Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a two-dose schedule in adolescent girls: Five-year clinical data and modeling predictions from a randomized study

Figures & data

Figure 1. Flow of participants through the trial. 2D, 2-dose schedule; 3D, 3-dose schedule; 20/20, licensed HPV-16/18 AS04-adjuvanted vaccine formulation containing 20 μg each of HPV-16 and −18 L1 virus-like particles and adjuvanted with AS04; 40/40, alternative HPV-16/18 AS04-adjuvanted vaccine formulation containing 40 μg each of HPV-16 and −18 L1 virus-like particles and adjuvanted with AS04; ATP-I, according-to-protocol immunogenicity cohort; M, month; y, years. *Excluding one subject who attended the Month 60 visit but did not sign the informed consent form for this visit. This article focuses on subjects randomized to receive the HPV-16/18 AS04-adjuvanted licensed vaccine formulation (3D 20/20 M0,1,6 and 2D 20/20 M0,6 groups; shaded boxes). Disposition data are also shown for subjects randomized to receive the alternative HPV-16/18 AS04-adjuvanted vaccine formulation (2D 40/40 M0,6 and 2D 40/40 M0,2 groups) for completeness.

Table 1. Summary of demographic characteristics and baseline serostatus by age stratum

	3D M0,1,6 schedule		2D M0,6 schedule
	Girls 9-14 years	Women 15-25 years	Girls 9-14 years	Women 15-25 years
	N = 58	N = 109	N = 55	N = 103
Month 60 TVCAge (years)
Mean (SD)	12.4 (1.67)	19.9 (3.12)	12.5 (1.63)	19.8 (3.21)
Median	13.0	20.0	13.0	19.0
Race, n (%)
White - Caucasian / European Heritage	58 (100)	107 (98.2)	52 (94.5)	97 (94.2)
African Heritage / African American	0 (0.0)	1 (0.9)	1 (1.8)	1 (1.0)
American Indian or Alaskan Native	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.9)
Asian - East Asian Heritage	0 (0.0)	1 (0.9)	1 (1.8)	0 (0.0)
Asian - Japanese Heritage	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.0)
Other	0 (0.0)	0 (0.0)	1 (1.8)	2 (1.9)
Month 60 ATP-I	N = 55	N = 91	N = 46	N = 85
HPV-16 baseline serostatus, n (%)
Seronegative	48 (87.3)	79 (86.8)	45 (97.8)	74 (87.1)
Seropositive	7 (12.7)	12 (13.2)	1 (2.2)	11 (12.9)
HPV-18 baseline serostatus, n (%)
Seronegative	49 (89.1)	76 (83.5)	43 (93.5)	73 (85.9)
Seropositive	6 (10.9)	15 (16.5)	3 (6.5)	12 (14.1)

2D, 2-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 3D, 3-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; ATP-I, according-to-protocol immunogenicity cohort at Month 60; ELISA, enzyme-linked immunosorbent assay; N, number of subjects in the cohort; n(%); number (percentage) of subjects in the given category; SD, standard deviation; TVC, total vaccinated cohort at Month 60;

* HPV-16 antibody titer equal to or above the ELISA cut-off of 8 ELISA unit(EU)/mL pre-vaccination.

^† HPV-18 antibody titer equal to or above the ELISA cut-off of 7 EU/mL pre-vaccination.

Figure 2. Observed HPV-16 and −18 geometric mean antibody titers (GMT) and corresponding 95% confidence intervals (CI) by enzyme-linked immunosorbent assay (ELISA) at each time point for subjects in the Month 60 according-to-protocol immunogenicity cohort (ATP-I) who were seronegative at baseline for the corresponding antigen. 2D, 2-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 3D, 3-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation. M, month; N, number of evaluable seronegative subjects in the Month 60 ATP-I; Plateau, GMTs at the plateau level (Month 45-50 time point) in women aged 15-25 y administered 3 doses of the HPV-16/18 AS04-adjuvanted vaccine at months 0, 1 and 6 in a previous trial (NCT00120848) were 397.8 and 297.3 ELISA unit (EU)/mL for HPV-16 and −18 antibodies, repectively.¹⁶ Natural infection, GMTs in women aged 15-25 y who had cleared a natural infection in a previous trial (NCT00122681) were 29.8 and 22.7 EU/mL for HPV-16 and −18 antibodies, repectively.¹

Table 2. Observed HPV-16 and −18 antibody responses by ELISA at Month 60 for initially seronegative subjects in the ATP-I

Antigen	Statistic	3D M0,1,6 schedule Women 15-25 years	2D M0,6 schedule Girls 9-14 years
HPV-16	N	79	45
	Seropositivity rate, n (%)	79 (100)	45 (100)
	GMT, EU/mL (95% CI)	1454.5 (1187.2, 1782.1)	1369.0 (1104.0, 1697.5)
	GMR (3D/2D) (95% CI)	—	1.06 (0.78, 1.45)
HPV-18	N	76	43
	Seropositivity rate, n (%)	76 (100)	43 (100)
	GMT, EU/mL (95% CI)	634.8 (497.9, 809.3)	627.2 (476.1, 826.1)
	GMR (3D/2D) (95% CI)	—	1.01 (0.69, 1.48)

* Post-hoc exploratory analysis.

