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Gardasil

"A new study looking at the prevalence of human papillomavirus (HPV) infections in girls and women before and after the introduction of the HPV vaccine shows a significant reduction in vaccine-type HPV in U.S. teens. The study, published in [th"...

Gardasil

Gardasil

CLINICAL PHARMACOLOGY

Mechanism of Action

HPV only infects human beings. Animal studies with analogous animal papillomaviruses suggest that the efficacy of L1 VLP vaccines may involve the development of humoral immune responses. Human beings develop a humoral immune response to the vaccine, although the exact mechanism of protection is unknown.

Clinical Studies

CIN 2/3 and 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; thus, they serve as surrogate markers for prevention of cervical cancer. In the clinical studies in girls and women aged 16 through 26 years, cases of CIN 2/3 and AIS were the efficacy endpoints to assess prevention of cervical cancer. In addition, cases of VIN 2/3 and VaIN 2/3 were the efficacy endpoints to assess prevention of HPV-related vulvar and vaginal cancers, and observations of external genital lesions were the efficacy endpoints for the prevention of genital warts.

In clinical studies in boys and men aged 16 through 26 years, efficacy was evaluated using the following endpoints: external genital warts and penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer.

Efficacy was assessed in 5 AAHS-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) (Study 1, N = 2391 girls and women) and the second evaluated all components of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) (Study 2, N = 551 girls and women). Two Phase III studies evaluated GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in 5442 (Study 3) and 12,157 (Study 4) girls and women. A third Phase III study, Study 5, evaluated GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in 4055 boys and men. Together, these five studies evaluated 24,596 individuals (20,541 girls and women 16 through 26 years of age at enrollment with a mean age of 20.0 years and 4055 boys and men 16 through 26 years of age at enrollment with a mean age of 20.5 years). The race distribution of the girls and women in the clinical trials was as follows: 70.4% White; 12.2% Hispanic (Black and White); 8.8% Other; 4.6% Black; 3.8% Asian; and 0.2% American Indian. The race distribution of the boys and men in the clinical trials was as follows: 35.2% White; 20.5% Hispanic (Black and White); 14.4% Other; 19.8% Black; 10.0% Asian; and 0.1% American Indian.

The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, and 2.3 years for Study 1, Study 2, Study 3, Study 4, and Study 5, respectively. Individuals received vaccine or AAHS control on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies in girls and women combined according to a prospective clinical plan.

Overall, 73% of 16- through 26-year-old girls and women and 83% of 16- through 26-year-old boys and men were na´ve (i.e., PCR [Polymerase Chain Reaction] negative and seronegative for all 4 vaccine HPV types) to all 4 vaccine HPV types at enrollment.

A total of 27% of 16- through 26-year-old girls and women and 17% of 16- through 26-year-old boys and men had evidence of prior exposure to or ongoing infection with at least 1 of the 4 vaccine HPV types. Among these individuals, 74% of 16- through 26-year-old girls and women and 78% of 16- through 26-yearold boys and men had evidence of prior exposure to or ongoing infection with only 1 of the 4 vaccine HPV types and were na´ve (PCR negative and seronegative) to the remaining 3 types.

In individuals who were na´ve (PCR negative and seronegative) to all 4 vaccine HPV types, CIN, genital warts, VIN, VaIN, PIN, and persistent infection caused by any of the 4 vaccine HPV types were counted as endpoints.

Among individuals who were positive (PCR positive and/or seropositive) for a vaccine HPV type at Day 1, endpoints related to that type were not included in the analyses of prophylactic efficacy. Endpoints related to the remaining types for which the individual was na´ve (PCR negative and seronegative) were counted.

For example, in individuals who were HPV 18 positive (PCR positive and/or seropositive) at Day 1, lesions caused by HPV 18 were not counted in the prophylactic efficacy evaluations. Lesions caused by HPV 6, 11, and 16 were included in the prophylactic efficacy evaluations. The same approach was used for the other types.

Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Girls and Women 16 Through 26 Years of Age

GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of girls and women regardless of baseline HPV status (i.e., PCR status or serostatus). Girls and women with current or prior HPV infection with an HPV type contained in the vaccine were not eligible for prophylactic efficacy evaluations for that type.

