CLINICAL PHARMACOLOGY
Mechanism Of Action
Animal studies suggest that the efficacy of L1 VLP
vaccines may be mediated by the development of IgG neutralizing antibodies
directed against HPV-L1 capsid proteins generated as a result of vaccination.
Clinical Studies
Cervical intraepithelial neoplasia (CIN) Grade 2 and 3
lesions or cervical adenocarcinoma in situ (AIS) are the immediate and
necessary precursors of squamous cell carcinoma and adenocarcinoma of the
cervix, respectively. Their detection and removal has been shown to prevent
cancer. Therefore, CIN2/3 and AIS (precancerous lesions) serve as surrogate
markers for the prevention of cervical cancer. In clinical studies to evaluate
the efficacy of CERVARIX, the endpoints were cases of CIN2/3 and AIS associated
with HPV-16, HPV-18, and other oncogenic HPV types. Persistent infection with
HPV-16 and HPV-18 that lasts for 12 months was also an endpoint.
The efficacy of CERVARIX to prevent
histopathologically-confirmed CIN2/3 or AIS was assessed in 2 double-blind,
randomized, controlled clinical studies that enrolled a total of 19,778 females
15 through 25 years of age.
Study 1 (HPV 001) enrolled women who were negative for
oncogenic HPV DNA (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
66, and 68) in cervical samples, seronegative for HPV-16 and HPV-18 antibodies,
and had normal cytology. This represents a population presumed “naive” without
current HPV infection at the time of vaccination and without prior exposure to
either HPV-16 or HPV-18. Subjects were enrolled in an extended follow-up study (Study
1 Extension [HPV 007]) to evaluate the long-term efficacy, immunogenicity, and
safety. These subjects have been followed for up to 6.4 years.
In Study 2 (HPV 008), women were vaccinated regardless of
baseline HPV DNA status, serostatus, or cytology. This study reflects a population
of women naive (without current infection and without prior exposure) or
non-naive (with current infection and/or with prior exposure) to HPV. Before
vaccination, cervical samples were assessed for oncogenic HPV DNA (HPV types
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and serostatus of
HPV-16 and HPV-18 antibodies.
In both studies, testing for oncogenic HPV types was
conducted using SPF10-LiPA25 PCR to detect HPV DNA in archived biopsy samples.
Prophylactic Efficacy Against HPV Types 16 And 18
Study 2
A randomized, double-blind, controlled clinical trial was
conducted in which 18,665 healthy females 15 through 25 years of age received
CERVARIX or Hepatitis A Vaccine control on a 0-, 1-, and 6-month schedule.
Among subjects, 54.8% of subjects were white, 31.5% Asian, 7.1% Hispanic, 3.7%
black, and 2.9% were of other racial/ethnic groups.
In this study, women were randomized and vaccinated
regardless of baseline HPV DNA status, serostatus, or cytology. Women with
HPV-16 or HPV-18 DNA present in baseline cervical samples (HPV DNA positive) at
study entry were considered currently infected with that specific HPV type. If
HPV DNA was not detected by PCR, women were considered HPV DNA negative. Additionally,
cervical samples were assessed for cytologic abnormalities and serologic
testing was performed for anti-HPV-16 and anti-HPV-18 serum antibodies at
baseline. Women with anti-HPV serum antibodies present were considered to have
prior exposure to HPV and characterized as seropositive. Women seropositive
for HPV-16 or HPV-18 but DNA negative for that specific serotype were
considered as having cleared a previous natural infection. Women without
antibodies to HPV-16 and HPV-18 were characterized as seronegative. Before vaccination,
73.6% of subjects were naive (without current infection [DNA negative] and without
prior exposure [seronegative]) to HPV-16 and/or HPV-18.
Efficacy endpoints included histological evaluation of
precancerous and dysplastic lesions (CIN Grade 1, Grade 2, or Grade 3), and
AIS. Virological endpoints (HPV DNA in cervical samples detected by PCR)
included 12-month persistent infection (defined as at least 2 positive specimens
for the same HPV type over a minimum interval of 10 months).
