Vaccine Information: GARDASIL 9 (Page 5 of 8)

14.4 Effectiveness in Prevention of HPV-Related Oropharyngeal and Other Head and Neck Cancers

The effectiveness of GARDASIL 9 against oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, is based on the effectiveness of GARDASIL and GARDASIL 9 to prevent anogenital disease caused by HPV types covered by the vaccine [see Clinical Studies (14.1, 14.2, 14.3)].

14.5 Immunogenicity of a 3-Dose Regimen

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

Type-specific immunoassays (i.e., cLIA) 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. 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).

Studies Supporting the Effectiveness of GARDASIL 9 against HPV Types 6, 11, 16, and 18

Effectiveness of GARDASIL 9 against persistent infection and disease related to HPV Types 6, 11, 16, or 18 was inferred from non-inferiority comparisons in Study 1 (16- through 26-year-old girls and women) and Study 3 (9- through 15-year-old girls) of GMTs following vaccination with GARDASIL 9 with those following vaccination with GARDASIL. A low number of efficacy endpoint cases related to HPV types 6, 11, 16 and 18 in both vaccination groups precluded a meaningful assessment of efficacy using disease endpoints associated with these HPV types. The primary analyses were conducted in the per-protocol population, which included subjects who received all three vaccinations within one year of enrollment, did not have major deviations from the study protocol, and were HPV-naïve. HPV-naïve individuals were defined as seronegative to the relevant HPV type(s) prior to dose 1 and among female subjects 16 through 26 years of age in Study 1 PCR negative to the relevant HPV type(s) in cervicovaginal specimens prior to dose 1 through Month 7.

Anti-HPV 6, 11, 16 and 18 GMTs at Month 7 for GARDASIL 9 among girls 9 through 15 years of age and young women 16 through 26 years of age were non-inferior to those among the corresponding populations for GARDASIL (Table 8). At least 99.7% of individuals included in the analyses for each HPV type became seropositive by Month 7.

Table 8: Comparison of Immune Responses (Based on cLIA) Between GARDASIL 9 and GARDASIL for HPV Types 6, 11, 16, and 18 in the PPI * Population of 9- through 26-Year-Old Girls and Women (Studies 1 and 3)

Population	GARDASIL 9		GARDASIL		GARDASIL 9/GARDASIL
	N †(n ‡)	GMTmMU §/ mL	N †(n ‡)	GMTmMU §/ mL	GMTRatio	(95% CI)¶
CI=Confidence Interval
GMT=Geometric Mean Titer
cLIA=competitive Luminex Immunoassay
* The PPI population consisted of individuals who received all three 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, were naïve (PCR negative [among 16- through 26-year old girls and women] and seronegative) to the relevant HPV type(s) (types 6, 11, 16, and 18) prior to dose 1, and among 16- through 26-year-old girls and women remained PCR negative to the relevant HPV type(s) through one month post-dose 3 (Month 7). The data for 16- through 26-year-old girls and women are from Study 1 (NCT00543543), and the data for 9- through 15-year-old girls are from Study 3 (NCT01304498). † N=Number of individuals randomized to the respective vaccination group who received at least one injection ‡ n=Number of individuals contributing to the analysis § mMU=milli-Merck Units ¶ Demonstration of non-inferiority required that the lower bound of the 95% CI of the GMT ratio be greater than 0.67
Anti-HPV 6
9- through 15-year-old girls	300(273)	1679.4	300(261)	1565.9	1.07	(0.93, 1.23)
16- through 26-year-old girls and women	6792(3993)	893.1	6795(3975)	875.2	1.02	(0.99, 1.06)
Anti-HPV 11
9- through 15-year-old girls	300(273)	1315.6	300(261)	1417.3	0.93	(0.80, 1.08)
16- through 26-year-old girls and women	6792(3995)	666.3	6795(3982)	830.0	0.80	(0.77, 0.83)
Anti-HPV 16
9- through 15-year-old girls	300(276)	6739.5	300(270)	6887.4	0.97	(0.85, 1.11)
16- through 26-year-old girls and women	6792(4032)	3131.1	6795(4062)	3156.6	0.99	(0.96, 1.03)
Anti-HPV 18
9- through 15-year-old girls	300(276)	1956.6	300(269)	1795.6	1.08	(0.91, 1.29)
16- through 26-year-old girls and women	6792(4539)	804.6	6795(4541)	678.7	1.19	(1.14, 1.23)

