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Vaccine Reports

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 in 915-Year-Old Girls
Timo Vesikari, MD, PhD,* Nicholas Brodszki, MD, Pierre van Damme, MD, PhD, Javier Diez-Domingo, MD, PhD,
Giancarlo Icardi, MD, Lone Kjeld Petersen, DMSc, Clment Tran, MSc,** Stphane Thomas, MSc,**
Alain Luxembourg, MD, PhD, and Martine Baudin, MD**
Background: A 9-valent human papillomavirus (9vHPV) vaccine has been
developed to prevent infections and diseases related to HPV 6/11/16/18 [as
per the licensed quadrivalent HPV (qHPV) vaccine], as well as 5 additional
oncogenic HPV types (HPV 31/33/45/52/58). Compared with the qHPV
vaccine, the 9vHPV vaccine potentially increases the coverage of protection
from 70% to 90% of cervical cancers. We compared the immunogenicity and
safety of the 9vHPV vaccine versus the qHPV vaccine in 915-year-old girls.
Methods: Participants (n = 600) were randomized to receive 9vHPV or
qHPV vaccines on day 1, month 2 and month 6. Serology testing was performed on day 1 and month 7. HPV type-specific antibody titers (anti-HPV
6/11/16/18/31/33/45/52/58) were determined by competitive Luminex
immunoassay and expressed as geometric mean titers and seroconversion
rates. Vaccine safety was also assessed.
Results: The HPV 6/11/16/18 immune responses elicited by the 9vHPV
vaccine were comparable with those elicited by the qHPV vaccine. All participants (except 1 for HPV 45) receiving the 9vHPV vaccine seroconverted
for HPV 31/33/45/52/58. The 9vHPV and qHPV vaccines showed comparable safety profiles, although the incidence of injection-site swelling was
higher in the 9vHPV vaccine group.
Conclusions: In addition to immune responses to HPV 31/33/45/52/58, a
3-dose regimen of the 9vHPV vaccine elicited a similar immune response to
HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 915
years. The safety profile was also similar for the 2 vaccines.

Accepted for publication April 14, 2015.


From the *Vaccine Research Centre, University of Tampere, Tampere, Finland;
Childrens Hospital, Lund University, Lund, Sweden; Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, University of
Antwerp, Antwerp, Belgium; Vaccine Research Department, FISABIOPublic Health, Valencia, Spain; Department of Health Sciences, University
of Genoa, IRCSS AOU San Martino-IST, Genoa, Italy; Department of
Gynaecology and Obstetrics, Aarhus University Hospital, Skejby, Denmark;
**Sanofi Pasteur MSD, Lyon, France; and Merck & Co., Inc., Whitehouse
Station, NJ.
This study was funded by Sanofi Pasteur MSD. T.V. has received payments in
respect of Board membership (Sanofi Pasteur MSD) and Consultancy (GSK,
Merck & Co., Novartis); N.B. has received payments in respect of Speaker
Bureaux services (MEDA Sweden); P.V.D. acts as investigator for Merck
vaccine trials conducted on behalf of the University of Antwerp, for which
the University obtains research grants; J.D-.D. has received payments in
respect of Consultancy (GSK) and Speaker Bureaux services (Pfizer); G.I.
has received payments in respect of Board membership (Sanofi Pasteur MSD
and GSK), meeting expenses (Sanofi Pasteur MSD and Pfizer) and research
grants from (Sanofi Pasteur MSD, GSK, Pfizer and Novartis); The institution of L.K.P. (Aarhus University Hospital, Skejby, Denmark) has received
research grants from Merck; A.L. is an employee of Merck & Co., Inc; C.T.,
S.T. and M.B. are employees of Sanofi Pasteur MSD.
Address for correspondence: Martine Baudin, MD, Sanofi Pasteur MSD, 162
avenue Jean Jaurs, CS 50712, 69367 Lyon Cedex 07, France. E-mail:
clinicaldevelopment@spmsd.com.
Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/15/3409-0992
DOI: 10.1097/INF.0000000000000773

