Vaccine Information: GARDASIL (Page 6 of 8)

14.6 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 will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which GARDASIL has shown protection, and those infections against which GARDASIL has not been shown to protect.

The efficacy of GARDASIL 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 does not protect against genital disease not related to HPV. One woman who received GARDASIL 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 reduced definitive cervical therapy procedures by 23.9% (95% CI: 15.2%, 31.7%).

14.7 Studies in Women 27 through 45 Years of Age

Study 6 evaluated efficacy in 3253 women 27 through 45 years of age based on a combined endpoint of HPV 6-, 11-, 16- or 18-related persistent infection, genital warts, vulvar and vaginal dysplastic lesions of any grade, CIN of any grade, AIS, and cervical cancer. These women were randomized 1:1 to receive either GARDASIL or AAHS control. The efficacy for the combined endpoint was driven primarily by prevention of persistent infection. There was no statistically significant efficacy demonstrated for CIN 2/3, AIS, or cervical cancer. In post hoc analyses conducted to assess the impact of GARDASIL on the individual components of the combined endpoint, the results in the population of women naïve to the relevant HPV type at baseline were as follows: prevention of HPV 6-, 11-, 16- or 18-related persistent infection (80.5% [95% CI: 68.3, 88.6]), prevention of HPV 6-, 11-, 16- or 18-related CIN (any grade) (85.8% [95% CI: 52.4, 97.3]), and prevention of HPV 6-, 11-, 16- or 18-related genital warts (87.6% [95% CI: 7.3, 99.7]).

Efficacy for disease endpoints was diminished in a population impact assessment of women who were vaccinated regardless of baseline HPV status (full analysis set). In the full analysis set (FAS), efficacy was not demonstrated for the following endpoints: prevention of HPV 16- and 18-related CIN 2/3, AIS, or cervical cancer and prevention of HPV 6- and 11-related condyloma. No efficacy was demonstrated against CIN 2/3, AIS, or cervical cancer in the general population irrespective of HPV type (FAS any type analysis).

14.8 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 naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received GARDASIL, 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 was assessed in 23,951 9- through 45-year-old girls and women (GARDASIL N = 12,634; AAHS control or saline placebo N = 11,317) and 5417 9- through 26-year-old boys and men (GARDASIL 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

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 16- through 26-year-old girls and women, 99.8%, 99.8%, 99.8%, and 99.4% who received GARDASIL 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 27- through 45-year-old women, 98.2%, 97.9%, 98.6%, and 97.1% who received GARDASIL 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 16- through 26-year-old boys and men, 98.9%, 99.2%, 98.8%, and 97.4% who received GARDASIL 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 18 and Table 19). GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline. Tables 20 and 21 display 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 has not been established.

