Phase III, randomized controlled trial in girls 9-15 years old to evaluate lot consistency of a novel nine-valent human papillomavirus L1 virus-like particle vaccine

Figures & data

Figure 1. Subject distribution between the adult-adolescent substudy and the lot consistency substudy. The V503-002 study (NCT #00943722) was designed to enroll 1800 girls 9 to 15 years of age, 600 boys 9 to 15 years of age, and 400 young women 16 to 26 years of age. The study was comprised of two immunogenicity substudies: 1. An adult-adolescent immunobridging substudy to compare 9vHPV vaccine immunogenicity at Month 7 in girls versus young women, and boys versus young women; 2. A lot consistency substudy to demonstrate consistent immunogenicity at Month 7 in subjects randomized to three different vaccine lots of the final manufacturing process.

Table 1. Subject characteristics

	Lot 1		Lot 2		Lot 3
	n	(%)	n	(%)	n	(%)
Subjects in population	648		643		644
Age (Years)
9 to 12 Years of Age	440	(67.9)	432	(67.2)	432	(67.1)
13 to 15 Years of Age	208	(32.1)	211	(32.8)	212	(32.9)
Mean	11.7		11.6		11.6
SD	1.8		1.8		1.9
Median	12.0		11.0		11.0
Range	9 to 15		9 to 15		9 to 15
Race
American Indian Or Alaska Native	1	(0.2)	1	(0.2)	0	(0.0)
Asian	150	(23.1)	141	(21.9)	139	(21.6)
Black Or African American	50	(7.7)	59	(9.2)	52	(8.1)
Multi-Racial	81	(12.5)	91	(14.2)	86	(13.4)
White	366	(56.5)	351	(54.6)	367	(57.0)
Ethnicity
Hispanic Or Latino	176	(27.2)	191	(29.7)	193	(30.0)
Not Hispanic Or Latino	472	(72.8)	452	(70.3)	451	(70.0)
Region
Africa	32	(4.9)	34	(5.3)	29	(4.5)
Asia-Pacific	148	(22.8)	137	(21.3)	138	(21.4)
Europe	206	(31.8)	182	(28.3)	185	(28.7)
Latin America	125	(19.3)	147	(22.9)	136	(21.1)
North America	137	(21.1)	143	(22.2)	156	(24.2)

Figure 2. Accounting of subjects in the lot consistency substudy. A total of 1935 subjects were randomized from 65 sites in Africa (South Africa), Asia (India, Korea, Taiwan, Thailand), Europe (Austria, Belgium, Finland, Poland, Sweden, Spain), Latin America (Brazil, Chile, Colombia, Costa Rica, Peru) and North America (United States). Withdrawal = patient withdrew consent.