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Key Words: human papillomavirus, cervical cancer, genital warts, vaccine,


immunogenicity
(Pediatr Infect Dis J 2015;34:992998)

nfection with human papillomavirus (HPV) can cause precancerous and cancerous lesions of the cervix, vagina, vulva, anus
and penis, and oropharyngeal cancers, as well as genital warts.110
The most clinically relevant HPV types are HPV 6/11/16/18, with
approximately 70% of all cervical cancers being caused by HPV
16/18 and approximately 90% of all genital warts being caused by
HPV 6/11.1114
The quadrivalent HPV (qHPV) virus-like particle (VLP)
prophylactic vaccine [4-valent HPV L1 VLP vaccine (recombinant,
adsorbed; Gardasil, Sanofi Pasteur MSD, Lyon, France, manufactured by Merck & Co., NJ)] against HPV types 6/11/16/18 was
licensed in 2006,15,16 and more than 183 million doses have been
administered (data on file). Clinical trials have shown the qHPV
vaccine to be effective in preventing infection by HPV 6/11/16/18
and protecting against cervical/vaginal/vulvar/anal dysplasia and
genital warts caused by HPV 6/11/16/18,1721 with a favorable safety
and tolerability profile.2228 Similarly, the bivalent HPV (16/18) VLP
vaccine was highly efficacious against HPV 16/18-related infection and cervical dysplasia29 and was well tolerated. Furthermore,
in countries with established vaccination programs, HPV vaccination has reduced, at a population level, the burden of HPV-related
diseases. Such programs have resulted in decreases in the incidence
of high-grade cervical abnormalities,3033 the prevalence of vaccine
HPV types3436 and the incidence of genital warts, as early as 3 years
after program implementation.3741
An investigational 9-valent HPV VLP (9vHPV) vaccine
has been developed by Merck & Co., NJ to protect against 5 additional oncogenic HPV types (31/33/45/52/58), as well as HPV
6/11/16/18. Current HPV vaccines address approximately 70% of
cervical cancers via protection from HPV 16/18. Partial cross-protection against nonvaccine HPV types has been reported for both
licensed vaccines, although its significance remains unproved over
time.42 The added value of the 9vHPV vaccine versus the qHPV
vaccine primarily concerns the prevention of cervical lesions, with
the 9vHPV vaccine offering the potential to protect against an additional 20% of cervical cancers and an additional 30% of high-grade
cervical intraepithelial neoplasias.2,43,44 Furthermore, the 9vHPV
vaccine may also protect against an extra 10% of vaginal/vulvar
cancers and high-grade vaginal/vulvar intraepithelial neoplasias1,45
and an extra 5% of anal cancers and high-grade anal intraepithelial
neoplasias.46
In developing a second-generation HPV vaccine, it must
be ensured that the adjusted composition of the existing HPV

The Pediatric Infectious Disease Journal Volume 34, Number 9, September 2015

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The Pediatric Infectious Disease Journal Volume 34, Number 9, September 2015

VLPs, addition of new HPV VLPs and adjuvant do not compromise the immunogenicity and efficacy against the HPV 16/18
VLPs contained in the first-generation vaccine, which has been
shown to be challenging in another HPV vaccine development
program.47 However, results from a phase IIb/III efficacy and
immunogenicity study in young women aged 1626 years have
shown that the 9vHPV vaccine elicits noninferior anti-HPV
6/11/16/18 responses compared with the qHPV vaccine and is
highly efficacious in preventing disease associated with the 9
vaccine HPV types.48
Efficacy studies of HPV vaccines are not conducted in
children aged 15 years because of low exposure to HPV in this
age group and the social, cultural and legal constraints regarding
gynecological examination in children. As a consequence, efficacy
findings in adults are extended to preadolescents/adolescents based
on similar vaccine immunogenicity profiles observed in adults
and preadolescents/adolescents.49 Results from a phase III study
demonstrated that the 9vHPV vaccine induces anti-HPV antibody
responses in girls and boys 915 years of age that are noninferior
to responses in young women 1626 years of age for all 9 vaccine
HPV types.50
This article reports the results from a study that was designed
to directly compare the immunogenicity for HPV 6/11/16/18 and
safety of the investigational 9vHPV vaccine versus the licensed
qHPV vaccine in 915-year-old girls.