The according-to-protocol (ATP) cohort for efficacy
analyses for HPV-16 and/or HPV-18 included all subjects who received 3 doses of
vaccine, for whom efficacy endpoint measures were available and who were HPV-16
and/or HPV-18 DNA negative and seronegative at baseline and HPV-16 and/or
HPV-18 DNA negative at Month 6 for the HPV type considered in the analysis.
Case counting for the ATP cohort started on Day 1 after the third dose of
vaccine. This cohort included women who had normal or low-grade cytology
(cytological abnormalities including atypical squamous cells of undetermined
significance [ASC-US] or low-grade squamous intraepithelial lesions [LSIL]) at
baseline and excluded women with high-grade cytology.
The total vaccinated cohort (TVC) for each efficacy
analysis included all subjects who received at least one dose of the vaccine,
for whom efficacy endpoint measures were available, irrespective of their HPV
DNA status, cytology, and serostatus at baseline. This cohort included women
with or without current HPV infection and/or prior exposure. Case counting for
the TVC started on Day 1 after the first dose.
The TVC naive is a subset of the TVC that had normal
cytology and were HPV DNA negative for 14 oncogenic HPV types and seronegative
for HPV-16 and HPV-18 at baseline.
The pre-defined final analysis was event-triggered, i.e.,
performed when at least 36 CIN2/3 or AIS cases associated with HPV-16 or HPV-18
were accrued in the ATP cohort. The mean follow-up after the first dose was
approximately 39 months and included approximately 3,300 women who completed
the Month 48 visit.
The pre-defined end-of-study analysis was performed at
the end of the 4-year follow-up period (i.e., after all subjects completed the
Month 48 visit) and included all subjects from the TVC. The mean follow-up
after the first dose was approximately 44 months and included approximately
15,600 women who completed the Month 48 visit.
CERVARIX was efficacious in the prevention of
precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 5).
Table 5: Efficacy of CERVARIX against
Histopathological Lesions Associated with HPV- 16 or HPV-18 in Females 15
through 25 Years of Age (According-to-Protocol Cohorta) (Study 2)
|
Final Analysis |
End-of-Study Analysis |
CERVARIX |
Controlb |
% Efficacy (96.1% CI)c |
CERVARIX |
Controlb |
% Efficacy (95% CI) |
N |
n |
N |
n |
N |
n |
N |
n |
CIN2/3 or AIS |
7,344 |
4 |
7,312 |
56 |
92.9 (79.9, 98.3) |
7,338 |
5 |
7,305 |
97 |
94.9 (87.7, 98.4) |
CIN1/2/ 3 or AIS |
7,344 |
8 |
7,312 |
96 |
91.7 (82.4, 96.7) |
7,338 |
12 |
7,305 |
165 |
92.8 (87.1, 96.4) |
CI = Confidence Interval; n = Number of cases.
a Subjects (including women who had normal cytology, ASC-US, or LSIL
at baseline) who received 3 doses of vaccine and were HPV DNA negative and
seronegative at baseline and HPV DNA negative at Month 6 for the corresponding
HPV type (N).
bHepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg
Al(OH)3].
c The 96.1% confidence interval reflected in the final analysis
results from statistical adjustment for the previously conducted interim
analysis. |
Since CIN3 or AIS represents a more immediate precursor
to cervical cancer, cases of CIN3 or AIS associated with HPV-16 or HPV-18 were
evaluated. In the ATP cohort, CERVARIX was efficacious in the prevention of
CIN3 or AIS associated with HPV-16 or HPV-18 in the final analysis (80.0%
[96.1% CI: 0.3, 98.1]); these results were confirmed in the end-of-study
analysis (91.7% [95% CI: 66.6, 99.1]).
Subjects who were already infected with one vaccine HPV
type (16 or 18) prior to vaccination were protected from precancerous lesions
or AIS and infection caused by the other vaccine HPV type.
Efficacy of CERVARIX against 12-month persistent
infection with HPV-16 or HPV-18 was also evaluated. In the ATP cohort, CERVARIX
reduced the incidence of 12-month persistent infection with HPV-16 and/or
HPV-18 by 91.4% (96.1% CI: 86.1, 95.0) in the final analysis; these results
were confirmed in the end-of-study analysis (92.9% [95% CI: 89.4, 95.4]).
