1.1 Indications

CERVARIX® is indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18 [see Clinical Studies (14)]:

•

cervical cancer,

•

cervical intraepithelial neoplasia (CIN) Grade 2 or worse and adenocarcinoma in situ, and

•

cervical intraepithelial neoplasia (CIN) Grade 1.

CERVARIX is approved for use in females 9 through 25 years of age.

1.2 Limitations of Use and Effectiveness

CERVARIX does not provide protection against disease due to all HPV types [see Clinical Studies (14.3)].

CERVARIX has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity [see Clinical Studies (14.2)].

Females should continue to adhere to recommended cervical cancer screening procedures [see Patient Counseling Information (17)].

Vaccination with CERVARIX may not result in protection in all vaccine recipients.

2.1 Preparation for Administration

Shake syringe well before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If either of these conditions exists, the vaccine should not be administered. With thorough agitation, CERVARIX is a homogeneous, turbid, white suspension. Do not administer if it appears otherwise.

Attach a sterile needle and administer intramuscularly.

Do not administer this product intravenously, intradermally, or subcutaneously.

2.2 Dose and Schedule

Immunization with CERVARIX consists of 3 doses of 0.5-mL each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. The preferred site of administration is the deltoid region of the upper arm.

5.1 Syncope

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with CERVARIX. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position.

5.2 Latex

The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions.

5.3 Preventing and Managing Allergic Vaccine Reactions

Prior to administration, the healthcare provider should review the immunization history for possible vaccine hypersensitivity and previous vaccination‑related adverse reactions to allow an assessment of benefits and risks. Appropriate medical treatment and supervision should be readily available in case of anaphylactic reactions following administration of CERVARIX.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of CERVARIX could reveal adverse reactions not observed in clinical trials.

Studies in Females 9 through 25 Years of Age

The safety of CERVARIX was evaluated by pooling data from controlled and uncontrolled clinical trials involving 23,952 females 9 through 25 years of age in the pre-licensure clinical development program. In these studies, 13,024 females (9 through 25 years of age) received at least one dose of CERVARIX and 10,928 females received at least one dose of a control [Hepatitis A Vaccine containing 360 EL.U. (10 through 14 years of age), Hepatitis A Vaccine containing 720 EL.U. (15 through 25 years of age), or Al(OH)3 (500 mcg, 15 through 25 years of age)].

Data on solicited local and general adverse events were collected by subjects or parents using standardized diary cards for 7 consecutive days following each vaccine dose (i.e., day of vaccination and the next 6 days). Unsolicited adverse events were recorded with diary cards for 30 days following each vaccination (day of vaccination and 29 subsequent days). Parents and/or subjects were also asked at each study visit about the occurrence of any adverse events and instructed to immediately report serious adverse events throughout the study period. These studies were conducted in North America, Latin America, Europe, Asia, and Australia. Overall, the majority of subjects were white (59.5%), followed by Asian (25.9%), Hispanic (8.5%), black (3.4%), and other racial/ethnic groups (2.7%).

Solicited Adverse Events: The reported frequencies of solicited local injection site reactions (pain, redness, and swelling) and general adverse events (fatigue, fever, gastrointestinal symptoms, headache, arthralgia, myalgia, and urticaria) within 7 days after vaccination in females 9 through 25 years of age are presented in Table 1. An analysis of solicited local injection site reactions by dose is presented in Table 2. Local reactions were reported more frequently with CERVARIX when compared with the control groups; in ≥76% of recipients of CERVARIX, these local reactions were mild to moderate in intensity. Compared with Dose 1, pain was reported less frequently after Doses 2 and 3 of CERVARIX, in contrast to redness and swelling where there was a small increased incidence. There was no increase in the frequency of general adverse events with successive doses.

aTotal vaccinated cohort included subjects with at least one documented dose (N).

bHAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].

cHAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3].

dAl(OH)3 Control = Control containing 500 mcg Al(OH)3.

eGI = Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and/or abdominal pain.

fAdverse events solicited in a subset of subjects.

aTotal vaccinated cohort included subjects with at least one documented dose (N).

bHAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].

cHAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3].

dAl(OH)3 Control = Control containing 500 mcg Al(OH)3.

eDefined as spontaneously painful or pain that prevented normal daily activities.

