Human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for the prevention of cervical cancer and HPV-related diseases

Figures & data

Figure 1. PRISMA flowchart for article selection.

Table 1. Overview of studies.

Reference	Timepoint of efficacy assessment	Key efficacy endpoints reported	Design	Population	Location
HPV-001; NCT00689741
Harper et al. [18]	18 months after first vaccination	Cervical HPV infection, cytological abnormalities, CIN1+ and CIN2+ associated with HPV-16/18	Randomized, placebo-controlled, double-blind phase III trial	Healthy women aged 15–25 years ≤6 lifetime sexual partners No history of abnormal Pap test, no treatment of the cervix or genital warts, and cytologically negative Seronegative for HPV-16/18 and HPV DNA-negative for oncogenic HPV types N = 560 (vaccine) N = 553 (placebo)	Brazil, Canada, USA
HPV-007 (extension of HPV-001); NCT00120848
Harper et al. [19]	Follow-up up to 4.5 years after first vaccination	Cervical HPV infection, cytological abnormalities, CIN1+ and CIN2+ associated with oncogenic HPV types	As HPV-001	As HPV-001 N = 393 (vaccine) N = 383 (placebo) Analyses reported for HPV-001/007 combined	Brazil, Canada, USA
Romanowski et al. [20]	Follow-up up to 6.4 years after first vaccination
HPV-023 (extension of HPV-001 and −007); NCT00518336
De Carvalho et al. [21]	Follow-up up to 7.3 years after first vaccination	Cervical HPV infection, cytological abnormalities, CIN1+ and CIN2+ associated with oncogenic HPV types	As HPV-001	As HPV-001 N = 224 (vaccine) N = 213 (placebo) Analyses reported for HPV-001/007/023 combined	Brazil
Roteli-Martins et al. [22]	Follow-up up to 8.4 years after first vaccination
Naud et al. [23]	Follow-up up to 9.4 years after first vaccination
HPV-008; PATRICIA; NCT00122681
Paavonen et al. [24]	Interim event-driven analysis^a (mean follow-up 14.8 months after first vaccination)	Cervical HPV infection, CIN1+ and CIN2+ associated with oncogenic HPV types	Randomized, double-blind, phase III trial with control hepatitis A vaccine	Healthy women aged 15–25 years ≤6 lifetime sexual partners Enrolled irrespective of HPV DNA status, HPV serostatus or cytology at baseline N = 9319 (vaccine) N = 9325 (control)	14 countries in Europe, North and South America, Asia, and Australia
Paavonen et al. [25]	Final event-driven analysis^a (mean follow-up 39.4 months after first vaccination)	Cervical HPV infection, CIN1+, CIN2+, and CIN3+ associated with oncogenic HPV types
Apter et al. [43]	Final event-driven analysis^a (mean follow-up 39.4 months after first vaccination)	Cervical HPV infection, CIN1+, CIN2+, and CIN3+ associated with oncogenic HPV types
Lehtinen et al. [26]	End-of-study analysis (4 years after first vaccination)	Cervical HPV infection, cytological abnormalities, CIN1+, CIN2+, CIN3+, and AIS associated with oncogenic HPV types
Wheeler et al. [27]	End-of-study analysis (4 years after first vaccination)	Cervical HPV infection and CIN2+ associated with non-vaccine oncogenic HPV types (cross protection)
Struyf et al. [44]	End-of-study analysis (4 years after first vaccination)	Cervical HPV infection and CIN2+ associated with non-vaccine oncogenic HPV types (cross-protection). Post hoc analysis using alternative assay method
Szarewski et al. [28]	End-of-study analysis (4 years after first vaccination)	Cervical HPV infection, CIN1+, and CIN2+ associated with HPV-16/18 according to previous infection status
Szarewski et al. [29]	End-of-study analysis (4 years after first vaccination)	Persistent cervical infection with non-oncogenic HPV types