Immune response following natural infection does not
reliably confer protection against future infections. Among subjects who
received 3 doses of CERVARIX and who were seropositive at baseline and DNA
negative for HPV-16 or HPV-18 at baseline and Month 6, CERVARIX reduced the
incidence of 12-month persistent infection by 95.8% (96.1% CI: 72.4, 99.9) in
the final analysis; these results were confirmed in the end-of-study analysis (94.0%
[95% CI: 76.7, 99.3]). However, the number of cases of CIN2/3 or AIS was too
few in these analyses to determine efficacy against histopathological endpoints
in this population.
Study 1 And Study 1 Extension
In a second double-blind, randomized, controlled study
(Study 1), the efficacy of CERVARIX in the prevention of HPV-16 or HPV-18
incident and persistent infections was compared with aluminum hydroxide control
in 1,113 females 15 through 25 years of age. The population was naive to
current oncogenic HPV infection or prior exposure to HPV-16 and HPV-18 at the
time of vaccination (total cohort). A total of 776 subjects were enrolled in
the extended follow-up study (Study 1 Extension) to evaluate the long-term
efficacy, immunogenicity, and safety of CERVARIX. These subjects have been
followed for up to 6.4 years.
In Study 1 and Study 1 Extension, with up to 6.4 years of
follow-up (mean 5.9 years), in naïve females 15 through 25 years of age,
efficacy against CIN2/3 or AIS associated with HPV-16 or HPV-18 was 100%
(98.67% CI: 28.4, 100). Efficacy against 12-month persistent infection with HPV-16
or HPV-18 was 100% (98.67% CI: 74.4, 100). The confidence interval reflected in
this final analysis results from statistical adjustment for analyses previously
conducted.
Efficacy Against HPV Types 16 And 18, Regardless Of Current
Infection Or Prior Exposure To HPV-16 Or HPV-18
Study 2
The study included women regardless of HPV DNA status
(current infection) and serostatus (prior exposure) to vaccine types HPV-16 or
HPV-18 at baseline. Efficacy analyses included lesions arising among women
regardless of baseline DNA status and serostatus, including HPV infections
present at first vaccination and those from infections acquired after Dose 1.
In this population, which includes naive (without current infection and prior
exposure) and non-naïve women, CERVARIX was efficacious in the prevention of
precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 6).
However, among women HPV DNA positive regardless of serostatus
at baseline, there was no clear evidence of efficacy against precancerous
lesions or AIS associated with HPV-16 or HPV-18 (Table 6).
Table 6: Efficacy of CERVARIX against Disease
Associated with HPV-16 or HPV-18 in Females 15 through 25 Years of Age,
Regardless of Current or Prior Exposure to Vaccine HPV Types (Study 2)
|
Final Analysis |
End-of-Study Analysis |
CERVARIX |
Controla |
% Efficacy (96.1% CI)b |
CERVARIX |
Controla |
% Efficacy (95% CI) |
N |
n |
N |
n |
N |
n |
N |
n |
CIN1/2/3 or AIS |
Prophylactic Efficacyc |
5,449 |
3 |
5,436 |
85 |
96.5 (89.0, 99.4) |
5,466 |
5 |
5,452 |
141 |
96.5 (91.6, 98.9) |
HPV-16 or 18 DNA Positive at Baselined |
641 |
90 |
592 |
92 |
|
642 |
99 |
593 |
101 |
|
Regardless of Baseline Statuse |
8,667 |
107 |
8,682 |
240 |
55.5f (43.2, 65.3) |
8,694 |
121 |
8,708 |
324 |
62.9f (54.1, 70.1) |
CIN2/3 or AIS |
Prophylactic Efficacyc |
5,449 |
1 |
5,436 |
63 |
98.4 (90.4, 100) |
5,466 |
1 |
5,452 |
97 |
99.0 (94.2, 100) |
HPV-16 or 18 DNA Positive at Baselined |
641 |
74 |
592 |
73 |
|
642 |
80 |
593 |
82 |
|
Regardless of Baseline Statuse |
8,667 |
82 |
8,682 |
174 |
52.8f (37.5, 64.7) |
8,694 |
90 |
8,708 |
228 |
60.7f (49.6, 69.5) |
CIN3 or AIS |
Prophylactic Efficacyc |
5,449 |
0 |
5,436 |
13 |
100 (64.7, 100) |
5,466 |
0 |
5,452 |
27 |
100 (85.5, 100) |
HPV-16 or 18 DNA Positive at Baselined |
641 |
41 |
592 |
38 |
|
642 |
48 |
593 |
47 |
|
Regardless of Baseline Statuse |
8,667 |
43 |
8,682 |
65 |
33.6f (-1.1, 56.9) |
8,694 |
51 |
8,708 |
94 |
45.7f (22.9, 62.2) |
CI = Confidence Interval; n = Number of histopathological
cases associated with HPV-16 and/or HPV-18.