The pattern of solicited local adverse reactions and general adverse events following administration of CERVARIX was similar between the age cohorts (9 through 14 years and 15 through 25 years).

Unsolicited Adverse Events: The frequency of unsolicited adverse events that occurred within 30 days of vaccination (≥1% for CERVARIX and greater than any of the control groups) in females 9 through 25 years of age are presented in Table 3.

aTotal vaccinated cohort included subjects with at least one dose administered (N).

bHAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].

cHAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3].

dAl(OH)3 Control = Control containing 500 mcg Al(OH)3.

New Onset Autoimmune Diseases (NOADs): The pooled safety database, which included controlled and uncontrolled trials which enrolled females 9 through 25 years of age, was searched for new medical conditions indicative of potential new onset autoimmune diseases. Overall, the incidence of potential NOADs, as well as NOADs, in the group receiving CERVARIX was 0.8% (96/12,772) and comparable to the pooled control group (0.8%, 87/10,730) during the 4.3 years of follow-up (Table 4).

In the largest randomized, controlled trial (Study 2) which enrolled females 15 through 25 years of age and which included active surveillance for potential NOADs, the incidence of potential NOADs and NOADs was 0.8% among subjects who received CERVARIX (78/9,319) and 0.8% among subjects who received Hepatitis A Vaccine [720 EL.U. of antigen and 500 mcg Al(OH)3] control (77/9,325).

aTotal vaccinated cohort included subjects with at least one documented dose (N).

bPooled Control Group = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3], Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3], and a control containing 500 mcg Al(OH)3.

cn (%): Number and percentage of subjects with medical condition.

dTerm includes reactive arthritis and arthritis.

eTerm includes Basedow's disease, goiter, and hyperthyroidism.

fTerm includes thyroiditis, autoimmune thyroiditis, and hypothyroidism.

gTerm includes colitis ulcerative, Crohn's disease, proctitis ulcerative, and inflammatory bowel disease.

hTerm includes psoriatic arthropathy, nail psoriasis, guttate psoriasis, and psoriasis.

iTerm includes systemic lupus erythematosus and cutaneous lupus erythematosus.

jTerm includes idiopathic thrombocytopenic purpura and thrombocytopenia.

kTerm includes leukocytoclastic vasculitis and vasculitis.

Serious Adverse Events

In the pooled safety database, inclusive of controlled and uncontrolled studies, which enrolled females 9 through 72 years of age, 5.3% (864/16,381) of subjects who received CERVARIX and 5.9% (814/13,811) of subjects who received control reported at least one serious adverse event, without regard to causality, during the entire follow-up period (up to 7.4 years).

Among females 9 through 25 years of age enrolled in these clinical studies, 6.3% of subjects who received CERVARIX and 7.2% of subjects who received the control reported at least one serious adverse event during the entire follow-up period (up to 7.4 years).

Deaths

In completed and ongoing studies which enrolled 57,323 females 9 through 72 years of age, 37 deaths were reported during the 7.4 years of follow-up: 20 in subjects who received CERVARIX (0.06%, 20/33,623) and 17 in subjects who received control (0.07%, 17/23,700). Causes of death among subjects were consistent with those reported in adolescent and adult female populations. The most common causes of death were motor vehicle accident (5 subjects who received CERVARIX; 5 subjects who received control) and suicide (2 subjects who received CERVARIX; 5 subjects who received control), followed by neoplasm (3 subjects who received CERVARIX; 2 subjects who received control), autoimmune disease (3 subjects who received CERVARIX; 1 subject who received control), infectious disease (3 subjects who received CERVARIX; 1 subject who received control), homicide (2 subjects who received CERVARIX; 1 subject who received control), cardiovascular disorders (2 subjects who received CERVARIX), and death of unknown cause (2 subjects who received control). Among females 10 through 25 years of age, 31 deaths were reported (0.05%, 16/29,467 of subjects who received CERVARIX and 0.07%, 15/20,192 of subjects who received control).