HPV-009; CVT; NCT00128661
Hildesheim et al. [30]	6 and 12 months after first vaccination	Clearance of cervical HPV infection in women positive for HPV DNA at enrolment	Randomized, blinded, phase III trial with control hepatitis A vaccine	Healthy women aged 18–25 years Enrolled irrespective of past sexual behavior, HPV status, or cytology N = 3727 (vaccine) N = 3739 (control)	Costa Rica
Herrero et al. [31]	4 years after first vaccination	Persistent cervical infection with HPV-16, 18, 31, 33, and 45
Rodríguez et al. [49]	4 years after first vaccination	Colposcopy referrals and excision treatment
Hildesheim et al. [32]	4 years after first vaccination	Cervical HPV infection and CIN2+ associated with oncogenic HPV types
Lang Kuhs et al. [33]	4 years after first vaccination	Persistent cervical infection and CIN2+ in HPV-naïve cohort
Kreimer et al. [34]	4 years after first vaccination	Persistent cervical infection with HPV-16/18 after 1 or 2 vaccine doses
Lang Kuhs et al. [35]	4 years after first vaccination	Vulvar infection with HPV-16/18
Kreimer et al. [36]	4 years after first vaccination	Anal infection with oncogenic HPV types
Herrero et al. [37]	4 years after first vaccination	Oral infection with HPV-16/18
Combined analysis of PATRICIA (NCT00122681) and CVT (NCT00128661)
Kreimer et al. [50]	4 years after first vaccination)	Incident and persistent cervical infection with HPV-16/18 and HPV-31/33/45 after one, two, or three vaccine doses	As PATRICIA and CVT	As PATRICIA and CVT N = 12013 (vaccine) N = 12042 (control)	As PATRICIA and CVT
HPV-032; NCT00316693
Konno et al. [38]	Interim event-driven analysis^b (mean follow-up 13.6 months after 3rd vaccination in ATP cohort)	Incident and persistent cervical infection and cytological abnormalities associated with HPV-16/18	Randomized, double-blind phase II trial with control hepatitis A vaccine	Healthy women aged 20–25 years Enrolled regardless of serological, cytological or HPV DNA status N = 519 (vaccine) N = 521 (control)	Japan
Konno et al. [39]	Final analysis, 24 months after first vaccination	Incident and persistent cervical infection, cytological abnormalities, CIN1+ and CIN2+ associated with HPV-16/18
HPV-063 (extension of HPV-032); NCT00929526
Konno et al. [40]	4 years after first vaccination	Incident and persistent cervical infection, cytological abnormalities, CIN1+ and CIN2+ associated with oncogenic HPV types and irrespective of HPV type	As HPV-032	Open-label follow-up of HPV-032 N = 375 (vaccine) N = 377 (control) Analyses reported for HPV-032/063 combined	Japan
HPV-039; NCT00779766
Zhu et al. [41]	Final event-driven analysis^c (mean follow-up 21.0 months after first vaccination)	Incident and persistent cervical infection, cytological abnormalities, CIN1+ and CIN2+ associated with HPV-16/18	Randomized, double-blind, placebo-controlled phase II/III trial	Healthy women aged 18–25 years All women were sexually active N = 3026 (vaccine) N = 3025 (control)	China
HPV-015; VIVIANE; NCT00294047
Skinner et al. [42]	Interim analysis, 4 years after first vaccination (mean follow-up 44.3 months after first vaccination)	Persistent cervical infection, cytological abnormalities, CIN1+ and CIN2+ associated with oncogenic HPV types	Randomized, double-blind, placebo-controlled phase III trial	Healthy women aged >25 years (26–35, 36–45, and 46+ age strata) Up to 15% in each stratum could have a history of HPV infection/disease N = 2881 (vaccine) N = 2871 (control)	Australia, Canada, Mexico, the Netherlands, Peru, Philippines, Portugal, Russia, Singapore, Thailand, the UK, the USA