MATERIALS AND METHODS


This was a multicenter, double-blind, randomized (1:1), controlled (with qHPV vaccine) study of the immunogenicity and tolerability of the 9vHPV vaccine in girls aged 915 years, conducted
in 24 centers across Belgium, Denmark, Finland, Italy, Spain and
Sweden (NCT01304498). Participating centers included hospitals,
pediatric and gynecological departments and vaccination clinics.
Participants were equally enrolled within 2 age strata (912 and
1315 years) to allow immune responses to be assessed separately
in young girls and adolescents.
The study was conducted in accordance with national and
local requirements regarding ethical committee review, the International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use, Good Clinical Practice standards, the Ethical Principles for Medical Research
Involving Human Subjects of the World Medical Association,
Declaration of Helsinki and local/national guidelines. Parents/
legal guardians provided written, informed consent, and assent was
obtained from participants before any study procedure.

Study Population
Eligible participants were girls aged 9 to <16 years at
enrolment, in good physical health, who were virgins and who
were not planning to become sexually active through month 7
of the study.
Individuals with a known allergy to any vaccine component,
a history of severe allergic reaction, thrombocytopenia, coagulation disorder, positive urine pregnancy test or a previous positive
HPV test were excluded. Others who were ineligible for the study
included those who were immunocompromised (including anyone
who had had a splenectomy), had received immunosuppressive
therapy in the previous year, had received immunoglobulin or a
blood-derived product within the previous 6 months, had enrolled
in any other clinical study of an investigational medicinal product,
had received a marketed HPV vaccine or participated in a previous
HPV vaccine clinical trial (active agent or placebo) or had a history
of any other condition that could confound study results or interfere
with participation in the study.
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Human Papillomavirus Virus Vaccine

Randomization
A central randomization system, which used an interactive
web response system, assigned participants to a vaccine group
(blinded) and an allocation number according to the randomized
allocation schedules. The randomized allocation schedule was agestratified (912 years and 1315 years), with a capping at 300 participants per stratum, and was based on balanced randomization
blocks of size 6 (ie, 50 blocks of size 6 per stratum). Participants
were randomized in a 1:1 ratio within each age stratum to receive
the investigational 9vHPV vaccine or the licensed qHPV vaccine.

Study Vaccination
The vaccines were administered as a 0.5-mL injection in the
deltoid muscle of the nondominant arm on day 1, and in month 2
and month 6. Participants were required to be afebrile (oral temperature <37.8C) for 24 hours before vaccination.

Vaccine Immunogenicity
Immunogenicity Objectives

The primary immunogenicity objective was to demonstrate that the 9vHPV vaccine induces noninferior geometric mean
titers (GMTs) for anti-HPV 16/18 versus the qHPV vaccine, at 4
weeks postdose 3. Secondary immunogenicity objectives were to
summarize the humoral immune response in terms of anti-HPV
6/11/16/18 GMTs and seroconversion rates at 4 weeks postdose 3.
The humoral immune response after vaccination with the 9vHPV
vaccine (anti-HPV 31/33/45/52/58 GMTs and seroconversion rates
at 4 weeks postdose 3) was investigated as exploratory immunogenicity objectives.

Immunoassay

Serum samples were obtained at day 1 and month 7 for antiHPV antibody testing. The serum samples were assessed for antibodies to HPV VLP types 6/11/16/18/31/33/45/52/58 by competitive Luminex immunoassay (HPV-9 cLIA Version 2.0; performed
by PPD Vaccines and Biologics Lab, Wayne, PA), as described
previously.51 Antibody titers for each individual HPV type were
determined using type-specific monoclonal antibodies, so it is not
possible to directly compare assay results across HPV types.
The serum samples from day 1 were analyzed to identify participants who were seropositive for each vaccine HPV type before
enrolment, and these participants were subsequently excluded from
the per-protocol immunogenicity analysis for the corresponding
HPV type.

Vaccine Safety and Tolerability


Participants were observed for 30 minutes after each vaccination for any immediate reaction. All subjects received a vaccination report card at the day 1, month 2 and month 6 study vaccination visits. Oral temperature was reported from day 1 to day 5 after
any vaccination, and injection-site reactions and systemic adverse
events (AEs) were recorded on the vaccination report card from day
1 to day 15 after any vaccination. An elevated temperature (fever)
was defined as maximum temperature 37.8C during the followup period. Investigators assigned causality to AEs based on exposure, time course, likely cause and consistency with the vaccines
known profile. Vaccine-related AEs were determined by the investigator to be possibly, probably or definitely vaccine-related. For each
AE, participants rated the symptom as mild (awareness of symptom
but easily tolerated), moderate (discomfort enough to cause interference with usual activities) or severe (incapacitating with inability to work or do usual activity); injection-site AEs of swelling and
erythema were rated by size. Serious AEs were predefined as any
AE that resulted in death, were deemed by the investigator to be
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Vesikari et al

life-threatening, resulted in a persistent or significant disability or


incapacity, resulted in or prolonged an existing in-patient hospitalization or was a congenital anomaly, a cancer or an other important
medical event. Serious AEs (SAEs) were monitored throughout
the study regardless of cause.