6.2 Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for CERVARIX since market introduction (2007) are listed below. This list includes serious events or events that have suspected causal association to CERVARIX. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

Blood and Lymphatic System Disorders

Lymphadenopathy.

Immune System Disorders

Allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema, erythema multiforme.

Nervous System Disorders

Syncope or vasovagal responses to injection (sometimes accompanied by tonic-clonic movements).

7.1 Concomitant Vaccine Administration

There are no data to assess the concomitant use of CERVARIX with other vaccines.

Do not mix CERVARIX with any other vaccine in the same syringe or vial.

7.2 Hormonal Contraceptives

Among 7,693 subjects 15 through 25 years of age in Study 2 (CERVARIX, N = 3,821 or Hepatitis A Vaccine 720 EL.U., N = 3,872) who used hormonal contraceptives for a mean of 2.8 years, the observed efficacy of CERVARIX was similar to that observed among subjects who did not report use of hormonal contraceptives.

7.3 Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may reduce the immune response to CERVARIX [see Use in Specific Populations (8.6)].

8.1 Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats at a dose approximately 47 times the human dose (on a mg/kg basis) and revealed no evidence of impaired fertility or harm to the fetus due to CERVARIX. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-clinical Studies

An evaluation of the effect of CERVARIX on embryo-fetal, pre- and post-natal development was conducted using rats. One group of rats was administered CERVARIX 30 days prior to gestation and during the period of organogenesis (gestation Days 6, 8, 11, and 15). A second group of rats was administered saline at 30 days prior to gestation followed by CERVARIX on Days 6, 8, 11, and 15 of gestation. Two additional groups of rats received either saline or adjuvant following the same dosing regimen. CERVARIX was administered at 0.1 mL/rat/occasion (approximately 47-fold excess relative to the projected human dose on a mg/kg basis) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, or embryo-fetal, pre- and post-natal development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis.

Clinical Studies

Overall Outcomes: In pre-licensure clinical studies, pregnancy testing was performed prior to each vaccine administration and vaccination was discontinued if a subject had a positive pregnancy test. In all clinical trials, subjects were instructed to take precautions to avoid pregnancy until 2 months after the last vaccination. During pre-licensure clinical development, a total of 7,276 pregnancies were reported among 3,696 females receiving CERVARIX and 3,580 females receiving a control (Hepatitis A Vaccine 360 EL.U., Hepatitis A Vaccine 720 EL.U., or 500 mcg Al(OH)3). The overall proportions of pregnancy outcomes were similar between treatment groups. The majority of women gave birth to normal infants (62.2% and 62.6% of recipients of CERVARIX and control, respectively). Other outcomes included spontaneous abortion (11.0% and 10.8% of recipients of CERVARIX and control, respectively), elective termination (5.8% and 6.1% of recipients of CERVARIX and control, respectively), abnormal infant other than congenital anomaly (2.8% and 3.2% of recipients of CERVARIX and control, respectively), and premature birth (2.0% and 1.7% of recipients of CERVARIX and control, respectively). Other outcomes (congenital anomaly, stillbirth, ectopic pregnancy, and therapeutic abortion) were reported less frequently in 0.1% to 0.8% of pregnancies in both groups.

Outcomes around Time of Vaccination: In pre-licensure studies, sub-analyses were conducted to describe pregnancy outcomes in 761 women (N = 396 for CERVARIX and N = 365 for pooled control, HAV 360 EL.U., HAV 720 EL.U., or 500 mcg Al(OH)3) who received a dose of CERVARIX or control between 45 days prior to and 30 days after the last menstrual period (LMP) and for whom pregnancy outcome was known. The majority of women gave birth to normal infants (65.2% and 69.3% of recipients of CERVARIX and control, respectively). Spontaneous abortion was reported in a total of 11.7% of subjects (13.6% of recipients of CERVARIX and 9.6% of control recipients), and elective termination was reported in a total of 9.7% of subjects (9.9% of recipients of CERVARIX and 9.6% of control recipients). Abnormal infant other than congenital anomaly was reported in a total of 4.9% of subjects (5.1% of recipients of CERVARIX and 4.7% of control recipients), and premature birth was reported in a total of 2.5% of subjects (2.5% of both groups). Other outcomes (congenital anomaly, stillbirth, ectopic pregnancy, and therapeutic abortion) were reported in 0.3% to 1.8% of pregnancies among recipients of CERVARIX and in 0.3% to 1.4% of pregnancies among control recipients.