^aThe interim analysis was triggered according to an event-driven analysis plan when at least 23 cases of CIN2+ associated with HPV-16/18 were identified in the TVC-E; the final analysis was triggered when at least 36 cases of CIN2+ associated with HPV-16/18 (including at least 15 cases associated with HPV-18) were identified in the ATP cohort.

^bThe interim analysis was triggered according to an event-driven analysis plan when at least eight cases of 6-month persistent infection with HPV-16/18 were identified in the ATP cohort.

^cThe final analysis was triggered according to an event-driven analysis plan when at least 17 cases of 6-month persistent infection and/or CIN1+ associated with HPV-16/18 were identified in the ATP cohort.

Oncogenic HPV types: HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68.

Non-oncogenic HPV types: HPV-6, 11, 34, 40, 42, 43, 44, 53, 54, 70, 74

AIS: adenocarcinoma in situ; ATP: according-to-protocol; CIN: cervical intraepithelial neoplasia; CVT: Costa Rica HPV-16/18 Vaccine Trial; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC-E: total vaccinated cohort for efficacy; VIVIANE: Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy

Table 2. Vaccine efficacy against persistent cervical infection and ASC-US+ associated with HPV-16/18 in women with no baseline evidence of infection with the HPV type under analysis.

Endpoint	Timepoint	Vaccine efficacy (% [95% CI])
		ATP cohort	TVC-E	TVC^a	TVC-naïve
HPV-001/007/023, 15–25 years, Canada/Brazil/USA
6MPI	18 (ATP) or 27 (TVC) months [18]	100	–	95.1	–
		(47.0–100)		(63.5–99.3)
	4.5 years [19]	96.0	–	94.4	–
		(75.2–99.9)		(78.2–99.4)
	6.4 years [20]	100	–	–	–
		(90.0–100)
	7.3 years [21]	100	–	–	–
		(79.5, 100)
	8.4 years [22]	100	–	–	–
		(79.8–100)
	9.4 years [23]	100	–	–	–
		(84.1–100)
ASC-US+	18 or 27 months [18]	93.5	–	92.9	–
		(51.3–99.1)		(70.0–98.3)
	4.5 years [19]	–	–	95.7	–
				(83.5–99.5)
	6.4 years [20]	–	–	96.7	–
				(87.3–99.6)
	7.3 years [21]	–	–	96.7	–
				(79.9–99.9)
	8.4 years [22]	–	–	96.9	–
				(81.0–99.9)
	9.4 years [23]	–	–	97.1	–
				(82.5–99.9)
PATRICIA (HPV-008), 15–25 years, multinational
6MPI	Interim (mean follow-up 14.8 months)^b [24]	–	80.4	–	–
			(70.4–87.4)
	Final (mean follow-up 39.4 months)^c [25,43]	93.8	–	–	93.0
		(91.0–95.9)			(89.7–95.3)
	End-of-study (4 years) [26]	–	–	–	93.7
					(91.1–95.6)
ASC-US+	Interim (mean follow-up 14.8 months)^b [24]	–	–	–	–
	Final (mean follow-up 39.4 months^c [25,43]	–	–	–	–
	End-of-study (4 years) [26]	–	–	–	–
CVT (HPV-009), 18–25 years, Costa Rica
12MPI	4 years [31,33]	90.9	–	–	88.6
		(82.0–95.9)			(77.3–94.9)
HPV-032/063, 20–25 years, Japan
6MPI	Interim (mean follow-up 13.6 months) [38]	100	100	–	–
		(20.5–100)	(54.4–100)
	2 years [39]	100	100	–	–
		(71.3–100)	(79.4–100)
12MPI	4 years [40]	100	–	–	100
		(74.8–100)			(62.1–100)
ASC-US+	Interim (mean follow-up 13.6 months) [38]	83.4	88.8	–	–
		(−116.2–99.9)	(−20.1–100)
	2 years [39]	91.7	93.3	–	–
		(42.1–99.8)	(55.3–99.9)
	4 years [40]	80.6	–	–	94.1
		(41.9–95.2)			(61.8–99.9)
HPV-039, 18–25 years, China
6MPI	Final (mean follow-up 21.0 months) [41]	93.4	91.0	–	–
		(57.1–99.8)	(71.2–98.2)
ASC-US+	Final (mean follow-up 21.0 months) [41]	93.8	88.5	–	–
		(60.2–99.9)	(62.5–97.8)
VIVIANE (HPV-015), >25 years, multinational
6MPI	Interim (4 years)^d [42]	82.9	77.4	–	–
		(53.8–95.1)	(49.7–91.1)
ASC-US+	Interim (4 years)^d [42]	93.7	86.1	–	–
		(71.5–99.5)	(59.8–96.5)

^aMost TVC data reported for the PATRICIA, CVT, and VIVIANE trials include women irrespective of their HPV DNA status at baseline, and are therefore considered elsewhere in the paper;^b97.9% CI; ^c96.1% CI; ^d97.7% CI

6MPI: 6-month persistent infection; 12MPI: 12-month persistent infection; ASC-US+: atypical squamous cell of undetermined significance or worse; ATP: according-to-protocol; CI: confidence interval; CVT: Costa Rica HPV-16/18 Vaccine Trial; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort; TVC-E: total vaccinated cohort for efficacy; TVC-naïve: women DNA-negative for all HPV types tested at baseline; VIVIANE: Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy

A dash in the table cell indicates that the study endpoint was not reported in the publication

Table 3. Vaccine efficacy against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 in women with no baseline evidence of infection with the HPV type under analysis.

