Human Papillomavirus (HPV) causes squamous cell cervical cancer (and its histologic precursor lesions Cervical Intraepithelial Neoplasia [CIN] 1 or low grade dysplasia and CIN 2/3 or moderate to high grade dysplasia) and cervical adenocarcinoma (and its precursor lesion adenocarcinoma in situ [AIS]). HPV also causes approximately 35-50% of vulvar and vaginal cancers. Vulvar Intraepithelial Neoplasia (VIN) Grade 2/3 and Vaginal Intraepithelial Neoplasia (VaIN) Grade 2/3 are immediate precursors to these cancers.

Cervical cancer prevention focuses on routine screening and early intervention. This strategy has reduced cervical cancer rates by approximately 75% in compliant individuals by monitoring and removing premalignant dysplastic lesions.

HPV also causes genital warts (condyloma acuminata) which are growths of the cervicovaginal, vulvar, and the external genitalia that rarely progress to cancer. HPV 6, 11, 16, and 18 are common HPV types.

HPV 16 and 18 cause approximately:

· 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 cases and
· 50% of CIN 2 cases.

HPV 6, 11, 16, and 18 cause approximately:

· 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases and
· 90% of genital wart cases.

HPV only infects humans, but animal studies with analogous (animal, not human) papillomaviruses suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.

CLINICAL STUDIES

CIN 2/3 and AIS are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer thus, they serve as surrogate markers for prevention of cervical cancer.

Efficacy was assessed in 4 placebo-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of GARDASIL (Protocol 005, N = 2391) and the second evaluated all components of GARDASIL (Protocol 007, N = 551). The Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease), evaluated GARDASIL in 5442 (FUTURE I or Protocol 013) and 12,157 (FUTURE II or Protocol 015) subjects. Together, these four studies evaluated 20,541 women 16 to 26 years of age at enrollment. The median duration of follow-up was 4.0, 3.0, 2.4, and 2.0 years for Protocol 005, Protocol 007, FUTURE I, and FUTURE II, respectively. Subjects received vaccine or placebo on the day of enrollment, and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies combined according to a prospective clinical plan.

GARDASIL is designed to prevent HPV 6-, 11-, 16-, and/or 18-related cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts. GARDASIL was administered without prescreening for presence of HPV infection and the efficacy trials allowed enrollment of subjects regardless of baseline HPV status (i.e., Polymerase Chain Reaction [PCR] status or serostatus). Subjects who were infected with a particular vaccine HPV type (and who may already have had disease due to that infection) were not eligible for prophylactic efficacy evaluations for that type.

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