A post-hoc analysis was performed on a pooled database of pregnancies with known outcome among women 15 to 25 years of age enrolled in controlled clinical trials (N = 4,670 for CERVARIX and N = 4,689 for pooled control, HAV 360 EL.U., HAV 720 EL.U., or 500 mcg Al(OH)3). In an analysis of pregnancies with exposure to CERVARIX or control between 45 days prior to and 30 days after the LMP, the relative risk of spontaneous abortion was 1.54 (95% CI: 0.95, 2.54) for exposure to one dose of CERVARIX (n/N = 46/326) compared with one dose of control (n/N = 33/338) and 1.21 (95% CI: 0.27, 7.33) for exposure to 2 doses of CERVARIX (n/N = 8/71) compared with 2 doses of control (n/N = 3/38).

The association between vaccination with CERVARIX and spontaneous abortion was evaluated in a post-marketing, retrospective, observational, cohort study using primary care medical records in the United Kingdom. The study assessed the risk of spontaneous abortion during weeks 1 to 19 of gestation in two cohorts of women 15 to 25 years of age: one cohort who received one or more doses of CERVARIX between 45 days prior to and 30 days after the LMP (close exposure) and another cohort who received the last dose of CERVARIX between 18 months and 120 days prior to the LMP (remote exposure). The hazard ratio for spontaneous abortion was 1.26 (95% CI: 0.77, 2.09) for the close-exposure cohort (n/N = 23/207) compared with the remote-exposure cohort (n/N = 56/632). In sensitivity analyses for the close-exposure cohort, the hazard ratio compared with the remote-exposure cohort was 1.07 (95% CI: 0.61, 1.86) for women who received only one dose of CERVARIX (n/N = 17/178) and 2.59 (95% CI: 1.11, 6.04) for women who received 2 doses of CERVARIX (n/N = 6/29).

8.3 Nursing Mothers

In non-clinical studies in rats, serological data suggest a transfer of anti–HPV-16 and anti–HPV-18 antibodies via milk during lactation in rats. Excretion of vaccine-induced antibodies in human milk has not been studied for CERVARIX. Because many drugs are excreted in human milk, caution should be exercised when CERVARIX is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients younger than 9 years of age have not been established. The safety and effectiveness of CERVARIX have been evaluated in 1,275 subjects 9 through 14 years of age and 6,362 subjects 15 through 17 years of age. [See Adverse Reactions (6.1), Clinical Studies (14.5).]

8.5 Geriatric Use

Clinical studies of CERVARIX did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. CERVARIX is not approved for use in subjects 65 years of age and older.

8.6 Immunocompromised Individuals

The immune response to CERVARIX may be diminished in immunocompromised individuals [see Drug Interactions (7.3)].

12.1 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

CERVARIX has not been evaluated for its carcinogenic or mutagenic potential. Vaccination of female rats with CERVARIX, at doses shown to be significantly immunogenic in the rat, had no effect on fertility.

14.1 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 naïve (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 naïve 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).

CI = Confidence Interval; n = Number of cases.

aSubjects (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].

cThe 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 naïve 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.

14.2 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 naïve (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).

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.

aHepatitis 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.

cTVC naïve: 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.

eTVC: 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.

14.3 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 naïve to oncogenic HPV (TVC naïve), 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 naïve and non-naïve (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).

CI = Confidence Interval; n = Number of cases.

aHepatitis 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.

cTVC naïve: 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 naïve.

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-naïve 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.

14.4 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.

aSubjects 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.

bEnzyme 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).

cPseudovirion-based neutralization assay (assay cut-off 40 ED50 for both anti–HPV‑16 antibody and anti–HPV‑18 antibody).

14.5 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.

aSubjects 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).

aSubjects who received 3 doses of vaccine for whom assay results were available for at least one post-vaccination antibody measurement (N).

bNon-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.

cNon-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.