Study Supporting the Effectiveness of GARDASIL 9 against Vaccine HPV Types in 9- through 15-Year-Old Girls and Boys

Effectiveness of GARDASIL 9 against persistent infection and disease related to vaccine HPV types in 9- through 15-year-old girls and boys was inferred from non-inferiority comparison conducted in the PPI population in Study 2 of GMTs following vaccination with GARDASIL 9 among 9- through 15-year-old girls and boys with those among 16- through 26-year-old girls and women. Anti-HPV GMTs at Month 7 among 9- through 15-year-old girls and boys were non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women (Table 9).

Table 9: Comparison of Immune Responses (Based on cLIA) between the PPI * Populations of 16- through 26-Year-Old Girls and Women, 9- through 15-Year-Old Girls, and 9- through 15-Year-Old Boys for All GARDASIL 9 Vaccine HPV Types (Study 2)

Population	N †	n ‡	GMTmMU §/mL	GMT Ratio relative to 16-through 26-year-old girls and women(95% CI)¶
cLIA=competitive Luminex Immunoassay
CI=Confidence Interval
GMT=Geometric Mean Titer
* The PPI population consisted of individuals who received all three 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, were naïve (PCR negative [among 16- through 26-year old girls and women] and seronegative) to the relevant HPV type(s) prior to dose 1 and among 16- through 26-year-old girls and women remained PCR negative to the relevant HPV types through one month post-dose 3 (Month 7). The data are from Study 2 (NCT00943722). † N=Number of individuals randomized to the respective vaccination group who received at least one injection ‡ n=Number of individuals contributing to the analysis § mMU=milli-Merck Units ¶ Demonstration of non-inferiority required that the lower bound of the 95% CI of the GMT ratio be greater than 0.67
Anti-HPV 6
9- through 15-year-old girls	630	503	1703.1	1.89 (1.68, 2.12)
9- through 15-year-old boys	641	537	2083.4	2.31 (2.06, 2.60)
16- through 26-year-old girls and women	463	328	900.8	1
Anti-HPV 11
9- through 15-year-old girls	630	503	1291.5	1.83 (1.63, 2.05)
9- through 15-year-old boys	641	537	1486.3	2.10 (1.88, 2.36)
16- through 26-year-old girls and women	463	332	706.6	1
Anti-HPV 16
9- through 15-year-old girls	630	513	6933.9	1.97 (1.75, 2.21)
9- through 15-year-old boys	641	546	8683.0	2.46 (2.20, 2.76)
16- through 26-year-old girls and women	463	329	3522.6	1
Anti-HPV 18
9- through 15-year-old girls	630	516	2148.3	2.43 (2.12, 2.79)
9- through 15-year-old boys	641	544	2855.4	3.23 (2.83, 3.70)
16- through 26-year-old girls and women	463	345	882.7	1
Anti-HPV 31
9- through 15-year-old girls	630	506	1894.7	2.51 (2.21, 2.86)
9- through 15-year-old boys	641	543	2255.3	2.99 (2.63, 3.40)
16- through 26-year-old girls and women	463	340	753.9	1
Anti-HPV 33
9- through 15-year-old girls	630	518	985.8	2.11 (1.88, 2.37)
9- through 15-year-old boys	641	544	1207.4	2.59 (2.31, 2.90)
16- through 26-year-old girls and women	463	354	466.8	1
Anti-HPV 45
9- through 15-year-old girls	630	518	707.7	2.60 (2.25, 3.00)
9- through 15-year-old boys	641	547	912.1	3.35 (2.90, 3.87)
16- through 26-year-old girls and women	463	368	272.2	1
Anti-HPV 52
9- through 15-year-old girls	630	517	962.2	2.21 (1.96, 2.49)
9- through 15-year-old boys	641	545	1055.5	2.52 (2.22, 2.84)
16- through 26-year-old girls and women	463	337	419.6	1
Anti-HPV 58
9- through 15-year-old girls	630	516	1288.0	2.18 (1.94, 2.46)
9- through 15-year-old boys	641	544	1593.3	2.70 (2.40, 3.03)
16- through 26-year-old girls and women	463	332	590.5	1

Study Supporting the Effectiveness of GARDASIL 9 against Vaccine HPV Types in 16- through 26-Year-Old Boys and Men