Endpoint	Timepoint	Vaccine efficacy (% [95% CI])
		ATP cohort	TVC-E	TVC^a	TVC-naïve
HPV-001/007/023, 15–25 years, Brazil/Canada/USA
CIN1+	18 or 27 months [18]	–	–	–	–
	4.5 years [19]	–	–	100	–
				(42.4–100)
	6.4 years [20]	–	–	100	–
				(73.4–100)
	7.3 years [21]	–	–	100	–
				(34.4–100)
	8.4 years [22]	–	–	100	–
				(35.0–100)
	9.4 years [23]	–	–	100	–
				(45.2–100)
CIN2+	18 or 27 months [18]	–	–	–	–
	4.5 years [19]	–	–	100	–
				(−7.7–100)
	6.4 years [20]	–	–	100	–
				(51.3–100)
	7.3 years [21]	–	–	100	–
				(−129.8–100)
	8.4 years [22]	–	–	100	–
				(−128.0–100)
	9.4 years [23]	–	–	100	–
				(−128.1–100)
PATRICIA (HPV-008), 15–25 years, multinational
CIN1+	Interim (mean follow-up 14.8 months)^b [24]	–	89.2	–	–
			(59.4–98.5)
	Final (mean follow-up 39.4 months)^c [43]	–	–	–	96.5
					(89.0–99.4)
	End of study (4 years) [26]	–	–	–	96.5
					(91.6–98.9)
CIN2+	Interim (mean follow-up 14.8 months)^b [24]	–	90.4	–	–
			(53.4–99.3)
	Final (mean follow-up 39.4 months)^c [25,43]	92.9	94.5	–	98.4
		(79.9–98.3)	(86.2–98.4)		(90.4–100)
	End of study (4 years) [26]	94.9	–	–	99.0
		(87.7–98.4)			(94.2–100)
CIN3+	Interim (mean follow-up 14.8 months)^b [24]	–	–	–	–
	Final (mean follow-up 39.4 months)^c [25,43]	80.0	90.9	–	100
		(0.3–98.1)	(60.8–99.1)		(64.7–100)
	End-of-study (4 years) [26]	91.7	–	–	100
		(66.6–99.1)			(85.5–100)
CVT (HPV-009), Costa Rica
CIN2+	4 years [32,33]	89.8	–	–	100
		(39.5–99.5)			(54.7–100)
HPV-032/063, 20–25 years, Japan
CIN1+	Interim (mean follow-up 13.6 months) [38]	–	–	–	–
	2 years [39]	100	100	–	–
		(−156.8–100)	(−15.2–100)
	4 years [40]	100	–	–	100
		(42.2–100)			(43.6–100)
CIN2+	Interim (mean follow-up 13.6 months) [38]	–	–	–	–
	2 years [39]	100	100	–	–
		(−428.9–100)	(−476.0–100)
	4 years [40]	100	–	–	100
		(−8.0–100)			(−5.4–100)
HPV-039, 18–25 years, China
CIN1+	Final (mean follow-up 21.0 months) [41]	100	83.3	–	–
		(−50.4–100)	(−37.3–99.6)
CIN2+	Final (mean follow-up 21.0 months) [41]	100	100	–	–
		(−140.2–100)	(−51.4–100)
VIVIANE (HPV-015), >25 years, multinational
CIN1+	Interim (4 years)^d [42]	86.1	75.5	–	–
		(−35.4–99.9)	(−49.4–98.3)
CIN2+	Interim (4 years)^d [42]	100	80.4	–	–
		(−100.7–100)	(−125.3–99.8)

^aMost TVC data reported for the PATRICIA, CVT, and VIVIANE trials include women irrespective of their HPV DNA status at baseline, and are therefore considered elsewhere in the paper; ^b97.9% CI; ^c96.1% CI; ^d97.7% CI

ATP: according-to-protocol; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CVT: Costa Rica HPV-16/18 Vaccine Trial; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort; TVC-E: total vaccinated cohort for efficacy; VIVIANE: Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy; TVC-naïve: women DNA-negative for all HPV types tested at baseline

A dash in the table cell indicates that the study endpoint was not reported in the publication

Table 4. Cross-protective vaccine efficacy against infection and CIN2+ in women with no baseline evidence of infection with the HPV type under analysis (ATP cohort).

