 percent of cervical cancers. In HPV-nave
women, infection rates due to these nonvaccine genotypes and related disease (eg, CIN13/adenocarcinoma in situ) was 25 percent and 29 percent, respectively [14]. In sexually active
women, the reductions in infections and related diseases were somewhat lower (eg, 18 and 19
percent, respectively) [15]. In a subsequent analysis of the same data, the cross-protective efficacy

of the quadrivalent vaccine among HPV-nave women appeared to be restricted to HPV 31 infection
[16].
Therapeutic effects In both FUTURE II and I trials, there was no evidence that vaccination
altered the course of disease or infection in women who had evidence of HPV infection at the time
of receipt of the first dose of vaccine [8,9]. These data reinforce the use of the HPV vaccine to
prevent infection rather than as a therapeutic intervention to treat preexisting HPV infection and
related diseases. (See 'Vaccine immunogenicity' below.)
Regulatory approval In June of 2006, the Food and Drug Administration approved the use of
Gardasil in females 9 to 26 years of age and in October 2009 it was approved for males of the same
age. Gardasil has also been approved for use in approximately 100 countries around the world,
although the specific age recommendations are country dependent.
Post-approval safety The Centers for Disease Control and Prevention (CDC) conducted a
review of the adverse events following immunization (AEFI) for Gardasil between June 1, 2006 and
December 1, 2008 [17]. There were 12,424 reports of AEFIs following Gardasil distribution, or 53.9
reports per 100,000 doses distributed. The proportion of AEFI per vaccine dose was similar to those
observed for other vaccines, but there was an increased reporting of syncope and venous
thromboembolic events. (See "Recommendations for the use of human papillomavirus vaccines",
section on 'Vaccine safety'.)
BIVALENT HPV 16/18 L1 VIRUS-LIKE PARTICLE VACCINE
Cervarix is a bivalent vaccine that targets HPV genotypes 16 and 18, which are associated with the
majority of cervical cancers and precancerous lesions (CIN2/3) found worldwide; unlike Gardasil it
does not target HPV 6 and 11. Cervarix has been evaluated in one large, randomized clinical trial
named PATRICIA (Papilloma trial against cancer in young adults) [18] and an autonomous US
National Cancer Institute (NCI)-sponsored trial in Costa Rica [19].
Efficacy In PATRICIA, a phase III, multi-national prospective, double-blind, placebo-controlled
trial, more than 18,000 women, aged 15 to 25 years (mean age of 20 years), were randomly
assigned to receive a three-dose regimen of vaccine or a control hepatitis A vaccine [18]. The
majority of the study participants were from Europe (38 percent) and Asia Pacific (33 percent).
Women with greater than six lifetime sexual partners or a history of colposcopy were excluded from
the study. Approximately 26 percent of women in both arms had current or evidence of past
infections by HPV 16 and HPV 18 (as measured by serology and DNA detection in cervical
specimens through one month follow-up following vaccination).
The primary efficacy analysis (According-To-Protocol [ATP] analysis) was performed in those
subjects who did not have evidence of either HPV 16 or 18 infections (by HPV DNA or HPV
serological testing) at enrollment and were HPV 16 and 18 DNA-negative at six months. The
primary composite end point was the development of CIN 2 or 3, adenocarcinoma in situ, or cervical
cancer related to HPV 16 or HPV 18. After a mean follow-up of three years, the following results
were demonstrated:
Vaccine efficacy for the prevention of the primary composite end point of CIN2, CIN3,
adenocarcinoma in situ, or cancer was 93 percent.

Vaccine efficacies for the prevention of incidentally-detected 6-month and 12-month