Statistical Methods
Sample Size and Power
The per-protocol set was to comprise participants who
received all 3 vaccinations, had a month 7 serology result, were
seronegative for the corresponding HPV type at day 1 and had no
protocol violations that could interfere with immune responses. It
was estimated that there would be approximately a 20% exclusion
rate from the per-protocol set, leaving 240 of 300 evaluable participants per vaccine group for the primary analysis.
The noninferiority margin was set at 0.67; the true GMT
ratio was estimated to be 1.0, and the standard deviation (natural
log scale) was estimated at 1.2 (for both HPV 16 and HPV 18 postvaccination titers). Based on these parameters, the study has over
90% power to demonstrate the noninferiority of the HPV 16/18
GMTs after vaccination with the 9vHPV vaccine versus the qHPV
vaccine.

Immunogenicity and Safety Analyses


Immunogenicity results are presented for the per-protocol
set. Noninferiority of anti-HPV 16 and anti-HPV 18 GMTs was
demonstrated by two 1-sided tests (1 for each HPV type) conducted at = 0.025 level (1-sided). Noninferiority was achieved
if the lower bound of the 2-sided 95% confidence intervals (CI)
for the GMT ratio (postdose 3 9vHPV vaccine GMT/postdose 3
qHPV vaccine GMT) was greater than 0.67. Each test was conducted using an analysis of variance model with a response of log
individual titers and a fixed effect for group and age strata (as per
randomization). Descriptive statistics were used for all other immunogenicity analyses.
Safety analyses are described for the safety set (all participants who received at least 1 study vaccine dose and for whom
safety follow-up data were available).

RESULTS
Study Population
A total of 603 individuals were screened between February
23, 2011 and May 11, 2011, of whom 600 were randomly allocated to receive either the 9vHPV or qHPV vaccine (Fig.1). Fortynine participants (9vHPV vaccine: n = 17, 5.7%; qHPV vaccine:

Screened
N = 603
Screening failures (n = 3)
Randomized
N = 600
9vHPV vaccine
qHPV vaccine
N = 300
N = 300
Received dose 1
N = 600
9vHPV vaccine
qHPV vaccine
N = 300
N = 300
Withdrawals (n = 2)

9vHPV vaccine
n=2
1
1

qHPV vaccine
n=0

9vHPV vaccine
n=2
1
1

qHPV vaccine
n=4
1
2
1

9vHPV vaccine
n=2
Participant withdrawal
1
Lost to follow-up
1

qHPV vaccine
n=1
1

Protocol violation
Lost to follow-up
Received dose 2
N = 598 (99.7%)
9vHPV vaccine
qHPV vaccine
N = 298 (99.3%)
N = 300 (100%)
Withdrawals (n = 6)

Received dose 3
N = 592 (98.7%)
9vHPV vaccine
qHPV vaccine
N = 296 (98.7%) N = 296 (98.7%)

Adverse event
Participant withdrawal
Lost to follow-up

Withdrawals (n = 3)

Completed the study


N = 589 (98.2%)
9vHPV vaccine
qHPV vaccine
N = 294 (98.0%) N = 295 (98.3%)

FIGURE 1. A summary of the disposition of participants throughout the study, from screening to study completion.

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The Pediatric Infectious Disease Journal Volume 34, Number 9, September 2015

dose was 12.6 years. Baseline characteristics were comparable


between vaccine groups (Table1).