Table does not include disease due to non-vaccine HPV types.
a Hepatitis A Vaccine control group [720 EL.U. of antigen and 500
mcg Al(OH)3].
b The 96.1% confidence interval reflected in the final analysis
results from statistical adjustment for the previously conducted interim
analysis.
c TVC naive: Includes all vaccinated subjects (who received at least
one dose of vaccine) who had normal cytology, were HPV DNA negative for 14
oncogenic HPV types, and seronegative for HPV-16 and HPV-18 at baseline (N).
Case counting started on Day 1 after the first dose.
dTVC subset: Includes all vaccinated subjects (who received at least
one dose of vaccine) who were HPV DNA positive for HPV-16 or HPV-18
irrespective of serostatus at baseline (N). Case counting started on Day 1
after the first dose.
e TVC: Includes all vaccinated subjects (who received at least one
dose of vaccine) irrespective of HPV DNA status and serostatus at baseline (N).
Case counting started on Day 1 after the first dose.
fObserved vaccine efficacy includes the prophylactic efficacy of
CERVARIX and the impact of CERVARIX on the course of infections present at
first vaccination. |
Efficacy Against Cervical Disease Irrespective Of HPV
Type, Regardless Of Current Or Prior Infection With Vaccine Or Non-vaccine HPV
Types
Study 2
The impact of CERVARIX against the overall burden of HPV-related
cervical disease results from a combination of prophylactic efficacy against,
and disease contribution of, HPV-16, HPV- 18, and non-vaccine HPV types.
In the population naive to oncogenic HPV (TVC naive),
CERVARIX reduced the overall incidence of CIN1/2/3 or AIS, CIN2/3 or AIS, and
CIN3 or AIS regardless of the HPV DNA type in the lesion (Table 7). In the
population of women naive and non-naive (TVC), vaccine efficacy against
CIN1/2/3 or AIS, CIN2/3 or AIS, and CIN3 or AIS was demonstrated in all women
regardless of HPV DNA type in the lesion (Table 7).
Table 7: Efficacy of CERVARIX in Prevention of CIN or
AIS Irrespective of Any HPV Type in Females 15 through 25 Years of Age,
Regardless of Current or Prior Infection with Vaccine or Non-vaccine Types
(Study 2)
|
Final Analysis |
End-of-Study Analysis |
CERVARIX |
Controla |
% Efficacy (96.1% CI)b |
CERVARIX |
Controla |
% Efficacy (95% CI) |
N |
n |
N |
n |
N |
n |
N |
n |
CIN1/2/3 or AIS |
Prophylactic Efficacyc |
5,449 |
106 |
5,436 |
211 |
50.1 (35.9, 61.4) |
5,466 |
174 |
5,452 |
346 |
50.3 (40.2, 58.8) |
Irrespective of HPV DNA at Baselined |
8,667 |
451 |
8,682 |
577 |
21.7 (10.7, 31.4) |
8,694 |
579 |
8,708 |
798 |
27.7 (19.5, 35.2) |
CIN2/3 or AIS |
Prophylactic Efficacyc |
5,449 |
33 |
5,436 |
110 |
70.2 (54.7, 80.9) |
5,466 |
61 |
5,452 |
172 |
64.9 (52.7, 74.2) |
Irrespective of HPV DNA at Baselined |
8,667 |
224 |
8,682 |
322 |
30.4 (16.4, 42.1) |
8,694 |
287 |
8,708 |
428 |
33.1 (22.2, 42.6) |
CIN3 or AIS |
Prophylactic Efficacyc |
5,449 |
3 |
5,436 |
23 |
87.0 (54.9, 97.7) |
5,466 |
3 |
5,452 |
44 |
93.2 (78.9, 98.7) |
Irrespective of HPV DNA at Baselined |
8,667 |
77 |
8,682 |
116 |
33.4 (9.1, 51.5) |
8,694 |
86 |
8,708 |
158 |
45.6 (28.8, 58.7) |
CI = Confidence Interval; n = Number of cases.