2D, 2-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 3D, 3-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 95% CI, exact 95% confidence interval; ATP-I, according-to-protocol immunogenicity cohort; ELISA, enzyme-linked immunosorbent assay; EU/mL, ELISA unit per milliliter; GMR, ratio of geometric mean antibody titers; GMT, geometric mean antibody titer; M, month; N, number of evaluable seronegative subjects in the Month 60 ATP-I; n (%), number (percentage) of seropositive subjects at Month 60.

Figure 3. Predicted HPV-16 and −18 geometric antibody mean antibody titers (GMTs) over 20 y, as predicted by the piecewise model (panels A and B) and modified power law model (panels C and D). Blue solid line, predicted GMTs for girls aged 9-14 y administered 2 doses of the licensed HPV-16/18 AS04-adjuvanted vaccine at months 0 and 6, modeled on the basis of 5 y of follow-up data from the current study. Red dashed line, predicted GMTs for women aged 15-25 y administered 3 doses of the licensed HPV-16/18 AS04-adjuvanted vaccine at months 0, 1 and 6, modeled on the basis of 5 y of follow-up data from the current study. Green dotted line, predicted GMTs for women aged 15-25 y administered 3 doses of the licensed HPV-16/18 AS04-adjuvanted vaccine at months 0, 1 and 6, modeled on the basis of 6.4 y of follow-up data from a previous efficacy study (NCT00120848).²¹ Black dashed line, GMTs in women who had cleared a natural infection in a previous trial (NCT00122681) (29.8 and 22.7 ELISA unit (EU)/mL for anti-HPV-16 and −18, respectively).¹ ELISA, enzyme-linked immunosorbent assay.

Table 3. Predicted HPV-16 and −18 antibody titers after 20 y and duration of persistence

		Predicted GMTs 20 y after first vaccine dose		Predicted duration of antibody persistence above natural infection levels in 95% of women
Antigen	Statistical model	3D M0,1,6 15-25 years	2D M0,6 9-14 years	3D M0,1,6 15-25 years	2D M0,6 9-14 years
HPV-16	Piecewise	189.7 EU/mL	157.9 EU/mL	22.0 years	24.4 years
	Modified power law	1054.2 EU/mL	1091.0 EU/mL	Always	Always
HPV-18	Piecewise	149.1 EU/mL	158.7 EU/mL	21.5 years	27.3 years
	Modified power law	497.4 EU/mL	530.3 EU/mL	Always	Always

Post-hoc exploratory analysis.

2D, 2-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 3D, 3-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; ELISA, enzyme-linked immunosorbent assay; EU/mL, ELISA unit per milliliter; GMT, geometric mean antibody titer; M, month.

* For those subjects who receive the scheduled number of vaccine doses.

^† Natural infection, GMTs in women aged 15-25 y who had cleared a natural infection in a previous trial (NCT00122681) were 29.8 and 22.7 EU/mL for HPV-16 and −18 antibodies, repectively.¹

Table 4. Summary of safety and pregnancy outcomes in the total vaccinated cohort (TVC)

	3D M0,1,6 schedule 9-25 years	2D M0,6 schedule 9-25 years
Safety Outcomes from Months 48 to 60
Number of subjects in Month 60 TVC	167	158
Subjects with at least one event, n (%) [95% CI]
Serious adverse events	2 (1.2) [0.1, 4.3]	0 (0.0) [0.0, 2.3]
Medically significant conditions	10 (6.0) [2.9, 10.7]	9 (5.7) [2.6, 10.5]
New onset autoimmune diseases	2 (1.2) [0.1, 4.3]	0 (0.0) [0.0, 2.3]
Safety Outcomes from Months 0 to 60
Number of subjects in TVC	239	240
Subjects with at least one event, n (%) [95% CI]
Serious adverse events	15 (6.3) [3.6, 10.1]	19 (7.9) [4.8, 12.1]
Medically significant conditions	89 (37.2) [31.1, 43.7]	92 (38.3) [32.2, 44.8]
New onset autoimmune diseases	6 (2.5) [0.9, 5.4]	5 (2.1) [0.7, 4.8]
Pregnancies from Months 0 to 60
Number of subjects with pregnancies	26	30
Outcomes, n (%)
Ectopic pregnancy	1 (3.8)	0 (0.0)
Elective termination no apparent congenital anomaly	6 (23.1)	4 (13.3)
Elective termination congenital anomaly	0 (0.0)	1 (3.3)
Live infant no apparent congenital anomaly	18 (69.2)	22 (73.3)
Spontaneous abortion no apparent congenital anomaly	1 (3.8)	3 (10.0)

2D, 2-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 3D, 3-dose schedule of the licensed HPV-16/18 AS04-adjuvanted vaccine formulation; 95% CI, exact 95% confidence interval; n (%), number (percentage) of subjects with at least one event within the given category.

* New events occurring since the previous reporting period for this trial.²⁰

^† Events for the entire study period from Months 0 to 60.

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