TABLE 1. Demographic Characteristics


9vHPV Vaccine
(N = 300)
Age at first dose, yr
Mean (SD)
12.6 (1.9)
Range
9.016.0
912 yr, n
150
Mean (SD)
10.9 (1.0)
1315 yr, n
150
Mean (SD)
14.3 (0.8)
Height, cm
Mean (SD)
154.6 (10.9)
Weight, kg
Mean (SD)
48.1 (12.6)

Human Papillomavirus Virus Vaccine

qHPV Vaccine
(N = 300)

All (N = 600)

12.6 (1.9)
9.016.0
150
11.0 (1.0)
150
14.3 (0.8)

12.6 (1.9)
9.016.0
300
11.0 (1.0)
150
14.3 (0.8)

155.0 (10.6)

154.8 (10.7)

47.4 (11.5)

47.8 (12.1)

qHPV types are 6/11/16/18; SD indicates standard deviation.

n = 32, 10.7%) were seropositive for at least 1 vaccine HPV type at


baseline and were excluded from the per-protocol set for the corresponding HPV type. The per-protocol set included 547 (91.2%)
participants (9vHPV vaccine: n = 276; qHPV vaccine: n = 271),
and the safety set included 599 participants (1 participant was lost
to follow-up before providing any safety data). Mean age at first

Vaccine Immunogenicity
Anti-HPV 6/11/16/18 Antibody Responses
Anti-HPV 16 and anti-HPV 18 GMTs postdose 3 (Table 2)
were similar between vaccines (anti-HPV 16 GMTs: 6739.5 vs.
6887.4 mMU/mL for 9vHPV and qHPV vaccines, respectively;
anti-HPV 18 GMTs: 1956.6 vs. 1795.6 mMU/mL for 9vHPV
and qHPV vaccines, respectively). Anti-HPV 16 and anti-HPV 18
GMTs elicited by the 9vHPV vaccine were noninferior to those elicited by the qHPV vaccine [the lower bound of the 2-sided 95% CI
for the GMT ratio (9vHPV vaccine/qHPV vaccine) was >0.67, and
the 95% CI included 1.0 for both HPV types; P <0.001; Table 2].
Anti-HPV 6 and anti-HPV 11 GMTs postdose 3 were
numerically similar between vaccines (anti-HPV 6: 1679.4 vs.
1565.9 mMU/mL for 9vHPV vs. qHPV vaccines, respectively;
anti-HPV 11: 1315.6 vs. 1417.3 mMU/mL for 9vHPV vs. qHPV
vaccines, respectively). The 95% CI for the GMT ratio (9vHPV
vaccine/qHPV vaccine) included 1.0 for both HPV types.
When stratified by age (912 and 1315 years), anti-HPV 16
and anti-HPV 18 GMTs were numerically higher for the younger

TABLE 2. Summary and Comparison of Post Dose 3 Anti-HPV GMTs (Per-Protocol Set)
9vHPV Vaccine
Assay
(cLIA)
Anti-HPV 16
All
912 yr
1315 yr
Anti-HPV 18
All
912 yr
1315 yr
Anti-HPV 6
All
912 yr
1315 yr
Anti-HPV 11
All
912 yr
1315 yr
Anti-HPV 31
All
912 yr
1315 yr
Anti-HPV 33
All
912 yr
1315 yr
Anti-HPV 45
All
912 yr
1315 yr
Anti-HPV 52
All
912 yr
1315 yr
Anti-HPV 58
All
912 yr
1315 yr

Seropositivity
cut-off value
(mMU/mL)
20

24

30

16

10

GMT
(mMU/mL)

qHPV Vaccine

95% CI

GMT
(mMU/mL)

95% CI

Estimated GMT
Ratio 9vHPV/
qHPV
(95% CI)

276
137
139

6739.5
8143.7
5592.6

6134.57404.1
7136.19293.5
4920.66356.3

270
131
139

6887.4
8426.8
5695

6220.87625.5
7346.19666.3
4930.86577.7

0.97 (0.851.11)*
0.97 (0.801.17)
0.98 (0.811.19)

276
137
139

1956.6
2475.5
1551.8

1737.32203.7
2117.52894.0
1306.31843.5

269
131
138

1795.6
2474.1
1324.6

1567.22057.3
2065.82963.0
1094.31603.5

1.08 (0.911.29)*
1.00 (0.791.27)
1.17 (0.911.51)

273
135
138

1679.4
2013.2
1406.5

1518.91856.9
1770.02289.8
1211.31633.2

261
129
132

1565.9
1919.8
1283.2

1412.21736.3
1673.02203.1
1107.11487.2

1.07 (0.931.23)
1.05 (0.871.26)
1.10 (0.891.35)