The primary analyses of efficacy with respect to HPV types 6, 11, 16, and 18 were conducted in the perprotocol efficacy (PPE) population, consisting of girls and women who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were na´ve (PCR negative in cervicovaginal specimens and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit.

GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) was efficacious in reducing the incidence of CIN (any grade including CIN 2/3); AIS; genital warts; VIN (any grade); and VaIN (any grade) related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (Table 11).

In addition, girls and women who were already infected with 1 or more vaccine-related HPV types prior to vaccination were protected from precancerous cervical lesions and external genital lesions caused by the other vaccine HPV types.

Table 11 : Analysis of Efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in the PPE* Population** of 16- Through 26-Year-Old Girls and Women for Vaccine HPV Types

Population GARDASIL AAHS Control % Efficacy (95% CI)
N Number of cases N Number of cases
HPV 16- or 18-related CIN 2/3 or AIS
Study 1*** 755 0 750 12 100.0 (65.1, 100.0)
Study 2 231 0 230 1 100.0 (-3744.9, 100.0)
Study 3 2201 0 2222 36 100.0 (89.2, 100.0)
Study 4 5306 2 5262 63 96.9 (88.2, 99.6)
Combined Protocols‡ 8493 2 8464 112 98.2 (93.5, 99.8)
HPV 16-related CIN 2/3 or AIS
Combined Protocols‡ 7402 2 7205 93 97.9 (92.3, 99.8)
HPV 18-related CIN 2/3 or AIS
Combined Protocols‡ 7382 0 7316 29 100.0 (86.6, 100.0)
HPV 16- or 18-related VIN 2/3
Study 2 231 0 230 0 Not calculated
Study 3 2219 0 2239 6 100.0 (14.4, 100.0)
Study 4 5322 0 5275 4 100.0 (-50.3, 100.0)
Combined Protocols‡ 7772 0 7744 10 100.0 (55.5, 100.0)
HPV 16- or 18-related VaIN 2/3
Study 2 231 0 230 0 Not calculated
Study 3 2219 0 2239 5 100.0 (-10.1, 100.0)
Study 4 5322 0 5275 4 100.0 (-50.3, 100.0)
Combined Protocols‡ 7772 0 7744 9 100.0 (49.5, 100.0)
HPV 6-, 11-, 16-, or 18-related CIN (CIN 1, CIN 2/3) or AIS
Study 2 235 0 233 3 100.0 (-138.4, 100.0)
Study 3 2241 0 2258 77 100.0 (95.1, 100.0)
Study 4 5388 9 5374 145 93.8 (88.0, 97.2)
Combined Protocols‡ 7864 9 7865 225 96.0 (92.3, 98.2)
HPV 6-, 11-, 16-, or 18-related Genital Warts
Study 2 235 0 233 3 100.0 (-139.5, 100.0)
Study 3 2261 0 2279 58 100.0 (93.5, 100.0)
Study 4 5404 2 5390 132 98.5 (94.5, 99.8)
Combined Protocols‡ 7900 2 7902 193 99.0 (96.2, 99.9)
HPV 6- and 11-related Genital Warts
Combined Protocols‡ 6932 2 6856 189 99.0 (96.2, 99.9)
*The PPE population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were na´ve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (month 7).
**See Table 13 for analysis of vaccine impact in the general population.
***Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine)
‡Analyses of the combined trials were prospectively planned and included the use of similar study entry criteria
N = Number of individuals with at least 1 follow-up visit after Month 7
CI = Confidence Interval
Note 1: Point estimates and confidence intervals are adjusted for person-time of follow-up
Note 2: The first analysis in the table (i.e., HPV 16- or 18-related CIN 2/3, AIS or worse) was the primary endpoint of the vaccine development plan.
Note 3: Table 11 does not include cases due to non-vaccine HPV types.
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Prophylactic efficacy against overall cervical and genital disease related to HPV 6, 11, 16, and 18 in an extension phase of Study 2, that included data through month 60, was noted to be 100% (95% CI: 12.3%, 100.0%) among girls and women in the per protocol population na´ve to the relevant HPV types.

GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) was efficacious against HPV disease caused by HPV types 6, 11, 16, and 18 in girls and women who were na´ve for those specific HPV types at baseline.

Prophylactic Efficacy – HPV Types 6, 11, 16, and 18 in Boys and Men 16 Through 26 Years of Age

The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. This population consisted of boys and men who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were na´ve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (month 7). Efficacy was measured starting after the Month 7 visit.

GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) was efficacious in reducing the incidence of genital warts related to vaccine HPV types 6 and 11 in those boys and men who were PCR negative and seronegative at baseline (Table 12). Efficacy against penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer was not demonstrated as the number of cases was too limited to reach statistical significance.

Table 12 : Analysis of Efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in the PPE Population of 16- Through 26-Year-Old Boys and Men for Vaccine HPV Types

Endpoint GARDASIL AAHS Control % Efficacy (95% CI)
N* Number of cases N Number of cases
External Genital Lesions HPV 6-, 11-, 16-, or 18- related
External Genital Lesions 1397 3 1408 31 90.4 (69.2, 98.1)
Condyloma 1397 3 1408 28 89.4 (65.5, 97.9)
PIN 1/2/3 1397 0 1408 3 100 (-141.2, 100.0)
*N = Number of individuals with at least 1 follow-up visit after Month 7
CI = Confidence Interval
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Population Impact in Girls and Women 16 Through 26 Years of Age

Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types

The clinical trials included girls and women regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) with respect to HPV 6- , 11-, 16-, and 18-related cervical and genital disease in these girls and women. Here, analyses included events arising among girls and women regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination.

The impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in girls and women regardless of current or prior exposure to a vaccine HPV type is shown in Table 13. Impact was measured starting 1 month Postdose 1. Prophylactic efficacy denotes the vaccine's efficacy in girls and women who are na´ve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in girls and women who were positive for vaccine HPV infection, as well as vaccine impact among girls and women regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of CIN and genital warts, VIN, and VaIN related to a vaccine HPV type detected in the group that received GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1.

There was no clear evidence of protection from disease caused by HPV types for which girls and women were PCR positive regardless of serostatus at baseline.

Table 13 : Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of HPV 6, 11, 16, or 18 Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types

Endpoint Analysis GARDASIL or HPV 16 L1 VLPVaccine AAHS Control % Reduction
(95% CI)
N Cases N Cases
HPV 16- or 18-related CIN 2/3 or AIS Prophylactic Efficacy* 9346 4 9407 155 97.4 (93.3, 99.3)
HPV 16 and/or HPV 18 Positive at Day 1 2870 142 2898 148** --***
Girls and Women Regardless of Current or Prior Exposure to HPV 16 or 18† 9836 146 9904 303 51.8 (41.1, 60.7)‡
HPV 16- or 18-related VIN 2/3 or VaIN 2/3 Prophylactic Efficacy* 8642 1 8673 34 97.0 (82.4, 99.9)
HPV 16 and/or HPV 18 Positive at Day 1 1880 8 1876 4 --***
Girls and Women Regardless of Current or Prior Exposure to HPV 16 or 18† 8955 9 8968 38 76.3 (50.0, 89.9)‡
HPV 6-, 11-, 16-,18-related CIN (CIN 1, CIN 2/3) or AIS Prophylactic Efficacy* 8630 16 8680 309 94.8 (91.5, 97.1)
HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1 2466 186# 2437 213# --***
Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types† 8819 202 8854 522 61.5 (54.6, 67.4)‡
HPV 6-, 11-, 16-, or 18-related Genital Warts Prophylactic Efficacy* 8761 10 8792 252 96.0 (92.6, 98.1)
HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1 2501 51§ 2475 55§ --***
Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types† 8955 61 8968 307 80.3 (73.9, 85.3)‡
HPV 6- or 11-related Genital Warts Prophylactic Efficacy* 7769 9 7792 246 96.4 (93.0, 98.4)
HPV 6 and/or HPV 11 Positive at Day 1 1186 51 1176 54 --***
Girls and Women Regardless of Current or Prior Exposure to Vaccine HPV Types† 8955 60 8968 300 80.1 (73.7, 85.2)‡
*Includes all individuals who received at least 1 vaccination and who were na´ve (PCR negative and seronegative) to HPV 6, 11, 16, and/or 18 at Day 1. Case counting started at 1 month postdose 1.
**Out of the 148 AAHS control cases of 16/18 CIN 2/3, 2 women were missing serology or PCR results for Day 1.
***There is no expected efficacy since GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) has not been demonstrated to provide protection against disease from vaccine HPV types to which a person has previously been exposed through sexual activity. †Includes all individuals who received at least 1 vaccination (regardless of baseline HPV status at Day 1). Case counting started at 1 month postdose 1.
çPercent reduction includes the prophylactic efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) as well as the impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) on the course of infections present at the start of the vaccination.
#Includes 2 AAHS control women with missing serology/PCR data at Day 1.
žIncludes 1 woman with missing serology/PCR data at Day 1.
CI = Confidence Interval
N = Number of individuals who have at least one follow-up visit after Day 1
Note 1: The 16- and 18-related CIN 2/3 or AIS composite endpoint included data from studies 1, 2, 3, and 4. All other endpoints only included data from studies 2, 3, and 4.
Note 2: Positive status at Day 1 denotes PCR positive and/or seropositive for the respective type at Day 1.
Note 3: Table 13 does not include disease due to non-vaccine HPV types.
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of Any HPV Type Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

The impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) against the overall burden of HPV-related cervical, vulvar, and vaginal disease (i.e., disease caused by any HPV type) results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, and the disease contribution from HPV types not contained in the vaccine.

Additional efficacy analyses were conducted in 2 populations: (1) a generally HPV-na´ve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-na´ve girls and women and (2) the general study population of girls and women regardless of baseline HPV status, some of whom had HPV-related disease at Day 1.

Among generally HPV-na´ve girls and women and among all girls and women in the study population (including girls and women with HPV infection at Day 1), GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) reduced the overall incidence of CIN 2/3 or AIS; of VIN 2/3 or VaIN 2/3; of CIN (any grade) or AIS; and of Genital Warts (Table 14). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in girls and women na´ve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected girls and women may already have CIN 2/3 or AIS at Day 1 and some will develop CIN 2/3 or AIS during followup, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a non-vaccine HPV type not present at the time of vaccination.

Table 14 : Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of Any HPV Type Related Genital Disease in Girls and Women 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

Endpoints Caused by Vaccine or Non-vaccine HPV Types Analysis GARDASIL AAHS Control % Reduction
(95% CI)
N Cases N Cases
CIN 2/3 or AIS Prophylactic Efficacy* 4616 77 4680 136 42.7 (23.7, 57.3)
Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 8559 421 8592 516 18.4 (7.0, 28.4)***
VIN 2/3 and VaIN 2/3 Prophylactic Efficacy* 4688 7 4735 31 77.1 (47.1, 91.5)
Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 8688 30 8701 61 50.7 (22.5, 69.3)***
CIN (Any Grade) or AIS Prophylactic Efficacy* 4616 272 4680 390 29.7 (17.7, 40.0)
Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 8559 967 8592 1189 19.1 (11.9, 25.8)***
Genital Warts Prophylactic Efficacy* 4688 29 4735 169 82.8 (74.3, 88.8)
Girls and Women Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 8688 132 8701 350 62.5 (54.0, 69.5)***
*Includes all individuals who received at least 1 vaccination and who had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1 and were na´ve to 14 common HPV types at Day 1. Case counting started at 1 month postdose 1.
**Includes all individuals who received at least 1 vaccination (regardless of baseline HPV status or Pap test result at Day 1). Case counting started at 1 month postdose 1.
***Percent reduction includes the prophylactic efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) as well as the impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) on the course of infections present at the start of the vaccination.
CI = Confidence Interval
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Population Impact in Boys and Men 16 Through 26 Years of Age

Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Genital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types

Study 5 included boys and men regardless of current or prior exposure to vaccine HPV types, and additional analyses were conducted to evaluate the impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) with respect to HPV 6-, 11-, 16-, and 18-related genital disease in these boys and men. Here, analyses included events arising among boys and men regardless of baseline PCR status and serostatus, including HPV infections that were present at the start of vaccination as well as events that arose from infections that were acquired after the start of vaccination.

The impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in boys and men regardless of current or prior exposure to a vaccine HPV type is shown in Table 15. Impact was measured starting at Day 1. Prophylactic efficacy denotes the vaccine's efficacy in boys and men who are na´ve (PCR negative and seronegative) to the relevant HPV types at Day 1. Vaccine impact in boys and men who were positive for vaccine HPV infection, as well as vaccine impact among boys and men regardless of baseline vaccine HPV PCR status and serostatus are also presented. The majority of genital disease related to a vaccine HPV type detected in the group that received GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) occurred as a consequence of HPV infection with the relevant HPV type that was already present at Day 1.

There was no clear evidence of protection from disease caused by HPV types for which boys and men were PCR positive regardless of serostatus at baseline.

Table 15 : Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of HPV Types 6-, 11-, 16-, or 18-Related Genital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types

Endpoint Analysis GARDASIL AAHS Control % Reduction
(95% CI)
N Cases N Cases
External Genital Lesions Prophylactic Efficacy* 1775 13 1770 52 75.5 (54.3, 87.7)
HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1 168 14 167 25 --**
Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types*** 1943 27 1937 77 65.5 (45.8, 78.6)†
Condyloma Prophylactic Efficacy* 1775 10 1770 48 79.6 (59.1, 90.8)
HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1 168 14 167 24 --**
Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types*** 1943 24 1937 72 67.2 (47.3, 80.3)†
PIN 1/2/3 Prophylactic Efficacy* 1775 4 1770 4 1.2 (-430.5, 81.6)
HPV 6, HPV 11, HPV 16, and/or HPV 18 Positive at Day 1 168 2 167 1 --**
Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types*** 1943 6 1937 5 -19.2 (-393.8, 69.7)†
*Includes all individuals who received at least 1 vaccination and who were HPV-na´ve (i.e., seronegative and PCR negative) at Day 1 to the vaccine HPV type being analyzed. Case counting started at Day 1.
**There is no expected efficacy since GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) has not been demonstrated to provide protection against disease from vaccine HPV types to which a person has previously been exposed through sexual activity.
***Includes all individuals who received at least 1 vaccination. Case counting started at Day 1.
†Percent reduction for these analyses includes the prophylactic efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) as well as the impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) on the course of infections present at the start of the vaccination.
CI = Confidence Interval
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of Any HPV Type Related Genital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

The impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) against the overall burden of HPV-related genital disease (i.e., disease caused by any HPV type) results from a combination of prophylactic efficacy against vaccine HPV types, disease contribution from vaccine HPV types present at time of vaccination, and the disease contribution from HPV types not contained in the vaccine.

Additional efficacy analyses from Study 5 were conducted in 2 populations: (1) a generally HPV-na´ve population that consisted of boys and men who are seronegative and PCR negative to HPV 6, 11, 16, and 18 and PCR-negative to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 at Day 1, approximating a population of sexually-na´ve boys and men and (2) the general study population of boys and men regardless of baseline HPV status, some of whom had HPV-related disease at Day 1.

Among generally HPV-na´ve boys and men and among all boys and men in Study 5 (including boys and men with HPV infection at Day 1), GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) reduced the overall incidence of genital disease (Table 16). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18 in boys and men na´ve (seronegative and PCR negative) for the specific relevant vaccine HPV type. Infected boys and men may already have genital disease at Day 1 and some will develop genital disease during follow-up, either related to a vaccine or non-vaccine HPV type present at the time of vaccination or related to a nonvaccine HPV type not present at the time of vaccination.

Table 16 : Effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Prevention of Any HPV Type Related Genital Disease in Boys and Men 16 Through 26 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non- Vaccine HPV Types