		Vaccine efficacy (% [95% CI])
	HPV-001/007 (up to 6.4 years’ follow-up) [20]	HPV-001/007/023 (up to 9.4 years’ follow-up) [23]	PATRICIA (4 years’ follow-up, protocol-specified analysis) [27]	PATRICIA (4 years’ follow-up, post hoc analysis) [44]	CVT (4 years’ follow-up) [31,32]	HPV-032/063 (4 years’ follow-up) [40]	VIVIANE (4 years’ follow-up)^a [42]
Infection	Incident infection	Incident infection	6MPI	6MPI	6MPI	12MPI	6MPI
HPV-31	59.8	40.4	76.8	80.2	64.7	–	79.1
	(20.5–80.7)	(−27.2–72.9)	(69.0–82.9)	(73.4–85.5)	(42.6–78.9)		(27.6–95.9)
HPV-33	–	34.8	44.8	50.7	32.1	–	−31.9
		(−51.9–72.9)	(24.6–59.9)	(35.2–62.8)	(−41.1–68.2)		(−460.8–66.3)
HPV-35	–	–	−19.8	−9.9	25.0	–	39.3
			(−74.1–17.2)	(−57.6–23.3)	(−40.6–60.6)		(−81.2–81.5)
HPV-39	–	–	4.8	–	−30.8	–	−79.0
			(−17.7–23.1)		(−109.2–17.6)		(−372.4–26.9)
HPV-45	77.7	70.8	73.6	81.0	73.0	–	76.9
	(39.3–93.4)	(23.2–90.5)	(58.1–83.9)	(70.5–88.3)	(45.3–87.8)		(18.5–95.6)
HPV-51	–	6.7	16.6	–	−56.1	–	−3.0
		(−41.9–38.6)	(3.6–27.9)		(−114.3 – −14.2)		(−100.6–47.0)
HPV-52	–	–	8.3	12.9	19.6	–	14.2
			(−6.5–21.0)	(−0.6–24.5)	(−8.1–40.4)		(−51.4–51.7)
HPV-56	–	–	−5.3	–	25.8	–	21.4
			(−27.5–13.1)		(−12.7–51.4)		(−77.4–65.9)
HPV-58	–	–	−18.3	8.2	2.8	–	−48.7
			(−51.8–7.7)	(−12.9–25.4)	(−48.0–36.2)		(−393.4–51.5)
HPV-59	–	–	−7.5	–	−30.3	–	−7.3
			(−51.8–23.8)		(−130.3–25.6)		(−208.4–62.2)
HPV-66	–	–	2.3	–	1.6	–	0.9
			(−18.7–19.6)		(−41.0–31.3)		(−91.5–48.7)
HPV-68^b	–	–	2.6	–	8.0	–	35.4
			(−21.5–21.9)		(−44.7–41.6)		(−43.1–72.0)
HPV-31/33/45	–	–	–	–	60.0	26.9	–
					(43.1–72.7)	(−332.0–89.3)
HPV-31/33/45/52/58	–	–	–	–	–	2.4	–
						(−103.4–53.2)
Composite of 12 non-vaccine oncogenic HPV types	–	–	–	13.6	–	18.0	13.7
				(7.2–19.6)		(−32.9–49.7)	(−10.8–32.8)
CIN2+
HPV-31	–	–	87.5	–	83.2	–	–
			(68.3–96.1)		(−13.8–99.3)
HPV-33	–	–	68.3	–	100	–	–
			(39.7–84.4)		(−74.7–100)
HPV-35	–	–	62.5	–	100	–	–
			(−56.5–93.6)		(−13.1–100)
HPV-39	–	–	74.9	–	No cases	–	–
			(22.3–93.9)
HPV-45	–	–	81.9	–	−1.9	–	–
			(17.0–98.1)		(−3874.3–97.4)
HPV-51	–	–	54.4	–	82.7	–	–
			(22.0–74.2)		(−16.8–99.3)
HPV-52	–	–	27.6	–	49	–	–
			(−26.3–59.1)		(−48.1–84.3)
HPV-56	–	–	46.1	–	79.7	–	–
			(−45.2–81.8)		(−46.7–99.1)
HPV-58	–	–	28.5	–	59.3	–	–
			(−45.5–65.7)		(−106.3–94.5)
HPV-59	–	–	80.0	–	−2.4	–	–
			(−79.1–99.6)		(−495.8–82.4)
HPV-66	–	–	56.4	–	–	–	–
			(−12.1–84.8)
HPV-68^b	–	–	26.8	–	74.4	–	–
			(−70.7–69.6)		(−103.5–99.0)
HPV-31/33/45	–	–	–	–	–	100	–
						(−3704.8–100)
HPV-31/33/45/52/58	–	–	–	–	–	75.7	–
						(−21.6–97.5)
Composite of 12 non-vaccine oncogenic types with or without HPV-16/18 coinfection	–	–	46.8	–	–	67.7	–
			(30.7–59.4)			(−6.6–92.4)

^a97.7% CI; ^bHPV-68/73 in CVT.