persistent infections by HPV 16/18 were 94 percent and 91 percent, respectively.
The vaccine was well tolerated and there were no differences in the serious adverse events
by study arm.
Importantly, the vaccine efficacy in preventing CIN2 or more severe lesions in the intention-to-treat
(ITT) analysis, which included participants with baseline or incident HPV infection by one month
after the last dose of vaccine, was significantly lower (53 percent) than in the according-to-protocol
analysis noted above. Vaccine efficacy for CIN2 or more severe disease due to all HPV types was
also significantly lower (30 percent) in the overall population of women who had undergone
randomization.
Efficacy in older females HPV vaccination appears to be safe and effective in preventing
subsequent infection in older women, but the overall benefit is less than that in younger females
[20]. In a trial of 5752 women older than 25 years who were randomly assigned to receive bivalent
vaccine or placebo and followed for a mean of 40 months, overall vaccine efficacy for the combined
endpoint (preventing six-month persistent cervical HPV type 16 or 18 infection or vaccine-type
associated CIN grade 1 or more severe diagnoses) was 44 percent [21]. Among those who did not
have a prior history of HPV infection and received all three doses of vaccine, vaccine efficacy was
81 percent. Rates of vaccine-type associated CIN2 or more severe diagnoses were not statistically
different between HPV-nave women who received vaccine or placebo.
Cross-protection Cervarix demonstrated partial protection against acquisition of the nonvaccine
HPV types (HPV 31/33/45/52/58) that cause approximately 20 percent of cervical cancers. In the
according-to-protocol (ATP) population, the reductions in six-month persistent infection, 12-month
persistent infection, and CIN2+ disease related to these genotypes were 30 percent, 24 percent,
and 53 percent, respectively. However, in a systematic review of bivalent vaccine trials, the efficacy
against infection with nonvaccine HPV types was lower in trials with longer follow-up periods,
suggesting the possibility of waning cross-protection over time [16].
Therapeutic effects There was no evidence that HPV vaccination altered the course of vaccinetype HPV infections present before or at the administration of the first dose of vaccine in the NCI
trial [10]. These data reinforce the use of HPV vaccine to prevent infection rather than as a
therapeutic intervention to treat preexisting HPV infection and related diseases.
Regulatory approval On October 19, 2009, the US Food and Drug Administration (FDA)
approved use of Cervarix in females 9 to 26 years of age. Cervarix has been approved for use in
approximately 100 countries around the world, although specific age recommendations are country
dependent.
Post-approval safety Not available.
VACCINE IMMUNOGENICITY An analysis of primary immunogenicity of Gardasil demonstrated
the following [22]:
All of the subjects had detectable HPV 6, 11, 16, and 18 antibodies after completion of the
vaccine series.

Anti-HPV geometric mean titers (GMT) were 27- to 145-fold higher than those observed in
placebo recipients who were HPV-seropositive at baseline, suggesting that HPV vaccine leads
to higher antibody titers than natural infection.
At 36 months of follow-up, vaccine-induced antibody titers were comparable or higher than
those of natural infection.
In the subset of seropositive women with detectable antibodies against vaccine types at
baseline, HPV vaccine led to rapid inclines, higher peaks, and longer persistence of antibody
levels compared with women who were seronegative for vaccine types, suggesting that HPV
vaccine may induce anamnestic responses.
Similarly excellent antibody responses have been reported for Cervarix, with sustained high
antibody concentrations after 6.4 years of follow-up [23,24]. In a head-to-head comparison of the
immunogenicity of the quadrivalent and bivalent HPV vaccines [25], immunization by Cervarix
induced geometric mean titers of serum neutralizing antibodies 2.3- to 4.8-fold higher for HPV 16
and 6.8- to 9.1-fold higher for HPV 18 across all age strata than did Gardasil. Whether the induction
of higher serum titers against HPV 16 and 18 has any impact on the degree and duration of
protection is unknown.
CLINICAL TRIALS OF HPV VACCINE IN MALES HPV infection is prevalent in men, affecting
more than one-fourth to one-half of sexually active men, particularly those with multiple sex partners
[26,27]. However, the burden of HPV-associated diseases such as anal, penile, and oropharyngeal
cancers in men is much less than that of cervical cancer in women [28]. (See "Epidemiology of
human papillomavirus infections".)
The rationale for including males in immunization programs has included protection of males from
HPV-related diseases and to decrease sexual transmission of HPV from males to females. Clinical
trials of HPV vaccine in males have demonstrated similar immunogenicity with a favorable side
effect profile. The efficacy of HPV in preventing anal intraepithelial neoplasia in males is discussed
below.
Bivalent vaccine (Cervarix) in males A phase I/II, observer-blind, parallel-group trial randomly
assigned 270 Finnish boys (aged 10 to 18 years) in a 2:1 ratio to receive either bivalent HPV
vaccine or a hepatitis B vaccine as a control [29]. At study entry, 11 percent of the participants were
seropositive for HPV 16 and/or HPV 18 antibodies. The study demonstrated that the vaccine was
highly immunogenic with 100 percent of the vaccinees attaining seroconversion for both HPV 16
and HPV 18 at two months and seven months.
Quadrivalent vaccine (Gardasil) in males
Prevention of genital warts In a randomized, double-blind trial, 1781 children, approximately
half of whom were male, were assigned 2:1 to quadrivalent HPV vaccine or saline placebo to
assess the tolerability and immunogenicity of the HPV vaccine [30]. At month seven,
seroconversion rates were >99 percent for the four vaccine types (HPV 6, 11, 16, and 18) and
geometric mean titers and seroconversion rates in boys were noninferior to those in girls.
The efficacy and safety of three doses of Gardasil was also evaluated among 4065 boys and men
from 16 to 26 years of age in a randomized double-blind international trial [31]. A total of 3463 of the
subjects were heterosexual and 602 had sex with male partners. The primary efficacy objective was
to demonstrate that Gardasil reduced the incidence of external genital lesions (penile, scrotal and