Endpoint Analysis GARDASIL AAHS Control % Reduction
(95%CI)
N Cases N Cases
External Genital Lesions Generally HPV Na´ve* 1275 6 1270 36 83.8 (61.2, 94.4)
Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 1943 36 1937 89 60.2 (40.8, 73.8)***
Condyloma Generally HPV Na´ve* 1275 5 1270 33 85.3 (62.1, 95.5)
Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 1943 32 1937 83 62.1 (42.4, 75.6)***
PIN 1/2/3 Generally HPV Na´ve* 1275 1 1270 3 67.4 (-306.5, 99.4)
Boys and Men Regardless of Current or Prior Exposure to Vaccine or Non-Vaccine HPV Types** 1943 7 1937 6 -15.9 (-317.5, 66.6)***
*Includes all individuals who received at least 1 vaccination and who were seronegative and PCR negative at enrollment to HPV 6, 11, 16 and 18, and PCR-negative at enrollment to HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59. Case counting started at Day 1.
**Includes all individuals who received at least 1 vaccination. Case counting started at Day 1.
***Percent reduction for these analyses includes the prophylactic efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) as well as the impact of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) on the course of infections present at the start of the vaccination.
CI = Confidence Interval
AAHS Control = Amorphous Aluminum Hydroxyphosphate Sulfate

Overall Population Impact

The subject characteristics (e.g. lifetime sex partners, geographic distribution of the subjects) influence the HPV prevalence of the population and therefore the population benefit can vary widely.

The overall efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) has shown protection, and those infections against which GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) has not been shown to protect.

The efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) for HPV types not included in the vaccine (i.e., cross-protective efficacy) is a component of the overall impact of the vaccine on rates of disease caused by HPV. Cross-protective efficacy was not demonstrated against disease caused by non-vaccine HPV types in the combined database of the Study 3 and Study 4 trials.

GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) does not protect against genital disease not related to HPV. One woman who received GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in Study 3 developed an external genital well-differentiated squamous cell carcinoma at month 24. No HPV DNA was detected in the lesion or in any other samples taken throughout the study.

In 18,150 girls and women enrolled in Study 2, Study 3, and Study 4, GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) reduced definitive cervical therapy procedures by 23.9% (95% CI: 15.2%, 31.7%).

Other Studies

Data are insufficient to establish effectiveness of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in women 27 through 45 years of age.

Immunogenicity

Assays to Measure Immune Response

The minimum anti-HPV titer that confers protective efficacy has not been determined.

Because there were few disease cases in individuals na´ve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) , it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical disease caused by HPV 6, 11, 16, and/or 18.

The immunogenicity of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) was assessed in 20,132 9- through 26-year-old girls and women (GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) N = 10,723; AAHS control or saline placebo N = 9409) and 5417 9- through 26-year-old boys and men (GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) N = 3109; AAHS control or saline placebo N = 2308).

Type-specific immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate.

Immune Response to GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine)

The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month postdose 3 (month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine.

Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT).

In clinical studies in girls and women, at least 99.8%, 99.8%, 99.8%, and 99.5% who received GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested.

In clinical studies in boys and men, at least 98.9%, 99.2%, 98.8%, and 97.4% who received GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month postdose 3 across all age groups tested.

Across all populations, anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at month 7 (Table 17 and Table 18). GMTs declined through month 24 and then stabilized through month 36 at levels above baseline. Table 19 displays the persistence of anti-HPV cLIA geometric mean titers by gender and age group. The duration of immunity following a complete schedule of immunization with GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) has not been established.

Table 17 : Summary of Month 7Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of Girls and Women

Population N** n*** % Seropositive
(95% CI)
GMT
(95% CI) mMU/mL†
Anti-HPV 6
9- through 15-year-old girls 1122 917 99.9 (99.4, 100.0) 929.2 (874.6, 987.3)
16- through 26-year-old girls and women 9862 3333 99.8 (99.6, 99.9) 545.2 (530.3, 560.6)
Anti-HPV 11
9- through 15-year-old girls 1122 917 99.9 (99.4, 100.0) 1304.6 (1224.7, 1389.7)
16- through 26-year-old girls and women 9862 3357 99.8 (99.5, 99.9) 749.0 (726.1, 772.7)
Anti-HPV 16
9- through 15-year-old girls 1122 915 99.9 (99.4, 100.0) 4918.5 (4556.6, 5309.1)
16- through 26-year-old girls and women 9862 3253 99.8 (99.6, 100.0) 2411.3 (2311.1, 2515.9)
Anti-HPV 18
9- through 15-year-old girls 1122 922 99.8 (99.2, 100.0) 1042.6 (967.6, 1123.3)
16- through 26-year-old girls and women 9862 3571 99.4 (99.1, 99.7) 475.6 (459.2, 492.6)
*The PPI population consisted of individuals who received all 3 vaccinations within pre-defined day ranges, did not have major deviations from the study protocol, met predefined criteria for the interval between the Month 6 and Month 7 visit, and were na´ve (PCR negative and seronegative) to the relevant HPV type(s) (types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7).
**Number of individuals randomized to the respective vaccination group who received at least 1 injection.
***Number of individuals contributing to the analysis.
cLIA = Competitive Luminex immunoassay
CI = Confidence interval
GMT = Geometric mean titers
†mMU = milli-Merck units

