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Cervarix

"Feb. 2, 2011 -- The human papillomavirus (HPV) vaccine can help stave off genital warts in boys and men, according to a new study in the Feb. 3 issue of the New England Journal of Medicine.

Of 4,065 boys and men aged 16 to 26 fro"...

Cervarix

Cervarix

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 (human papillomavirus bivalent vaccine) , 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 (human papillomavirus bivalent vaccine) 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 “na´ve” 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 na´ve (without current infection and without prior exposure) or non-na´ve (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 (human papillomavirus bivalent vaccine) 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 na´ve (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. The mean follow-up after the first dose was approximately 39 months. 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 na´ve 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.

CERVARIX (human papillomavirus bivalent vaccine) was efficacious in the prevention of precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 5).

Table 5. Efficacy of CERVARIX (human papillomavirus bivalent vaccine) Against Histopathological Lesions Associated With HPV-16 or HPV-18 in Females 15 Through 25 Years of Age (According to Protocol Cohorta) (Study 2)

  CERVARIX Controlb % Efficacy (96.1% CI)c
N Number of Cases N Number of Cases
CIN2/3 or AIS 7,344 4 7,312 56 92.9
(79.9, 98.3)
CIN1/2/3 or AIS 7,344 8 7,312 96 91.7
(82.4, 96.7)
CI = Confidence Interval.
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). The mean follow-up was approximately 35 months.
b Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].
c The 96.1% confidence interval reflected in this 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 (human papillomavirus bivalent vaccine) was efficacious in the prevention of CIN3 or AIS associated with HPV-16 or HPV-18 (vaccine efficacy = 80.0% [96.1% CI: 0.3, 98.1]).

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 (human papillomavirus bivalent vaccine) against 12-month persistent infection with HPV-16 or HPV-18 was also evaluated. In the ATP cohort, CERVARIX (human papillomavirus bivalent vaccine) reduced the incidence of 12-month persistent infection with HPV-16 and/or HPV-18 by 91.2% (96.1% CI: 85.9, 94.8).

Immune response following natural infection does not reliably confer protection against future infections. Among subjects who received 3 doses of CERVARIX (human papillomavirus bivalent vaccine) and who were seropositive at baseline and DNA negative for HPV-16 or HPV-18 at baseline and month 6, CERVARIX (human papillomavirus bivalent vaccine) reduced the incidence of 12-month persistent infection by 91.5% (96.1% CI: 64.0, 99.2%). However, the number of cases of CIN2/3 or AIS was too few 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 (human papillomavirus bivalent vaccine) 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 na´ve 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 (human papillomavirus bivalent vaccine) . 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 na´ve 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 na´ve (without current infection and prior exposure) and non-na´ve women, CERVARIX (human papillomavirus bivalent vaccine) 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 (human papillomavirus bivalent vaccine) 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)

  CERVARIX Control % Efficacy (96.1% CI)b
N Number of Casesa N Number of Casesa
CIN1/2/3 or AIS
  Prophylactic Efficacyc 5,449 3 5,436 85 96.5
(89.0, 99.4)
  HPV-16 or HPV-18 DNA Positiveat Baselined 641 90 592 92 --
  Regardless of Current Infection or Prior Exposure to HPV-16 orHPV-18e 8,667 107 8,682 240 55.5f
(43.2, 65.3)
CIN2/3 or AIS
  Prophylactic Efficacyc 5,449 1 5,436 63 98.4
(90.4, 100)
  HPV-16 or HPV-18 DNA Positiveat Baselined 641 74 592 73 --
  Regardless of Current Infection or Prior Exposure to HPV-16 orHPV-18e 8,667 82 8,682 174 52.8f
(37.5, 64.7)
CIN3 or AIS
  Prophylactic Efficacyc 5,449 0 5,436 13 100
(64.7, 100)
  HPV-16 or HPV-18 DNA Positiveat Baselined 641 41 592 38 --
  Regardless of Current Infection or Prior Exposure to HPV-16 orHPV-18e 8,667 43 8,682 65 33.6f
(-1.1, 56.9)
CI = Confidence Interval.
Table does not include disease due to non-vaccine HPV types.
a Cases = Histopathological cases associated with HPV-16 and/or HPV-18.
b The 96.1% confidence interval reflected in this final analysis results from statistical adjustment for the previously conducted interim analysis.
c TVC na´ve: 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.
d TVC 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.
f Observed vaccine efficacy includes the prophylactic efficacy of CERVARIX (human papillomavirus bivalent vaccine) and the impact of CERVARIX (human papillomavirus bivalent vaccine) 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 (human papillomavirus bivalent vaccine) 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 na´ve to oncogenic HPV (TVC na´ve), CERVARIX (human papillomavirus bivalent vaccine) 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 na´ve and non-na´ve (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 (human papillomavirus bivalent vaccine) 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)

