Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.
BACKGROUND
The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis.


METHODS
Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681.


RESULTS
Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC.


CONCLUSIONS
The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes.


BACKGROUND
GlaxoSmithKline Biologicals.
Paavonen
J
J
Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Finland. Jorma.Paavonen@hus.fi
Naud
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Salmerón
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Wheeler
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Chow
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Apter
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Kitchener
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Castellsague
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Teixeira
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Skinner
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Hedrick
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Jaisamrarn
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Limson
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Garland
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Szarewski
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Romanowski
B
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Aoki
F Y
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Schwarz
T F
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Poppe
W A J
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Bosch
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Jenkins
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Hardt
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Zahaf
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Descamps
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Lehtinen
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Dubin
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D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D005260:Female; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D032541:Mass Vaccination; D009367:Neoplasm Staging; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D053918:Papillomavirus Vaccines / Q000276:immunology*; D011230:Precancerous Conditions / Q000517:prevention & control / Q000821:virology; D012449:Safety; D012725:Sexual Behavior; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology; D014626:Vaginal Smears; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000517:prevention & control / Q000821:virology
D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18