Table 18 : Summary of Month 7 Anti-HPV cLIA Geometric Mean Titers in the PPI* Population of Boys and Men

Population N** n*** % Seropositive
(95% CI)
GMT
(95% CI) mMU/mL†
Anti-HPV 6
9- through 15-year-old boys 1072 884 99.9 (99.4, 100.0) 1037.5 (963.5, 1117.3)
16- through 26-year-old boys and men 2026 1094 98.9 (98.1, 99.4) 447.2 (418.4, 477.9)
Anti-HPV 11
9- through 15-year-old boys 1072 885 99.9 (99.4, 100.0) 1386.8 (1298.5, 1481.0)
16- through 26-year-old boys and men 2026 1094 99.2 (98.4, 99.6) 624.5 (588.6, 662.5)
Anti-HPV 16
9- through 15-year-old boys 1072 882 99.8 (99.2, 100.0) 6056.5 (5601.4, 6548.6)
16- through 26-year-old boys and men 2026 1137 98.8 (97.9, 99.3) 2401.5 (2241.8, 2572.6)
Anti-HPV 18
9- through 15-year-old boys 1072 887 99.8 (99.2, 100) 1357.4 (1249.4, 1474.7)
16- through 26-year-old boys and men 2026 1176 97.4 (96.3, 98.2) 402.6 (374.6, 432.6)
*The PPI population consisted of individuals who received all 3 vaccinations within pre-defined day ranges, did not have major deviations from the study protocol, met predefined criteria for the interval between the Month 6 and Month 7 visit, and were na´ve (PCR negative and seronegative) to the relevant HPV type(s) (types 6, 11, 16, and 18) prior to dose 1 and through 1 month Postdose 3 (Month 7).
**Number of individuals randomized to the respective vaccination group who received at least 1 injection.
***Number of individuals contributing to the analysis.
cLIA = Competitive Luminex immunoassay
CI = Confidence interval
GMT = Geometric mean titers
†mMU = milli-Merck units

Table 19 : Persistence of Anti-HPV cLIA Geometric Mean Titers by Gender and Age Group

Assay (cLIA)/Time Point 9- to15-year-
old Boys
(N* = 1072)
16- to26-year-
old Boysand Men
(N* = 2026)
9- to15-year-
old Girls
(N* = 1122)
16- to26-year-old
Girls and Women
(N* = 9859)
n** GMT
(95% CI)
mMU/mL***
n** GMT
(95% CI)
mMU/mL***
n** GMT
(95% CI)
mMU/mL***
n** GMT