273
135
138

1315.6
1571.6
1105.5

1183.81462.0
1375.51795.6
942.71296.4

261
129
132

1417.3
1662.6
1212.6

1274.21576.5
1437.81922.5
1041.11412.3

0.93 (0.801.08)
0.95 (0.781.15)
0.91 (0.731.14)

276
137
139

1770.4
2111.8
1488

1585.71976.6
1818.12452.9
1270.51742.7

268
131
137

22.2
28.4
17.5

18.926.1
22.535.8
14.021.9

275
136
139

937.1
1088.1
809.7

845.31038.9
941.91257.1
700.6935.8

269
131
138

4
4.8
3.4

3.64.5
4.05.7
3.03.9

275
137
138

622.4
728.8
532.1

545.4710.2
605.4877.4
441.6641.1

271
132
139

3.2
3.9
2.7

2.83.6
3.24.6
2.33.2

276
137
139

927.3
1092.1
789.3

837.51026.9
951.21254.0
681.7913.8

269
131
138

1.9
1.9
1.9

1.82.1
1.82.1
1.72.1

267
130
137

1348.8
1538.7
1190.3

1218.31493.2
1340.31766.4
1027.01379.5

261
128
133

9.4
12.8
7

8.110.9
10.315.9
5.88.4

*Noninferiority was achieved, as the lower bound of the 2-sided 95% CI for the GMT ratio was greater than 0.67. The estimated GMT ratio and associated CI are based on an
analysis of variance model including group and age stratum as independent variables.
CI, confidence intervals; cLIA, competitive Luminex immunoassay; n, number of participants with available data; qHPV types are 6/11/16/18.

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Vesikari et al

TABLE 3. Summary of Safety for Days 1 Through Month 7 After Any Vaccination
(Safety Set)
9vHPV Vaccine
(N = 299),
n (%)
No AE
One or more AE
With one or more vaccine-related AE
Injection-site adverse reaction from days 1 to 5
Solicited injection-site adverse reaction
Injection-site erythema
Injection-site pain
Injection-site swelling*
Other injection-site adverse reaction
Systemic AE from days 115
Vaccine-related systemic AE
Serious AE at any time
Serious vaccine-related adverse reaction
Death
Withdrawn due to an AE at any time
Withdrawn due to a vaccine-related adverse reaction
Withdrawn due to a serious AE
Withdrawn due to a serious vaccine-related adverse reaction

12 (4.0)
287 (96.0)
279 (93.3)
274 (91.6)
274 (91.6)
102 (34.1)
267 (89.3)
143 (47.8)
35 (11.7)
142 (47.5)
62 (20.7)
1 (0.3)
0 (0)
0 (0)
1 (0.3)
0 (0)
1 (0.3)
0 (0)

qHPV Vaccine
(N = 300),
n (%)
19 (6.3)
281 (93.7)
271 (90.3)
265 (88.3)
265 (88.3)
88 (29.3)
265 (88.3)
108 (36.0)
42 (14.0)
156 (52.0)
73 (24.3)
2 (0.7)
0 (0)
0 (0)
1 (0.3)
0 (0)
1 (0.3)
0 (0)

*The difference in AE incidence between vaccines was statistically significant only for injection-site swelling (P = 0.003).
n indicates number of participants presenting at least once with the considered event; qHPV types are 6/11/16/18.

age group and comparable for both vaccines (Table2). A similar profile was observed for anti-HPV 6 and anti-HPV 11 GMTs
(Table2).
All participants seroconverted for HPV 6/11/16/18 after
receiving 3 doses of the 9vHPV vaccine or qHPV vaccine.