  CERVARIX Control % Efficacy (96.1% CI)a
N Number of Cases N Number of Cases
CIN1/2/3 or AIS
  Prophylactic Efficacyb 5,449 106 5,436 211 50.1
(35.9, 61.4)
  Irrespective of HPV DNA atBaselinec 8,667 451 8,682 577 21.7
(10.7, 31.4)
CIN2/3 or AIS
  Prophylactic Efficacyb 5,449 33 5,436 110 70.2
(54.7, 80.9)
  Irrespective of HPV DNA atBaselinec 8,667 224 8,682 322 30.4
(16.4, 42.1)
CIN3 or AIS
  Prophylactic Efficacyb 5,449 3 5,436 23 87.0
(54.9, 97.7)
  Irrespective of HPV DNA atBaselinec 8,667 77 8,682 116 33.4
(9.1, 51.5)
CI = Confidence Interval.
a The 96.1% confidence interval reflected in this final analysis results from statistical adjustment for the previously conducted interim analysis.
b TVC na´ve: 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.
c 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.

In exploratory analyses, CERVARIX (human papillomavirus bivalent vaccine) reduced definitive cervical therapy procedures (includes loop electrosurgical excision procedure [LEEP], cold-knife Cone, and laser procedures) by 24.7% (96.1% CI: 7.4, 38.9) in the TVC and by 68.8% (96.1% CI: 50.0, 81.2) in the TVC na´ve.

To assess reductions in disease caused by non-vaccine HPV types, two analyses were conducted combining 12 non-vaccine oncogenic HPV types, including and excluding lesions in which HPV-16 or HPV-18 were also detected. In these analyses, among females who received 3 doses of CERVARIX (human papillomavirus bivalent vaccine) and were DNA negative for the specific HPV type at baseline and month 6, CERVARIX (human papillomavirus bivalent vaccine) reduced the incidence of CIN2/3 or AIS by 54.0% (96.1% CI: 34.0, 68.4) and 37.4% (96.1% CI: 7.4, 58.2), respectively.

Post-hoc analyses, adjusted for multiplicity, were conducted to assess the impact of CERVARIX (human papillomavirus bivalent vaccine) 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 (human papillomavirus bivalent vaccine) and were DNA negative for the specific HPV type at baseline and month 6. These post-hoc analyses were also conducted in the TVC na´ve 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 92.0% (99.7% CI: 49.0, 99.8) and 100% (99.7% CI: 62.3, 100), 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 89.4% (99.7% CI: 29.0, 99.7) and 100% (99.7% CI: 36.3, 100), 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 (human papillomavirus bivalent vaccine) 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, GMTs for ELISA and PBNA one month post-dose 3 were measured (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. Of subjects seronegative at baseline, 99.5% were seropositive for anti-HPV-16 and anti-HPV-18 antibodies at month 7 post-vaccination.

Table 8. Summary of Anti-HPV Geometric Mean Titers (GMTs) for HPV-16 and HPV-18 at Month 7 for Initially Seronegative Females 15 Through 25 Years of Age (According to Protocol Cohort for Immunogenicitya) (Study 2)

Antibody Assay N CERVARIX GMT (95% CI) N Control GMT (95% CI)
ELISAb (EL.U./mL)
  Anti-HPV-16 861 9,206.4 (8,607.2, 9,847.2) 738 4.4 (4.2, 4.6)
  Anti-HPV-18 924 4,744.6 (4,454.1, 5,053.9) 769 3.8 (3.6, 3.9)
PBNAc (ED50)
  Anti-HPV-16 46 27,364.8 (19,780.1, 37,857.9) 44 20.0 (20.0, 20.0)
  Anti-HPV-18 46 9,052 (6,851.8, 11,960.5) 44 20.0 (20.0, 20.0)
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 (human papillomavirus bivalent vaccine) was evaluated in 2 clinical studies involving 1,193 girls 10 through 14 years of age who received CERVARIX (human papillomavirus bivalent vaccine) .

Study 3 (HPV 013) was a double-blind, randomized, controlled study in which 1,035 subjects received CERVARIX (human papillomavirus bivalent vaccine) 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 (human papillomavirus bivalent vaccine) 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 (human papillomavirus bivalent vaccine) administered to girls 10 through 14 years of age was compared to 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 to 15 Through 25 Years of Age (According To Protocol Cohort for Immunogenicitya) (Study 4)

  10-14 Years of Age 15-25 Years of Age
Antibody Assay N GMTb EL.U./mL
(95% CI)
Seropositivity Ratec % N GMTb EL.U./mL (95% CI) Seropositivity 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 (15-25 year olds/10-14 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 10-14 year olds and 15-25 year olds was < 10%. Based on these immunogenicity data, the efficacy of CERVARIX (human papillomavirus bivalent vaccine) is inferred in girls 10 through 14 years of age.

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

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