Table 18: Summary of Month 7 Anti-HPV cLIA Geometric Mean Titers in the PPI * Population of Girls and Women
Population N n % Seropositive(95% CI) GMT(95% CI) mMU §/mL
cLIA = Competitive Luminex Immunoassay
CI = Confidence Interval
GMT = Geometric Mean Titers
*
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 naïve (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.
§
mMU = milli-Merck Units
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 9859 3329 99.8 (99.6, 99.9) 545.0 (530.1, 560.4)
27- through 34-year-old women 667 439 98.4 (96.7, 99.4) 435.6 (393.4, 482.4)
35- through 45-year-old women 957 644 98.1 (96.8, 99.0) 397.3 (365.2, 432.2)
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 9859 3353 99.8 (99.5, 99.9) 748.9 (726.0, 772.6)
27- through 34-year-old women 667 439 98.2 (96.4, 99.2) 577.9 (523.8, 637.5)
35- through 45-year-old women 957 644 97.7 (96.2, 98.7) 512.8 (472.9, 556.1)
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 9859 3249 99.8 (99.6, 100.0) 2409.2 (2309.0, 2513.8)
27- through 34-year-old women 667 435 99.3 (98.0, 99.9) 2342.5 (2119.1, 2589.6)
35- through 45-year-old women 957 657 98.2 (96.8, 99.1) 2129.5 (1962.7, 2310.5)
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 9859 3566 99.4 (99.1, 99.7) 475.2 (458.8, 492.1)
27- through 34-year-old women 667 501 98.0 (96.4, 99.0) 385.8 (347.6, 428.1)
35- through 45-year-old women 957 722 96.4 (94.8, 97.6) 324.6 (297.6, 354.0)
Table 19: 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
cLIA = Competitive Luminex Immunoassay
CI = Confidence Interval
GMT = Geometric Mean Titers
*
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 naïve (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.
§
mMU = milli-Merck Units
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 1093 98.9 (98.1, 99.4) 447.8 (418.9, 478.6)
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 1093 99.2 (98.4, 99.6) 624.3 (588.4, 662.3)
Anti-HPV 16
9- through 15-year-old boys 1072 882 99.8 (99.2, 100.0) 6056.5 (5601.3, 6548.7)
16- through 26-year-old boys and men 2026 1136 98.8 (97.9, 99.3) 2403.3 (2243.4, 2574.6)
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 1175 97.4 (96.3, 98.2) 402.6 (374.6, 432.7)
Table 20: Persistence of Anti-HPV cLIA Geometric Mean Titers in 9- Through 45-Year-Old Girls and Women
Assay (cLIA)/ Time Point 9- to 15-Year-Old Girls(N * = 1122) 16- to 26-Year-Old Girls and Women(N * = 9859) 27- to 34-Year-Old Women(N * = 667) 35- to 45-Year-Old Women(N * = 957)
n GMT(95% CI) mMU /mL n GMT(95% CI) mMU /mL n GMT(95% CI) mMU /mL n GMT(95% CI) mMU /mL
cLIA = Competitive Luminex Immunoassay
CI = Confidence Interval
GMT = Geometric Mean Titers
*
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
§
Month 37 for 9- to 15-year-old 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 girls were planned to end prior to 48 months and therefore no serology samples were collected.
Anti-HPV 6
Month 07 917 929.2(874.6, 987.3) 3329 545.0(530.1, 560.4) 439 435.6(393.4, 482.4) 644 397.3(365.2, 432.2)
Month 24 214 156.1(135.6, 179.6) 2788 109.1(105.2, 113.1) 421 70.7(63.8, 78.5) 628 69.3(63.7, 75.4)
Month 36§ 356 129.4(115.6, 144.8) - - 399 79.5(72.0, 87.7) 618 81.1(75.0, 87.8)
Month 48 - - 2514 73.8(70.9, 76.8) 391 58.8(52.9, 65.3) 616 62.0(57.0, 67.5)
Anti-HPV 11
Month 07 917 1304.6(1224.7, 1389.7) 3353 748.9(726.0, 772.6) 439 577.9(523.8, 637.5) 644 512.8(472.9, 556.1)
Month 24 214 218.0(188.3, 252.4) 2817 137.1(132.1, 142.3) 421 79.3(71.5, 87.8) 628 73.4(67.4, 79.8)
Month 36§ 356 148.0(131.1, 167.1) - - 399 81.8(74.3, 90.1) 618 77.4(71.6, 83.6)
Month 48 - - 2538 89.4(85.9, 93.1) 391 67.4(60.9, 74.7) 616 62.7(57.8, 68.0)
Anti-HPV 16
Month 07 915 4918.5(4556.6, 5309.1) 3249 2409.2(2309.0, 2513.8) 435 2342.5(2119.1, 2589.6) 657 2129.5(1962.7, 2310.5)
Month 24 211 944.2(804.4, 1108.3) 2721 442.6(425.0, 460.9) 416 285.9(254.4, 321.2) 642 271.4(247.1, 298.1)
Month 36§ 353 642.2(562.8, 732.8) - - 399 291.5(262.5, 323.8) 631 276.7(254.5, 300.8)
Month 48 - - 2474 326.2(311.8, 341.3) 394 211.8(189.5, 236.8) 628 192.8(176.5, 210.6)
Anti-HPV 18
Month 07 922 1042.6(967.6, 1123.3) 3566 475.2(458.8, 492.1) 501 385.8(347.6, 428.1) 722 324.6(297.6, 354.0)
Month 24 214 137.7(114.8, 165.1) 3002 50.8(48.2, 53.5) 478 31.8(28.1, 36.0) 705 26.0(23.5, 28.8)
Month 36§ 357 87.0(74.8, 101.2) - - 453 32.1(28.5, 36.3) 689 27.0(24.5, 29.8)
Month 48 - - 2710 33.2(31.5, 35.0) 444 25.2(22.3, 28.5) 688 21.2(19.2, 23.4)
Table 21: Persistence of Anti-HPV cLIA Geometric Mean Titers in 9- Through 26-Year-Old Boys and Men
Assay (cLIA)/ Time Point 9- to 15-Year-Old Boys(N * = 1072) 16- to 26-Year-Old Boys and Men(N * = 2026)
n GMT(95% CI) mMU /mL n GMT(95% CI) mMU /mL
cLIA = Competitive Luminex Immunoassay
CI = Confidence Interval
GMT = Geometric Mean Titers
*
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
§
Month 36 time point for 16- to 26-year-old boys and men; Month 37 for 9- to 15-year-old boys.
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.
Anti-HPV 6
Month 07 884 1037.5(963.5, 1117.3) 1094 447.2(418.4, 477.9)
Month 24 323 134.1(119.5, 150.5) 907 80.3(74.9, 86.0)
Month 36§ 342 126.6(111.9, 143.2) 654 72.4(68.0, 77.2)
Month 48 - - - -
Anti-HPV 11
Month 07 885 1386.8(1298.5, 1481.0) 1094 624.5(588.6, 662.5)
Month 24 324 188.5(168.4, 211.1) 907 94.6(88.4, 101.2)
Month 36§ 342 148.8(131.1, 169.0) 654 80.3(75.7, 85.2)
Month 48 - - - -
Anti-HPV 16
Month 07 882 6056.5(5601.4, 6548.6) 1137 2401.5(2241.8, 2572.6)
Month 24 322 938.2(825.0, 1067.0) 938 347.7(322.5, 374.9)
Month 36§ 341 708.8(613.9, 818.3) 672 306.7(287.5, 327.1)
Month 48 - - - -
Anti-HPV 18
Month 07 887 1357.4(1249.4, 1474.7) 1176 402.6(374.6, 432.6)
Month 24 324 131.9(112.1, 155.3) 967 38.7(35.2, 42.5)
Month 36§ 343 113.0(94.7, 135.0) 690 33.4(30.9, 36.1)
Month 48 - - - -

Tables 18 and 19 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. 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 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.

Duration of the Immune Response to GARDASIL

The duration of immunity following a complete schedule of immunization with GARDASIL 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.

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