Table 2. Statistical analysis of equivalence of geometric mean titers at month 7

		9vHPV Vaccine						Estimated
		Comparison Group A			Comparison Group B			Fold Difference	p-Value for
	Comparison Group A vs.			GMT^‡			GMT^‡	Group A / Group B	Equivalence		Equivalence met
Assay (cLIA)	Comparison Group B	N	n	(mMU/mL)	N	n	(mMU/mL)	(95% CI)	Left^§	Right^¦¦	(YES/NO)
Anti-HPV 6	Lot 1 vs. Lot 2	646	517	1,603.6	642	536	1,645.8	0.97 (0.88, 1.08)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	517	1,603.6	644	544	1,550.0	1.03 (0.93, 1.16)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	536	1,645.8	644	544	1,550.0	1.06 (0.95, 1.19)	<0.001	<0.001	YES
Anti-HPV 11	Lot 1 vs. Lot 2	646	517	1,221.9	642	536	1,223.2	1.00 (0.90, 1.11)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	517	1,221.9	644	544	1,143.6	1.07 (0.95, 1.20)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	536	1,223.2	644	544	1,143.6	1.07 (0.95, 1.20)	<0.001	<0.001	YES
Anti-HPV 16	Lot 1 vs. Lot 2	646	529	6,465.1	642	542	6,764.7	0.96 (0.86, 1.06)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	529	6,465.1	644	556	6,456.5	1.00 (0.90, 1.12)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	542	6,764.7	644	556	6,456.5	1.05 (0.94, 1.17)	<0.001	<0.001	YES
Anti-HPV 18	Lot 1 vs. Lot 2	646	531	1,976.8	642	547	1,969.5	1.00 (0.89, 1.14)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	531	1,976.8	644	563	1,778.3	1.11 (0.98, 1.26)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	547	1,969.5	644	563	1,778.3	1.11 (0.97, 1.26)	<0.001	<0.001	YES
Anti-HPV 31	Lot 1 vs. Lot 2	646	522	1,742.3	642	542	1,736.2	1.00 (0.89, 1.13)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	522	1,742.3	644	553	1,701.7	1.02 (0.91, 1.16)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	542	1,736.2	644	553	1,701.7	1.02 (0.90, 1.15)	<0.001	<0.001	YES
Anti-HPV 33	Lot 1 vs. Lot 2	646	534	913.6	642	543	873.0	1.05 (0.94, 1.16)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	534	913.6	644	560	868.6	1.05 (0.94, 1.17)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	543	873.0	644	560	868.6	1.01 (0.90, 1.12)	<0.001	<0.001	YES
Anti-HPV 45	Lot 1 vs. Lot 2	646	534	643.3	642	548	770.3	0.84 (0.73, 0.95)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	534	643.3	644	565	620.8	1.04 (0.91, 1.18)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	548	770.3	644	565	620.8	1.24 (1.08, 1.42)	<0.001	<0.001	YES
Anti-HPV 52	Lot 1 vs. Lot 2	646	533	862.7	642	547	934.1	0.92 (0.83, 1.03)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	533	862.7	644	562	905.4	0.95 (0.85, 1.07)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	547	934.1	644	562	905.4	1.03 (0.92, 1.16)	<0.001	<0.001	YES
Anti-HPV 58	Lot 1 vs. Lot 2	646	531	1,197.7	642	539	1,255.5	0.95 (0.86, 1.06)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	646	531	1,197.7	644	560	1,118.3	1.07 (0.96, 1.20)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	642	539	1,255.5	644	560	1,118.3	1.12 (1.00, 1.26)	<0.001	<0.001	YES

^†The per-protocol immunogenicity population includes all subjects who were not general protocol violators, received all 3 vaccinations within acceptable day ranges, were seronegative at Day 1 for the relevant HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

^‡Based on an ANCOVA model with a response of the natural log of individual titers and fixed effects for lots and age strata.

^§p-value for the comparison of the GMT ratio to the lower bound (0.5).

^¦¦p-value for the comparison of the GMT ratio to the upper bound (2.0).

A p-value (Left) <= 0.025 and a p-value (Right) <= 0.025 together support a conclusion of equivalence. If equivalence can be established in all 3 pairwise comparison for a given HPV type and endpoint, the 3 lots will be considered consistent for that HPV type. Equivalence must be established for all 9 HPV types for the 3 HPV vaccine lots to be considered consistent.

N = Number of subjects randomized to the respective vaccination group who received at least 1 injection.

n = Number of subjects with evaluable serology data and are eligible for the indicated analysis population.

CI = Confidence interval; cLIA = Competitive Luminex immunoassay; GMT = Geometric mean titer; mMU = Milli Merck units.

PCR = Polymerase chain reaction, HPV = Human papillomavirus, VLP = Virus-like particles.