peri-anal) related to HPV-6, 11, 16, or 18 as compared with placebo. The secondary endpoint was
to determine if immunization was protective against persistent HPV infection, which was defined as
detection of the same HPV type (6, 11, 16, or 18) in an anogenital swab or biopsy specimen over a
six-month time interval.
Efficacy analyses were performed in a per-protocol population, represented by patients who did
not have evidence of infection with the relevant HPV types at enrollment (ie, HPV 6, 11, 16, or 18)
and who received all three doses of vaccine. Additional intention-to-treat analyses were also
conducted for patients who received at least one dose of vaccine or placebo, regardless of baseline
HPV status. A total of 175 subjects did not return for follow-up after their first dose and were
eliminated from the analyses (with comparable numbers in each arm).
The trial demonstrated the following results:
Within one month after the third dose of vaccine, seroconversion for HPV-6, 11, 16, and 18
occurred in more than 97 percent of participants randomly assigned to the vaccine arm.
In the per protocol population, vaccine efficacy for genital lesions related to HPV-6, 11, 16, or
18 was 90 percent (95% CI 69-98).
In the intention to treat population, 36 external genital lesions were seen in the vaccine group
as compared with 89 in the placebo group for an overall efficacy rate of 60 percent (95% CI
41-74).
Protection against persistent infection with vaccine HPV types was significantly higher
among those patients who did not have HPV infection at baseline compared with those who
did (86 versus 48 percent).
Injection site pain was significantly higher among those receiving vaccine compared with
placebo (57 versus 51 percent).
When the analysis of efficacy was broken down into low- and high-risk HPV types, the vaccine was
associated with significant reductions in lesions related to HPV-6 and 11 and nonsignificant
reductions in lesions related to HPV 16 and 18. However, the study design was limited by the shortterm follow-up (median of 2.9 years) and the young age of the study population (since lesions, such
as penile intraepithelial neoplasia, tend to occur later in life).
Prevention of anal intraepithelial neoplasia As noted above, the HPV quadrivalent vaccine
was effective in preventing genital warts in a clinical trial involving 4065 males [31]. A planned
substudy of that trial analyzed the impact of HPV vaccine on the development of anal intraepithelial
neoplasia (AIN) in 602 men who have sex with men (MSM) [32]. The study population consisted of
HIV-seronegative males aged 16 to 26 years who had a history of five or fewer lifetime sexual
partners. The primary endpoint of the trial was the development of AIN associated with HPV types
6, 11, 16, or 18.
Two separate analyses were performed. The intent to treat analysis included all participants,
regardless of HPV positivity at baseline, who received at least one dose of vaccine and had at least
one follow-up visit. In a separate per protocol analysis, events were analyzed among patients
without evidence of HPV infection who completed the vaccine series. The trial demonstrated the
following findings:

In the per protocol population (n = 402), the incidence of AIN associated with HPV vaccine
types declined by 78 percent and the risk of persistent HPV declined by 95 percent compared
with those who received placebo.
In the intent-to-treat population, the overall incidence of AIN associated with HPV 6, 11, 16,
or 18 declined by 50 percent among those receiving vaccine compared with placebo (6.3
versus 12.6 events per 100 person years at risk).
The risk of persistent HPV infection with the relevant vaccine HPV types declined by 59
percent in the HPV vaccine recipients (8.8 versus 21.6 events per 100 person years at risk).
The results of this trial indicate that the use of the quadrivalent vaccine can decrease the incidence
of AIN related to HPV 6, 11, 16 and 18 in MSM.
The HPV vaccine has also been evaluated for secondary prevention of AIN in older HIV-uninfected
MSM previously treated for AIN grade 2 or worse lesions [33]. In a retrospective chart review
analysis of 202 such patients with a mean age of 40 years, the rate of subsequent detection of AIN
grade 2 or worse was lower in the 88 men who received the quadrivalent HPV vaccine compared
with the 114 who did not (10 versus 16 events per 100 person-years). The difference in incidence of
AIN grade 2 or worse after vaccination was even more pronounced among those having baseline
infection with oncogenic HPV types (15 versus 28 events per 100 person-years in the
unvaccinated). The association of vaccination with decreased detection of AIN grade 2 or worse
persisted for at least two years. Interpretation of this study was limited by significant clinical
heterogeneity between the two groups. The use of the quadrivalent HPV vaccine in this population
has yet to be evaluated in a randomized controlled trial. Moreover, there are no data on the
population effectiveness or cost effectiveness to support vaccination of this subgroup.
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Basics topics (see "Patient information: Human papillomavirus (HPV) vaccine (The Basics)")
Beyond the Basics topics (see "Patient information: Human papillomavirus (HPV) vaccine
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Two vaccines have been developed to protect against HPV infection, including a quadrivalent
vaccine that targets HPV 6, 11, 16, and 18 (Gardasil) and a bivalent vaccine that targets HPV
16 and 18 (Cervarix). HPV genotypes 16 and 18 are associated with the majority of cervical
cancers and cervical intraepithelial neoplasias worldwide, and HPV genotypes 6 and 11 are
associated with the vast majority of genital warts. (See 'Vaccine development' above.)

Gardasil has demonstrated efficacy against the development of cervical intraepithelial

neoplasia (CIN) 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV 16 or HPV
18 among the "HPV-naive" women and genital warts secondary to HPV 6 or 11.
(See 'Quadrivalent HPV 6/11/16/18 L1 virus-like particle vaccine'above.)
Cervarix has demonstrated efficacy against the development of CIN 2 or 3, adenocarcinoma
in situ, or cervical cancer among HPV-naive women. (See 'Bivalent HPV 16/18 L1 virus-like
particle vaccine' above.)
There is no evidence that either HPV vaccine formulation alters the course of vaccine-type
HPV infections present before immunization. These data reinforce the use of HPV vaccine to
prevent infection rather than as a therapeutic intervention to treat preexisting HPV infection
and related diseases. Maximal benefit of HPV immunization is therefore expected when
individuals are vaccinated prior to onset of sexual activity or as soon as possible after sexual
debut. (See 'Quadrivalent HPV 6/11/16/18 L1 virus-like particle vaccine' above and 'Bivalent
HPV 16/18 L1 virus-like particle vaccine' above.)
Gardasil has demonstrated efficacy against the development of genital warts and anal
intraepithelial neoplasia related to HPV 6, 11, 16, and 18 in males. (See'Clinical trials of HPV
vaccine in males' above.)
Indications for use and adverse events related to HPV immunization are discussed in detail
elsewhere. (See "Recommendations for the use of human papillomavirus vaccines".)
Vaccine efficacy is measured only by the prevention of virologic infection or related clinical
events. The immunogenicity of the HPV vaccines is not equated with vaccine efficacy primarily
because there is no established correlate between a titer level and protection against HPV
infection or the development of cervical intraepithelial neoplasia and/or cancer. (See 'Tools for
assessment of vaccine efficacy' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1.

Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and
L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology
1991; 185:251.

2.