Effectiveness of GARDASIL 9 against persistent infection and disease related to vaccine HPV types in 16- through 26-year-old boys and men was inferred from non-inferiority comparison conducted in the PPI population in Study 7 of GMTs following vaccination with GARDASIL 9 among 16- through 26-year-old HM with those among 16- through 26-year-old girls and women. Anti-HPV GMTs at Month 7 among 16- through 26-year-old HM were non-inferior to anti-HPV GMTs among 16- through 26-year-old girls and women (Table 10). Study 7 also enrolled 313 16- through 26-year-old HIV-negative MSM. At Month 7, anti-HPV GMT ratios for MSM relative to HM ranged from 0.6 to 0.8, depending on HPV type. The GMT ratios for MSM relative to HM were generally similar to those previously observed in clinical trials with GARDASIL.

Table 10: Comparison of Immune Responses (Based on cLIA) between the PPI * Populations of 16- through 26-Year-Old Girls and Women and 16- through 26-Year-Old Boys and Men Self-Identified as Heterosexual (HM) for All GARDASIL 9 Vaccine HPV Types (Study 7)

Population	N †	n ‡	GMTmMU §/mL	GMT Ratio relative to 16- through 26-year-old girls and women(95% CI)¶
cLIA=competitive Luminex Immunoassay
CI=Confidence Interval
GMT=Geometric Mean Titer
* The PPI population consisted of individuals who received all three 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 seronegative to the relevant HPV type(s) (types 6, 11, 16, 18, 31, 33, 45, 52, and 58) prior to dose 1. The data are from Study 7 (NCT01651949). † Number of individuals randomized to the respective vaccination group who received at least one injection ‡ Number of individuals contributing to the analysis § mMU=milli-Merck Units ¶ Demonstration of non-inferiority required that the lower bound of the 95% CI of the GMT ratio be greater than 0.67
Anti-HPV 6
16- through 26-year-old HM	1103	847	782.0	1.11 (1.02, 1.21)
16- through 26-year-old girls and women	1099	708	703.9	1
Anti-HPV 11
16- through 26-year-old HM	1103	851	616.7	1.09 (1.00, 1.19)
16- through 26-year-old girls and women	1099	712	564.9	1
Anti-HPV 16
16- through 26-year-old HM	1103	899	3346.0	1.20 (1.10, 1.30)
16- through 26-year-old girls and women	1099	781	2788.3	1
Anti-HPV 18
16- through 26-year-old HM	1103	906	808.2	1.19 (1.08, 1.31)
16- through 26-year-old girls and women	1099	831	679.8	1
Anti-HPV 31
16- through 26-year-old HM	1103	908	708.5	1.24 (1.13, 1.37)
16- through 26-year-old girls and women	1099	826	570.1	1
Anti-HPV 33
16- through 26-year-old HM	1103	901	384.8	1.19 (1.10, 1.30)
16- through 26-year-old girls and women	1099	853	322.0	1
Anti-HPV 45
16- through 26-year-old HM	1103	909	235.6	1.27 (1.14, 1.41)
16- through 26-year-old girls and women	1099	871	185.7	1
Anti-HPV 52
16- through 26-year-old HM	1103	907	386.8	1.15 (1.05, 1.26)
16- through 26-year-old girls and women	1099	849	335.2	1
Anti-HPV 58
16- through 26-year-old HM	1103	897	509.8	1.25 (1.14, 1.36)
16- through 26-year-old girls and women	1099	839	409.3	1

Study Supporting the Effectiveness of GARDASIL 9 against Vaccine HPV Types in 27- through 45-Year-Old Women

Effectiveness of GARDASIL 9 against persistent infection and disease related to vaccine HPV types in 27- through 45-year-old women was supported by immunobridging comparisons conducted in the PPI population in Study 9. In Study 9, the GMT ratios of anti-HPV responses at Month 7 among 27- through 45-year-old women relative to anti-HPV responses among 16- through 26-year-old girls and women met the success criteria of having the lower bound of the 95% CI of the GMT ratios greater than 0.50 for HPV 16, 18, 31, 33, 45, 52, and 58 (Table 11).

