Table 4. Summary of Findings from Randomized Clinical Trials of Prophylactic Virus-Like Particle Human Papillomavirus Vaccines.

	Bivalent vaccine trials (HPV-16/18 AS04-adjuvanted vaccine)						Quadrivalent vaccine trials (HPV-6/11/16/18 vaccine)
		Costa Rica Vaccine Trial (CVT) Phase III; NCT00128661		Japan Efficacy Trial [26] Phase II; NCT00316693/NCT00929526		PApilloma TRIal against Cancer In young Adults (PATRICIA) [6,28] Phase III; NCT00122681		Pooled analysis from 2-3 studies [9,37-39]: – 007: phase II; NCT n/a – 013 (FUTURE I): phase III; NCT00092521 – 015 (FUTURE II): phase III; NCT00092534
Countries	Community-based trial (Guanacaste; Costa Rica)		Japan		Multi-country trial (Australia, Belgium, Brazil, Canada, Finland, Germany, Italy, Mexico, Philippines, Spain, Taiwan, Thailand, UK, and USA).		Multi-country trials (Australia, Austria, Brazil, Canada, Colombia, Czech Republic, Denmark, Finland, Germany, Hong Kong, Iceland, Italy, Mexico, New Zealand, Norway, Peru, Poland, Puerto Rico, Russia, Singapore, Sweden, Thailand, UK, USA)
Age	18–25 years		20–25 years		15–25 years		16–26 years
Total enrolled subjects	7,466		1,046		18,729		18,174 (protocols 007, 013 and 015)
Analytical cohort	ATP cohort for efficacy: received 3 doses within protocol defined windows, HPV DNA negative for the HPV type under consideration at Months 0 and 6, no biopsy or treatment (Loop Electrosurgical Excisional Procedure) during the vaccination phase, no protocol violation		ATP cohort for efficacy: received 3 doses within protocol defined windows, HPV DNA negative for the HPV type under consideration at Months 0 and 6, seronegative for the HPV type under consideration at Month 0, normal or low-grade cytology at Month 0, no protocol violation				Per-protocol: received 3 doses within 1 year, PCR negative and seronegative to HPV-6, HPV-11, HPV-16, or HPV-18 at enrolment, remained PCR negative to the same vaccine HPV type (s), to which they were naïve at enrolment, through 1 month post-dose 3, no protocol violation
Endpoints	CIN2+: CIN2, CIN3, adenocarcinoma in situ or invasive carcinoma		CIN2+: CIN2, CIN3, adenocarcinoma in situ or invasive carcinoma		CIN2+: CIN2, CIN3, adenocarcinoma in situ or invasive carcinoma		CIN2 or worse
Follow-up	48 months post-dose 1		48 months post-dose 1		48 months post-dose 1		42 months post-dose 1
Efficacy estimates
HPV-16/18 types	Current Manuscript		Konno et al. 2014 [26]		Lehtinen et al. 2012 [6]		Kjaer et al. 2009 [37]
	Vaccine	Control	Vaccine	Control	Vaccine	Control	Vaccine	Control
N	2,635	2,677	406	404	7,338	7,305	7,864	7,865
Cases	1	10	0	5	5	97	2	110
Efficacy (95% CI)	88.7% (31.3, 99.5)a		100% (-8.0, 100)		94.9% (87.7, 98.4)		98.2% (93.3, 99.8)b
Non-vaccine oncogenic types	HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -68/73 Current Manuscript		HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -68/73 [26]		HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68/73 [28]		HPV-31, -33, -35, -39, -45, -51, -52, -56, -58, -59 [38,39]
	Vaccine	Control	Vaccine	Control	Vaccine	Control	Vaccine	Control
N	2,643	2,697	444	435	8,067	8,047	4,616	4,680
Cases	5	24	4	12	88	165	62	93
Efficacy (95% CI)	78.7% (47.1, 92.8)a		67.7% (-6.6, 92.4)c		46.8% (30.7, 59.4)		32.5% (6.0, 51.9)d
Irrespective of HPV	Current Manuscript		Konno et al., 2014 [26]		Lehtinen et al., 2012 [6]		Munoz et al., 2010 [9]
	Vaccine	Control	Vaccine	Control	Vaccine	Control	Vaccine	Control
N	2,643	2,697	254	251	5466	5642	4,616	4,680
Cases	8	33	3	11	61	172	77	136
Efficacy (95% CI)	75.3% (48.1, 89.3)a		73.9% (1.1, 95.3)e		64.9% (52.7, 74.2)e		42.7% (23.7, 57.3)d

^aVaccine efficacy using exploratory definition described in the Methods section

^bVaccine efficacy against HPV-6/11/16/18-related types for the quadrivalent vaccine

^cVaccine efficacy in the ATP cohort for efficacy, regardless of baseline serostatus

^dVaccine efficacy restricted to subjects who received ≥1 vaccine dose and, at enrolment, were HPV DNA negative for vaccine and nonvaccine types (31, 33, 35, 39, 45, 51, 52, 56, 58 and 59), seronegative for HPV-6, -11, -16 and -18, and had normal cytology

^eVaccine efficacy in the TVC-naive cohort, i.e. women who received ≥1 vaccine dose and, at baseline, were HPV DNA negative for vaccine and nonvaccine types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68/73), seronegative for HPV-16 and -18, and had normal cytology

ATP: according-to-protocol; CI: Confidence Interval; CIN2+: cervical intraepithelial neoplasia 2 or more severe disease; n/a: not available; N: number of women in each arm considered in the analysis; TVC: total vaccinated cohort