Table 3. Statistical analysis of equivalence of proportions of subjects who seroconverted by month 7

		9vHPV Vaccine						Estimated
		Seroconversion Rate Comparison Group A			Seroconversion Rate Comparison Group B			Percentage Point
				Estimated			Estimated	Difference	p-Value for
	Comparison Group A vs.			Response			Response	Group A / Group B	Equivalence
Assay (cLIA)	Comparison Group B	N	n	(%)	N	n	(%)	(95% CI)	Left^§	Right^║	Equivalence met (YES/NO)
cLIA 6	Lot 1 vs. Lot 2	517	516	99.8	536	535	99.8	−0.0 (−0.9, 0.9)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	517	516	99.8	544	540	99.3	0.5 (−0.4, 1.7)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	536	535	99.8	544	540	99.3	0.6 (−0.4, 1.7)	<0.001	<0.001	YES
cLIA 11	Lot 1 vs. Lot 2	517	517	100	536	536	100	0.0 (−0.7, 0.7)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	517	517	100	544	542	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	536	536	100	544	542	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
cLIA 16	Lot 1 vs. Lot 2	529	529	100	542	542	100	0.0 (−0.7, 0.7)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	529	529	100	556	554	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	542	542	100	556	554	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
cLIA 18	Lot 1 vs. Lot 2	531	530	99.8	547	547	100	−0.2 (−1.1, 0.5)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	531	530	99.8	563	561	99.7	0.2 (−0.7, 1.1)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	547	547	100	563	561	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
cLIA 31	Lot 1 vs. Lot 2	522	522	100	542	542	100	0.0 (−0.7, 0.7)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	522	522	100	553	552	99.8	0.2 (−0.6, 1.0)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	542	542	100	553	552	99.8	0.2 (−0.5, 1.0)	<0.001	<0.001	YES
cLIA 33	Lot 1 vs. Lot 2	534	534	100	543	543	100	0.0 (−0.7, 0.7)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	534	534	100	560	558	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	543	543	100	560	558	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
cLIA 45	Lot 1 vs. Lot 2	534	533	99.8	548	548	100	−0.2 (−1.1, 0.5)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	534	533	99.8	565	563	99.7	0.2 (−0.7, 1.1)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	548	548	100	565	563	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
cLIA 52	Lot 1 vs. Lot 2	533	533	100	547	547	100	0.0 (−0.7, 0.7)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	533	533	100	562	560	99.7	0.3 (−0.4, 1.3)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	547	547	100	562	560	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
cLIA 58	Lot 1 vs. Lot 2	531	531	100	539	539	100	0.0 (−0.7, 0.7)	<0.001	<0.001	YES
	Lot 1 vs. Lot 3	531	531	100	560	558	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES
	Lot 2 vs. Lot 3	539	539	100	560	558	99.6	0.4 (−0.4, 1.3)	<0.001	<0.001	YES

^†The per-protocol immunogenicity population includes all subjects who were not general protocol violators, received all 3 vaccinations within acceptable day ranges, were seronegative at Day 1 for the relevant HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

^§p-value for the comparison of the difference of seroconversion rates to the lower bound (-5%).

^║p-value for the comparison of the difference of seroconversion rates to the upper bound (5%).

Seroconversion was defined as changing serostatus from seronegative to seropositive. Cutoff values for HPV seropositivity are ≥ 30, 16, 20, 24, 10, 8, 8, 8, and 8 mMU/mL for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, respectively.

A p-value (Left) ≤ 0.025 and a p-value (Right) ≤ 0.025 together support a conclusion of equivalence. If equivalence can be established in all 3 pairwise comparison for a given HPV type and endpoint, the 3 lots will be considered consistent for that HPV type. Equivalence must be established for all 9 HPV types for the 3 HPV vaccine lots to be considered consistent.

The estimated proportions, proportion difference, associated confidence intervals, and p-values are based on the method of Miettinen and Nurminen, stratified by age strata using CMH weights.

N = Number of subjects with evaluable serology data and are eligible for the indicated analysis population.

n = Number of subjects who had seroconversion.

CI = Confidence interval; cLIA = Competitive Luminex immunoassay; GMT = Geometric mean titer; mMU = Milli Merck units.

HPV = Human papillomavirus; VLP = Virus-like particles.