6MPI: 6-month persistent infection; 12MPI: 12-month persistent infection; ATP: according-to-protocol; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CVT: Costa Rica HPV-16/18 Vaccine Trial; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; VIVIANE: Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy

No cross-protection data reported for the HPV-039 trial. Significant vaccine efficacy estimates shown in bold type. A dash in the table cell indicates that the study endpoint was not reported in the publication.

Figure 2. Vaccine efficacy against CIN2+ and CIN3+ associated with a composite of 12 non-vaccine HPV types, with or without HPV-16/18 coinfection and excluding HPV-16/18 coinfection (PATRICIA).[27] ATP: according to protocol – women DNA-negative for HPV type under analysis at baseline; CI: confidence interval; CIN: cervical intraepithelial neoplasia; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort – women irrespective of HPV status at baseline; TVC-naïve: women DNA-negative for all HPV types tested at baseline;

Figure 3. Vaccine efficacy against CIN1+, CIN2+, CIN3+, and AIS irrespective of HPV DNA (4-year, end-of-study analysis of PATRICIA).[26] AIS: adenocarcinoma in situ; CI: confidence interval; CIN: cervical intraepithelial neoplasia; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort – women irrespective of HPV status at baseline; TVC-naïve: women DNA-negative for all HPV types tested at baseline.

Figure 4. Number of cases of CIN3+ associated with vaccine and non-vaccine HPV types in the TVC and TVC-naïve (4-year, end-of-study analysis of PATRICIA).[26] CI: confidence interval; CIN: cervical intraepithelial neoplasia; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort – women irrespective of HPV status at baseline; TVC-naïve: women DNA-negative for all HPV types tested at baseline. Reprinted from The Lancet Oncology, Lehtinen et al, Vol 13, Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomized, double-blind PATRICIA trial, pages 89–99, copyright 2012 with permission from Elsevier.

Figure 5. Vaccine efficacy against CIN2+ irrespective of HPV type in the lesion versus the contribution of HPV-16/18 to the lesion: a cross-trial comparison. In the CVT, the a priori analysis included all CIN2+ cases; the exploratory analysis considered evidence of HPV persistence preceding referral to colposcopy. Cohorts considered in the analyses: ATP – in the CVT, the analysis considered outcomes that occurred in the absence of HPV during the vaccination period; TVC – in the HPV-001/007/023 study, only women who were DNA-negative for all HPV types tested were enrolled; TVC-naïve: women DNA-negative for all HPV types tested at baseline. ATP: according to protocol; CI: confidence interval; CIN: cervical intraepithelial neoplasia; CVT: Costa Rica Vaccine Trial; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort.

Figure 6. Vaccine efficacy against HPV-16/18 incident one-time detection and 6-month persistent infection with three, two, and one dose of HPV-16/18 vaccine (combined analysis of PATRICIA and the CVT).[50] Women were excluded if they had less than 12 months of follow-up. 6MPI: 6-month persistent infection; CI: confidence interval; CVT: Costa Rica HPV-16/18 Vaccine Trial; HPV: human papillomavirus; PATRICIA: PApilloma TRial against Cancer in young Adults; m-TVC: modified total vaccinated cohort – excluding women DNA-positive at baseline for the HPV type under evaluation; TVC-naïve: women DNA-negative for all HPV types tested at baseline.

Panel A. Study cohorts.

Criteria	ATP	TVC-E	TVC	TVC-naïve
Cytology at baseline	Negative or low-grade	Negative or low-grade	Irrespective	Negative
Number of vaccine doses received	3	≥1	≥1	≥1
Case counting beginning (day after)	Third vaccination	First vaccination	First vaccination	First vaccination
Study and procedures^a	Met eligibility criteria and complied with protocol	No requirement	No requirement	No requirement

^aFor all cohorts, data had to be available for efficacy endpoints i.e. baseline PCR or cytology sample and one further sample.