Kirnbauer R, Booy F, Cheng N, et al. Papillomavirus L1 major capsid protein self-assembles

into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 1992; 89:12180.

3.

Harro CD, Pang YY, Roden RB, et al. Safety and immunogenicity trial in adult volunteers of
a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001; 93:284.

4.

Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16
vaccine. N Engl J Med 2002; 347:1645.

5.

Rowhani-Rahbar A, Mao C, Hughes JP, et al. Longer term efficacy of a prophylactic

monovalent human papillomavirus type 16 vaccine. Vaccine 2009; 27:5612.

6.

Kovacic MB, Castle PE, Herrero R, et al. Relationships of human papillomavirus type,
qualitative viral load, and age with cytologic abnormality. Cancer Res 2006; 66:10112.

7.

Rodriguez AC, Schiffman M, Herrero R, et al. Longitudinal study of HPV persistence and
CIN2/3: critical role of duration of infection. J Natl Cancer Inst 2009.

8.

FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent

high-grade cervical lesions. N Engl J Med 2007; 356:1915.

9.

Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human
papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928.

10.

Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1

viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA
2007; 298:743.

11.

Castle PE, Schiffman M, Herrero R, et al. A prospective study of age trends in cervical
human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis 2005;
191:1808.

12.

Muoz N, Manalastas R Jr, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of

quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45
years: a randomised, double-blind trial. Lancet 2009; 373:1949.

13.

Joura EA, Garland SM, Paavonen J, et al. Effect of the human papillomavirus (HPV)
quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled
analysis of trial data. BMJ 2012; 344:e1401.

14.

Brown DR, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus
(HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to
oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis
2009; 199:926.

15.

Wheeler CM, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human
papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease
due to oncogenic nonvaccine HPV types in sexually active women aged 16-26 years. J Infect Dis
2009; 199:936.

16.

Malagn T, Drolet M, Boily MC, et al. Cross-protective efficacy of two human papillomavirus
vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:781.

17.

Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent
human papillomavirus recombinant vaccine. JAMA 2009; 302:750.

18.

Paavonen J, Naud P, Salmern J, et al. Efficacy of human papillomavirus (HPV)-16/18

AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types
(PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009;
374:301.

19.

Herrero R, Hildesheim A, Rodrguez AC, et al. Rationale and design of a community-based

double-blind randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste, Costa Rica.
Vaccine 2008; 26:4795.

20.

Castle PE, Schmeler KM. HPV vaccination: for women of all ages? Lancet 2014; 384:2178.

21.

Skinner SR, Szarewski A, Romanowski B, et al. Efficacy, safety, and immunogenicity of the
human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim
follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet 2014;
384:2213.

22.

Villa LL, Ault KA, Giuliano AR, et al. Immunologic responses following administration of a
vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006; 24:5571.

23.

Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent
L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a
randomised control trial. Lancet 2006; 367:1247.

24.

GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, et al.

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted
vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 2009; 374:1975.

25.

Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and safety of
Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women
aged 18-45 years. Hum Vaccin 2009; 5:705.

26.

Giuliano AR, Lu B, Nielson CM, et al. Age-specific prevalence, incidence, and duration of
human papillomavirus infections in a cohort of 290 US men. J Infect Dis 2008; 198:827.

27.

Nielson CM, Flores R, Harris RB, et al. Human papillomavirus prevalence and type
distribution in male anogenital sites and semen. Cancer Epidemiol Biomarkers Prev 2007; 16:1107.

28.

Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine 2006; 24 Suppl
3:S3/11.

29.

Petj T, Kernen H, Karppa T, et al. Immunogenicity and safety of human papillomavirus

(HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10-18 years. J Adolesc Health 2009;
44:33.

30.

Reisinger KS, Block SL, Lazcano-Ponce E, et al. Safety and persistent immunogenicity of a
quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in
preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 2007; 26:201.

31.

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.

32.

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.

33.

Swedish KA, Factor SH, Goldstone SE. Prevention of recurrent high-grade anal neoplasia
with quadrivalent human papillomavirus vaccination of men who have sex with men: a
nonconcurrent cohort study. Clin Infect Dis 2012; 54:891.
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