Anti-HPV 31/33/45/52/58 Antibody Responses


As shown in Table 2, robust anti-HPV 31/33/45/52/58
GMTs postdose 3 were elicited by the 9vHPV vaccine. Anti-HPV
31/33/45/52/58 GMTs postdose 3 were numerically greater by 12
orders of magnitude in the 9vHPV vaccine group compared with
the qHPV vaccine group. Anti-HPV 31/33/45/52/58 GMTs were
numerically higher in 912 year olds than in 1315 year olds. All
participants seroconverted for HPV 31/33/45/52/58 after receiving
3 doses of the 9vHPV vaccine, except 1 participant who did not
seroconvert for HPV 45. This participant, who was 9 years of age
at the time of the first injection, had no relevant medical history
reported at baseline and was seronegative for all 9 HPV types before
vaccination. This participant also had low immune responses to the
other 8 HPV types with antibody titers generally 6- fold to 17-fold
lower than the GMTs. Although the GMTs were low, the qHPV
vaccine also induced some level of postdose 3 immune responses
to the HPV types not included in the vaccine (GMTs are shown in
Table 2), including a seroconversion rate as high as 73.5% for HPV
31 and 54.8% for HPV 58.

Vaccine Tolerability
Most participants experienced at least 1 AE during the
study. Vaccine-related AEs were reported for 93.3% of participants
receiving the 9vHPV vaccine and 90.3% of participants receiving
the qHPV vaccine from day 1 to month 7 (Table3).
A comparable percentage of participants reported at least
1 injection-site reaction from day 1 to day 5 after vaccination
(9vHPV vaccine: 91.6%; qHPV vaccine: 88.3%). Although more
participants reported swelling after receiving the 9vHPV vaccine
(47.8%) compared with the qHPV vaccine (36.0%; P = 0.003),
severe injection-site swelling (>5cm) was reported in a similar
proportion of participants in each vaccine group (9vHPV vaccine:
6.0%; qHPV vaccine: 6.3%).

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Vaccine-related systemic AEs were reported for 20.7% and


24.3% of participants receiving the 9vHPV and qHPV vaccines,
respectively. The most common vaccine-related systemic AEs in
the 9vHPV vaccine group were headache (11.4%), pyrexia (5.0%),
nausea (3.0%), oropharyngeal pain (2.7%) and upper abdominal
pain (1.7%). Among participants receiving the qHPV vaccine,
the most frequent vaccine-related systemic AEs were headache
(11.3%), nausea (3.7%), pyrexia (2.7%), fatigue (2.7%) and upper
abdominal pain (1.3%).
Three participants experienced SAEs, which led to the withdrawal of 2 participants from the study. None of these SAEs were
considered by the investigators as vaccine related. (1) A 13-yearold girl with no prior medical history experienced anemia and pulmonary vasculitis with positive antinuclear antibodies, diagnosed
approximately 2 months after the second dose of 9vHPV vaccine.
She was treated with cyclophosphamide and prednisone and fully
recovered. Further testing demonstrated positive antinuclear antibodies in a prevaccination serum sample. Within 33 months after
the resolution of the SAE, the participant reported no major medical
problems, and systemic autoimmune conditions, such as Wegeners
granulomatosis, microscopic polyangiitis or lupus pneumonia,
were ruled out. (2) A 12-year-old girl with no prior medical history experienced HenochSchnlein purpura 46 days after receiving the second dose of qHPV vaccine. She fully recovered and did
not receive the third dose of qHPV vaccine; it was noted that the
participant had otitis media, treated with amoxicillin, 2 days before
the onset of purpura. (3) A 14-year-old girl with no prior medical
history experienced complex partial seizures 36 days after receiving the first dose of the qHPV vaccine. She was treated with oxcarbazepine, which ended the seizures, and she received doses 2 and 3
without experiencing any further AEs.

DISCUSSION
In this study comparing the 9vHPV vaccine and the qHPV
vaccine in girls aged 915 years, we observed a similar antibody
response for HPV types 6/11/16/18 after a 3-dose regimen of the
9vHPV or qHPV vaccines. As the antibody responses to the oncogenic HPV types 16 and 18 elicited by the 9vHPV vaccine were
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Copyright 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