(95% CI)mMU/mL***
Anti-HPV 6
  Month 07 884 1037.5
(963.5, 1117.3)
1094 447.2
(418.4, 477.9)
917 929.2
(874.6, 987.3)
3333 545.2
(530.3, 560.6)
  Month 24 323 134.1
(119.5, 150.5)
907 80.3
(74.9, 86.0)
214 156.1
(135.6, 179.6)
2792 109.1
(105.2, 113.1)
  Month 36† 342 126.6
(111.9, 143.2)
654 72.4
(68.0, 77.2)
356 129.4
(115.6, 144.8)
- -
  Month 48‡ - - - - - - 2375 74.6
(71.6, 77.7)
Anti-HPV 11
  Month 07 885 1386.8
(1298.5, 1481.0)
1094 624.5
(588.6, 662.5)
917 1304.6
(1224.7, 1389.7)
3357 749.0
(726.1, 772.7)
  Month 24 324 188.5
(168.4, 211.1)
907 94.6
(88.4, 101.2)
214 218.0
(188.3, 252.4)
2821 137.0
(132.0, 142.2)
  Month 36† 342 148.8
(131.1, 169.0)
654 80.3
(75.7, 85.2)
356 148.0
(131.1, 167.1)
- -
  Month 48‡ - - - - - - 2399 90.3
(86.6, 94.1)
Anti-HPV 16
  Month 07 882 6056.5
(5601.4, 6548.6)
1137 2401.5
(2241.8, 2572.6)
915 4918.5
(4556.6, 5309.1)
3253 2411.3
(2311.1, 2515.9)
  Month 24 322 938.2
(825.0, 1067.0)
938 347.7
(322.5, 374.9)
211 944.2
(804.4, 1108.3)
2725 442.6
(425.0, 460.9)
  Month 36† 341 708.8
(613.9, 818.3)
672 306.7
(287.5, 327.1)
353 642.2
(562.8, 732.8)
- -
  Month 48‡ - - - - - - 2330 334.6
(319.4, 350.5)
Anti-HPV 18
  Month 07 887 1357.4
(1249.4, 1474.7)
1176 402.6
(374.6, 432.6)
922 1042.6
(967.6, 1123.3)
3571 475.6
(459.2, 492.6)
  Month 24 324 131.9
(112.1, 155.3)
967 38.7
(35.2, 42.5)
214 137.7
(114.8, 165.1)
3007 50.8
(48.2, 53.5)
  Month 36† 343 113.0
(94.7, 135.0)
690 33.4
(30.9, 36.1)
357 87.0
(74.8, 101.2)
- -
  Month 48‡ - - - - - - 2536 33.8
(32.0, 35.7)
*N = Number of individuals randomized in the respective group who received at least 1 injection.
**n = Number of individuals in the indicated immunogenicity population.
***mMU = milli-Merck units per Ml
†Month 36 time point for 16- to 26-year-old boys and men; Month 37 for 9- to 15-year-old boys and girls. No serology samples were collected at this time point for 16- to 26-year-old girls and women.
‡Month 48/End-of-study visits for 16- to 26-year-old girls and women were generally scheduled earlier than Month 48. Mean visit timing was Month 44. The studies in 9- to 15-year-old boys and girls and 16- to 26-year-old boys and men were planned to end prior to 48 months and therefore no serology samples were collected.
cLIA = Competitive Luminex immunoassay
CI = Confidence interval
GMT = Geometric mean titers

Tables 17 and 18 display the Month 7 immunogenicity data for girls and women and boys and men. Anti- HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent girls were non-inferior to anti-HPV responses in 16- through 26-year-old girls and women in the combined database of immunogenicity studies for GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) . Anti-HPV responses 1 month postdose 3 among 9- through 15-year-old adolescent boys were non-inferior to anti-HPV responses in 16- through 26-year-old boys and men in Study 5.

On the basis of this immunogenicity bridging, the efficacy of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) in 9- through 15-year-old adolescent girls and boys is inferred.

GMT Response to Variation in Dosing Regimen in 18- Through 26-Year-Old Women

Girls and women evaluated in the PPE population of clinical studies received all 3 vaccinations within 1 year of enrollment. An analysis of immune response data suggests that flexibility of ▒1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ▒2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not impact the immune responses to GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) .

Duration of the Immune Response to GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine)

The duration of immunity following a complete schedule of immunization with GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) has not been established. The peak anti-HPV GMTs for HPV types 6, 11, 16, and 18 occurred at month 7. Anti-HPV GMTs for HPV types 6, 11, 16, and 18 were similar between measurements at month 24 and month 60 in Study 2.

Studies with RECOMBIVAX HB

The safety and immunogenicity of co-administration of GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) with RECOMBIVAX HB hepatitis B vaccine (recombinant) (same visit, injections at separate sites) were evaluated in a randomized study of 1871 women aged 16 through 24 years at enrollment. Immune response to both hepatitis B vaccine (recombinant) and GARDASIL (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) was non-inferior whether they were administered at the same visit or at a different visit.

Last reviewed on RxList: 1/26/2010
This monograph has been modified to include the generic and brand name in many instances.

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