a Hepatitis A Vaccine control group [720 EL.U. of antigen and 500
mcg Al(OH)3].
bThe 96.1% confidence interval reflected in the final analysis
results from statistical adjustment for the previously conducted interim
analysis.
c TVC naive: Includes all vaccinated subjects (who received at least
one dose of vaccine) who had normal cytology, were HPV DNA negative for 14
oncogenic HPV types (including HPV-16 and HPV-18), and seronegative for HPV-16
and HPV-18 at baseline (N). Case counting started on Day 1 after the first
dose.
dTVC: Includes all vaccinated subjects (who received at least one
dose of vaccine) irrespective of HPV DNA status and serostatus at baseline (N).
Case counting started on Day 1 after the first dose. |
In exploratory end-of-study analyses, CERVARIX reduced
definitive cervical therapy procedures (includes loop electrosurgical excision
procedure [LEEP], cold-knife Cone, and laser procedures) by 33.2% (95% CI:
20.8, 43.7) in the TVC and by 70.2% (95% CI: 57.8, 79.3) in the TVC naive.
To assess reductions in disease caused by non-vaccine HPV
types, analyses were conducted combining 12 non-vaccine oncogenic HPV types,
including and excluding lesions in which HPV-16 or HPV-18 were also detected.
Among females who received 3 doses of CERVARIX and were DNA negative for the
specific HPV type at baseline and Month 6, CERVARIX reduced the incidence of
CIN2/3 or AIS in the final analysis by 54.0% (96.1% CI: 34.0, 68.4) and 37.4%
(96.1% CI: 7.4, 58.2), respectively. In the end-of-study analysis, CERVARIX reduced
the incidence of CIN2/3 or AIS by 46.8% (95% CI: 30.7, 59.4) and 24.1% (95% CI:
- 1.5, 43.5), respectively.
End-of-study analyses were conducted to assess the impact
of CERVARIX on CIN2/3 or AIS due to specific non-vaccine HPV types. The ATP
cohort for these analyses included all subjects irrespective of serostatus who
received 3 doses of CERVARIX and were DNA negative for the specific HPV type at
baseline and Month 6. These analyses were also conducted in the TVC-naive population.
In analyses including lesions in which HPV-16 or HPV-18
were also detected, vaccine efficacy in prevention of CIN2/3 or AIS associated
with HPV-31 was 87.5% (95% CI: 68.3, 96.1) and 89.4% (95% CI: 65.5, 97.9), respectively.
In analyses excluding lesions in which HPV-16 or HPV-18 were detected, vaccine
efficacy in prevention of CIN2/3 or AIS associated with HPV-31 was 84.3% (95%
CI: 59.5, 95.2) and 83.4% (95% CI: 43.3, 96.9), respectively.
Immunogenicity
The minimum anti-HPV titer that confers protective
efficacy has not been determined.
The antibody response to HPV-16 and HPV-18 was measured
using a type-specific binding ELISA (developed by GlaxoSmithKline) and a
pseudovirion-based neutralization assay (PBNA). In a subset of subjects tested
for HPV-16 and HPV-18, the ELISA has been shown to correlate with the PBNA. The
scales for these assays are unique to each HPV type and each assay, thus, comparison
between HPV types or assays is not appropriate.
Duration Of Immune Response
The duration of immunity following a complete schedule of
immunization with CERVARIX has not been established. In Study 1 and Study 1
Extension, the immune response against HPV-16 and HPV-18 was evaluated for up
to 76 months post-Dose 1, in females 15 through 25 years of age.