The Pediatric Infectious Disease Journal Volume 34, Number 9, September 2015

noninferior to those elicited by the qHPV vaccine, the primary


objective of the study was met. As the HPV 6/11/16/18 immune
responses elicited by the 9vHPV vaccine were demonstrated to be
similar to those elicited by the qHPV vaccine, the efficacy of the
9vHPV vaccine against HPV 6/11/16/18 can be inferred to be comparable with that of the qHPV vaccine.
The safety and tolerability profile was similar for the 2 vaccines and comparable with that observed previously in 1626-yearold women.48 The higher incidence of swelling reported with the
9vHPV vaccine versus the qHPV vaccine could be because of the
higher dose of VLPs and adjuvant contained in the 9vHPV vaccine.
However, HBVaxPro 10 g (Sanofi Pasteur MSD, manufactured by
Merck & Co.), which has been widely administered to children
and young adults and has a proven favorable safety profile,52 contains the same quantity of the same adjuvant as the 9vHPV vaccine. Moreover, there were no withdrawals from the study because
of injection-site reactions, so we do not anticipate injection-site
swelling to have a significant impact on vaccine uptake.
A relationship was observed between antibody response and
the age of the vaccine recipients, with higher GMTs obtained in
younger participants. Similar findings have also been reported in
the qHPV vaccine clinical development program.53 As it is anticipated that long-term immunogenicity, safety and effectiveness data
for the 9vHPV vaccine will be comparable with that for the qHPV
vaccine, this age-effect supports vaccination of children at the
younger end of the 915-year-old cohort.
Seroconversion rates for the nonvaccine HPV types after vaccination with the qHPV vaccine indicate the induction of cross-reactive antibodies, especially for HPV 31/58. Some degree of cross-protection for HPV 31/58 has been previously reported after vaccination
with the qHPV vaccine.54 However, in the current study, the GMTs
induced by the qHPV vaccine against HPV 31/33/45/52/58 were
much lower than those obtained after vaccination with the 9vHPV
vaccine. This correlates with a previous observation that protection
against nonvaccine HPV types was not reported to be of the same
magnitude over time as protection against vaccine HPV types.55
A recent study demonstrated that administration of a 2-dose
regimen of qHPV vaccine in girls aged 913 years induced antiHPV GMTs that were noninferior to those elicited by administration of a 3-dose regimen in young women aged 1626 years,56
thereby supporting that a 2-dose regimen may be an acceptable
alternative to a 3-dose regimen. Because the 9vHPV vaccine and
qHPV vaccine have similar immunogenicity profiles, it is anticipated that similar results may be verified with the 9vHPV vaccine.

CONCLUSION
A 3-dose regimen of the 9vHPV vaccine elicited a similar
immune response to HPV 6/11/16/18 when compared with the
qHPV vaccine in girls aged 915 years. The safety and tolerability
profile was also similar for the 2 vaccines, although more injection-site reactions were seen with the 9vHPV vaccine. We would
expect the efficacy of the 9vHPV vaccine against HPV 6/11/16/18
to be comparable with that of the qHPV vaccine based on the
immunogenicity of both vaccines in the primary vaccination
cohort (915-year-old girls). Furthermore, as recently reported,
the 9vHPV vaccine offers additional clinical benefit because of
the protection it offers against HPV types 31/33/45/52/58.48

ACKNOWLEDGMENTS
The authors take full responsibility for the content of this
contribution and thank Communigen Ltd, Oxford, United Kingdom
(supported by Sanofi Pasteur MSD) for preparing the manuscript
drafts.
2015 Wolters Kluwer Health, Inc. All rights reserved.

Human Papillomavirus Virus Vaccine

The authors thank the study participants, as well as the


investigators and their study-site personnel for their contribution
to the study: Belgium: Karel Hoppenbrouwers and Etienne Sokal;
Denmark: Ole Mogensen, Danny Svane and Kim Toftager-Larsen;
Finland: Anitta Ahonen, Tiina Karppa, Aino Karvonen (Forsten),
Pia-Maria Lagerstrm-Tirri and Samuli Rounioja; Italy: Maria
Desole, Giancarlo Tisi, Alberto Tozzi and Massimo Zuliani;
Spain: Mara Garces Sanchez, Federico Martinon Torres, Miguel
Tortajada, Isabel beda and ngels Ulied; Sweden: Kristiina
Kask, Lennart Nilsson, Sven-Eric Olsson and Jan Wall.
The authors also thank Xavier Cornen, Armelle Marais and
Catherine Lambermont (Sanofi Pasteur MSD, Lyon, France) and
Leena Kmri (TFS Develop, Espoo, Finland) for their contribution to the conduct of the study; Sandrine Samson (Sanofi Pasteur
MSD, Lyon, France) for her critical review of the manuscript and
Rhonda Heffelfinger-Wenner (PPD Vaccine and Biologics, LLC,
Wayne, PA) for overseeing the immune tests.
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