Table 11: Comparison of Immune Responses (Based on cLIA) Between the PPI * Populations of 27- through 45 Year-Old Women and 16- through 26-Year-Old Girls and Women for GARDASIL 9 Vaccine HPV Types (Study 9)

Population	N †	n ‡	GMTmMU §/mL	GMT Ratio relative to 16-through 26-year-old girls and women (95% CI)¶
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 seronegative to the relevant HPV type(s) (types 16, 18, 31, 33, 45, 52, and 58) prior to dose 1. The data are from Study 9 (NCT03158220). † 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 ¶ Immunobridging required that the lower bound of the 95% CI of the GMT ratio be greater than 0.50 # N.D=Not Determined. GMT ratios were not calculated because immunobridging comparison was not specified in the study protocol for HPV types 6 and 11.
Anti-HPV 6
27- through 45-year-old women	640	448	638.4	N.D #
16- through 26-year-old girls and women	570	421	787.8	N.D #
Anti-HPV 11
27- through 45-year-old women	640	448	453.5	N.D #
16- through 26-year-old girls and women	570	421	598.7	N.D #
Anti-HPV 16
27- through 45-year-old women	640	448	2,147.5	0.70 (0.63, 0.77)
16- through 26-year-old girls and women	570	436	3,075.8	1
Anti-HPV 18
27- through 45-year-old women	640	471	532.1	0.71 (0.64, 0.80)
16- through 26-year-old girls and women	570	421	744.5	1
Anti-HPV 31
27- through 45-year-old women	640	488	395.7	0.66 (0.60, 0.74)
16- through 26-year-old girls and women	570	447	596.1	1
Anti-HPV 33
27- through 45-year-old women	640	493	259.0	0.73 (0.67, 0.80)
16- through 26-year-old girls and women	570	457	354.5	1
Anti-HPV 45
27- through 45-year-old women	640	515	145.6	0.68 (0.60, 0.76)
16- through 26-year-old girls and women	570	470	214.9	1
Anti-HPV 52
27- through 45-year-old women	640	496	244.7	0.71 (0.64, 0.78)
16- through 26-year-old girls and women	570	456	346.5	1
Anti-HPV 58
27- through 45-year-old women	640	478	296.4	0.69 (0.63, 0.76)
16- through 26-year-old girls and women	570	451	428.0	1

Immune Response to GARDASIL 9 across All Clinical Trials

Across all clinical trials, at least 99.2% of individuals included in the analyses for each of the nine vaccine HPV types became seropositive by Month 7. Anti-HPV GMTs at Month 7 among 9- through 15-year-old girls and boys and 16- through 26-year-old boys and men were comparable to anti-HPV responses among 16- through 26-year-old girls and women in the combined database of immunogenicity studies for GARDASIL 9.

Persistence of Immune Response to GARDASIL 9

The duration of immunity following a 3-dose schedule of vaccination with GARDASIL 9 has not been established. The peak anti-HPV GMTs for each vaccine HPV type occurred at Month 7. Proportions of individuals who remained seropositive to each vaccine HPV type at Month 24 were similar to the corresponding seropositive proportions at Month 7.

Administration of GARDASIL 9 to Individuals Previously Vaccinated with GARDASIL

Study 4 evaluated the immunogenicity of 3 doses of GARDASIL 9 in 921 girls and women (12 through 26 years of age) who had previously been vaccinated with 3 doses of GARDASIL. Prior to enrollment in the study, over 99% of subjects had received three injections of GARDASIL within a one year period. The time interval between the last injection of GARDASIL and the first injection of GARDASIL 9 ranged from approximately 12 to 36 months.

Seropositivity to HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58 in the per protocol population ranged from 98.3 to 100% by Month 7 in individuals who received GARDASIL 9. The anti-HPV 31, 33, 45, 52 and 58 GMTs for the population previously vaccinated with GARDASIL were 25-63% of the GMTs in the combined populations from Studies 1, 2, 3, and 5, who had not previously received GARDASIL, although the clinical relevance of these differences is unknown. Efficacy of GARDASIL 9 in preventing infection and disease related to HPV Types 31, 33, 45, 52, and 58 in individuals previously vaccinated with GARDASIL has not been assessed.

Concomitant Use of Hormonal Contraceptives

Among 7,269 female recipients of GARDASIL 9 (16 through 26 years of age), 60.2% used hormonal contraceptives during the vaccination period of clinical studies 1 and 2. Use of hormonal contraceptives did not appear to affect the type specific immune responses to GARDASIL 9.