Vaccine-induced geometric mean titers (GMTs) for both HPV-16 and HPV-18 peaked
at Month 7 and thereafter reached a plateau that was sustained from Month 18 up
to Month 76. At all timepoints, >98% of subjects were seropositive for both
HPV-16 (≥8 EL.U./mL, the limit of detection) and HPV-18 (≥7
EL.U./mL, the limit of detection) by ELISA.
In Study 2, immunogenicity was measured by seropositivity
rates and GMTs for ELISA and PBNA (Table 8). The ATP cohort for immunogenicity
included all evaluable subjects for whom data concerning immunogenicity
endpoint measures were available. These included subjects for whom assay
results were available for antibodies against at least one vaccine type.
Subjects who acquired either HPV-16 or HPV-18 infection during the trial were
excluded.
Table 8: Persistence of Anti-HPV Geometric Mean Titers
(GMTs) and Seropositivity Rates for HPV-16 and HPV-18 for Initially
Seronegative Females 15 through 25 Years of Age (According-to-Protocol Cohort for
Immunogenicitya) (Study 2)
Time Point |
N |
% Seropositive (95% CI) |
GMT (95% CI) |
Anti-HPV-16 ELISAb (EL.U./mL) |
Month 7 |
816 |
99.5 |
9,120.0
(8,504.9, 9,779.7) |
Month 12 |
793 |
99.7 |
3,266.3
(3,043.3, 3,505.6) |
Month 24 |
755 |
99.9 |
1,587.7
(1,484.8, 1,697.7) |
Month 36 |
759 |
100 |
1,281.7
(1,198.3, 1,370.9) |
Month 48 |
746 |
100 |
1,174.3
(1,096.1, 1,258.0) |
Anti-HPV-18 ELISAb (EL.U./mL) |
Month 7 |
879 |
99.4 |
4,682.9
(4,388.8, 4,996.7) |
Month 12 |
853 |
100 |
1,514.7
(1,422.3, 1,613.0) |
Month 24 |
810 |
99.9 |
702.2
(655.2, 752.6) |
Month 36 |
817 |
100 |
538.1
(502.0, 576.8) |
Month 48 |
806 |
99.8 |
476.2
(443.2, 511.6) |
Anti-HPV-16 PBNAc (ED50) |
Month 7 |
46 |
100 |
26,457.0
(19,167.5, 36,518.6) |
Month 12 |
45 |
100 |
7,885.5
(5,500.4, 11,304.8) |
Month 24 |
46 |
100 |
3,396.4
(2,388.0, 4,830.6) |
Month 36 |
41 |
100 |
2,245.1
(1,616.6, 3,117.9) |
Month 48 |
41 |
97.6 |
1,931.1
(1,294.4, 2,880.8) |
Anti-HPV-18 PBNAc (ED50) |
Month 7 |
46 |
100 |
8,413.9
(6,394.7, 11,070.7) |
Month 12 |
45 |
97.8 |
1,748.2
(1,223.6, 2,497.7) |
Month 24 |
46 |
100 |
1,552.5
(1,112.9, 2,165.5) |
Month 36 |
41 |
100 |
1,326.9
(948.0, 1,857.3) |
Month 48 |
41 |
95.1 |
1,078.1
(714.9, 1,625.6) |
a Subjects who received 3 doses of vaccine for
whom assay results were available for at least one post-vaccination antibody
measurement (N). Subjects who acquired either HPV-16 or HPV-18 infection during
the study were excluded.
b Enzyme linked immunosorbent assay (assay cut-off 8 EL.U./mL for
anti-HPV-16 antibody and 7 EL.U./mL for anti-HPV-18 antibody).
c Pseudovirion-based neutralization assay (assay cut-off 40 ED50 for
both anti-HPV-16 antibody and anti-HPV-18 antibody). |
Bridging Of Efficacy From Women To Adolescent Girls
The immunogenicity of CERVARIX was evaluated in 3
clinical studies involving 1,275 girls 9 through 14 years of age who received
at least one dose of CERVARIX.