Panel A describes the inclusion criteria for the cohorts. Some women were excluded from some analyses, e.g. analyses of women without evidence of previous infection excluded women who were seropositive and/or DNA-positive at baseline. The inclusion criteria for the primary analyses of each study are shown in Panel B.

ATP: according-to-protocol; HPV: human papillomavirus; PCR: polymerase chain reaction; TVC: total vaccinated cohort; TVC-E: total vaccinated cohort for efficacy; TVC-naïve: women DNA-negative for all HPV types tested at baseline.

Panel B. Primary analysis populations reported for each study according to cohort and endpoint.

Study	Endpoint: HPV DNA associated with infection or abnormality	Women in analysis: HPV DNA status for 14 oncogenic HPV types^a and serostatus for HPV 16 18^b for corresponding HPV type at baseline and during vaccination course
		ATP	TVC-E	TVC	TVC-naïve
HPV-001/007/023	HPV-16/18	DNA-negative M0 and M6 for analysed type^b	–	DNA-negative for 14 types and seronegative per enrollment criteria^c	–
	Non-vaccine oncogenic HPV	DNA-negative M0 and M6 for analysed type^b	–	–	–
	Irrespective of HPV	–	–	DNA-negative for 14 types and seronegative per enrollment criteria^c	–
PATRICIA	HPV-16/18	DNA-negative M0 and M6, seronegative M0 for analysed type	DNA-negative and seronegative at M0 for analysed type	–	DNA-negative for 14 types M0, seronegative for HPV 16 and 18 M0^d
	Non-vaccine oncogenic HPV	DNA-negative M0 and M6 for analysed type	–	Irrespective of HPV DNA or serostatus	DNA-negative M0 for 14 types, seronegative M0^d
	Irrespective of HPV	–	–	Irrespective of HPV DNA or serostatus	DNA-negative M0 for 14 types, seronegative M0^d
CVT	HPV-16/18	DNA-negative M0 and M6 for analysed type	–	Irrespective of HPV DNA	DNA-negative M0 for 14 types, seronegative M0^d,e
	Non-vaccine oncogenic HPV	DNA-negative M0 and M6 for analysed type	–	Irrespective of HPV DNA	–
	Irrespective of HPV	DNA-negative M0 and M6	–	–	DNA-negative M0 for 14 types, seronegative M0^d,e
HPV-032/063 (Japan)	HPV-16/18	DNA-negative M0 and M6, stratified for serostatus at M0, for analysed type	DNA-negative at M0, stratified for serostatus at M0 for analysed type	–	–
	Non-vaccine oncogenic HPV	DNA-negative M0 and M6 for analysed type	–	–	–
	Irrespective of HPV	–	–	Irrespective of HPV DNA or serostatus	DNA-negative M0 for 14 types, seronegative M0^d
HPV-039 (China)	HPV-16/18	DNA-negative M0 and M6, seronegative M0 for analysed type	DNA-negative and seronegative at M0 for analysed type	–	–
	Non-vaccine oncogenic HPV	–	–	–	–
	Irrespective of HPV	–	–	–	–
VIVIANE	HPV-16/18	DNA-negative M0 and M6, stratified for serostatus at M0 for analysed type	DNA-negative and seronegative at M0 for analysed type	Irrespective of HPV DNA or serostatus	–
	Non-vaccine oncogenic HPV	DNA-negative M0 and M6 for analysed type	–	–	–
	Irrespective of HPV	–	–	Irrespective of HPV DNA or serostatus	–

A dash in the table cell indicates that the population description was not reported in the source literature. ^aThe 14 oncogenic HPV types analysed are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68; ^bSerostatus determined for HPV-16 and HPV-18 only; ^cThe HPV-001/007/023 study enrolled only women who were seronegative for HPV-16/18 and HPV DNA-negative for 14 oncogenic HPV types; ^dAs defined by cohort criteria; ^eAs PATRICIA.

ATP: according-to-protocol; CVT: Costa Rica HPV-16/18 Vaccine Trial; HPV: human papillomavirus; M0: Month 0; M6: Month 6; PATRICIA: PApilloma TRial against Cancer in young Adults; TVC: total vaccinated cohort; TVC-E: total vaccinated cohort for efficacy; TVC-naïve: women DNA-negative for all HPV types tested at baseline; VIVIANE: Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy.

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