Study 3 (HPV 013) was a double-blind, randomized,
controlled study in which 1,035 subjects received CERVARIX and 1,032 subjects
received a Hepatitis A Vaccine 360 EL.U. as the control vaccine with a subset
of subjects evaluated for immunogenicity. All initially seronegative subjects
in the group who received CERVARIX were seropositive after vaccination, i.e.,
had levels of antibody greater than the limit of detection of the assay to both
HPV-16 (≥8 EL.U./mL) and HPV-18 (≥7 EL.U./mL) antigens. The GMTs
for anti-HPV-16 and anti-HPV-18 antibodies in initially seronegative subjects
are presented in Table 9.
Table 9: Geometric Mean Titers (GMTs) at Months 7 and
18 for Initially Seronegative Females 10 through 14 Years of Age
(According-to-Protocol Cohort for Immunogenicitya) (Study 3)
Age Group |
Anti-HPV-16 Antibodies GMT EL.U./mL (95% CI) |
Anti-HPV-18 Antibodies GMT EL.U./mL (95% CI) |
N |
Month 7 |
Month 18 |
N |
Month 7 |
Month 18 |
10-14 years of age |
556- 619 |
19,882.0 (18,626.7, 21,221.9) |
3,888.8 (3,605.0, 4,195.0) |
562- 628 |
8,262.0 (7,725.0, 8,836.2) |
1,539.4 (1,418.8, 1,670.3) |
a Subjects who received 3 doses of vaccine for
whom assay results were available for at least one post-vaccination antibody
measurement (N). |
In Study 4 (HPV 012), the immunogenicity of CERVARIX
administered to girls 10 through 14 years of age was compared with that in
females 15 through 25 years of age. The immune response in girls 10 through 14
years of age measured one month post-Dose 3 was non-inferior to that seen in
females 15 through 25 years of age for both HPV-16 and HPV-18 antigens (Table
10).
Table 10: Geometric Mean Titers (GMTs) and
Seropositivity Rates at Month 7 for Initially Seronegative Females 10 through
14 Years of Age Compared with Females 15 through 25 Years of Age (According-to-Protocol
Cohort for Immunogenicitya) (Study 4)
Antibody Assay |
10-14 Years of Age |
15-25 Years of Age |
N |
GMTb EL.U./mL (95% CI) |
Sero-positivity Ratec % |
N |
GMTb EL.U./mL (95% CI) |
Sero-positivity Ratec % |
Anti-HPV-16 |
143 |
17,272.5
(15,117.9, 19,734.1) |
100 |
118 |
7,438.9
(6,324.6, 8,749.6) |
100 |
Anti-HPV-18 |
141 |
6,863.8
(5,976.3, 7,883.0) |
100 |
116 |
3,070.1
(2,600.0, 3,625.4) |
100 |
a Subjects who received 3 doses of vaccine for
whom assay results were available for at least one post-vaccination antibody
measurement (N).
b Non-inferiority based on the upper limit of the 2-sided 95% CI for
the GMT ratio (15- through 25-year olds/10- through 14-year olds) was <2.
c Non-inferiority based on the upper limit of the 2-sided 95% CI for
the difference between the seropositivity rates for 10- through 14-year olds
and 15- through 25-year olds was <10%. |
In Study 5, a post-hoc analysis compared the
immunogenicity of CERVARIX administered to girls 9 through 14 years of age (n =
68) with that in females 15 through 25 years of age (n = 114). In these
initially seronegative subjects, the immune response in girls 9 through 14
years of age measured one month post-Dose 3 was non-inferior to that observed
in females 15 through 25 years of age for both HPV-16 and HPV-18 antigens
[lower limit of the 2-sided 95% CI for the GMT ratio (9- through 14-year
olds/15- through 25-year olds) was >0.5]. The GMTs for anti-HPV-16 and
anti-HPV-18 antibodies at Month 7 were 22,261.3 EL.U./mL and 7,398.8 EL.U./mL,
respectively, in girls 9 through 14 years of age and 10,322.0 EL.U./mL and 4,261.5
EL.U./mL, respectively, in females 15 through 25 years of age.
Based on these immunogenicity data, the efficacy of
CERVARIX is inferred in girls 9 through 14 years of age.