1Mechanism of ActionHPV only infects human beings

The L1 proteins are produced by separate fermentationsin recombinant Saccharomyces cerevisiae and self-assembled into VLPs Thefermentation process involves growth of S. cerevisiae on chemically-definedfermentation media which include vitamins, amino acids, mineral salts, andcarbohydrates. The VLPs are released from the yeast cells by cell disruption andpurified by a series of chemical and physical methods. The purified VLPs areadsorbed on preformed aluminum-containing adjuvant (Amorphous AluminumHydroxyphosphate Sulfate).

GARDASIL is a sterile suspension for intramuscular administration. Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (asAmorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodiumchloride,0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodiumborate, < 7 mcg yeast protein/dose, and water for injection The product doesnot contain a preservative or antibiotics. After thorough agitation, GARDASIL is a white, cloudy liquid. 12CLINICAL PHARMACOLOGY12.1Mechanism of ActionHPV only infects human beings. Animal studies with analogous animalpapillomaviruses suggest that the efficacy of L1 VLP vaccines may involve thedevelopment of humoral immune responses.

Human beings develop a humoral immuneresponse to the vaccine, although the exact mechanism of protection is unknown. 13NONCLINICAL TOXICOLOGY13.1Carcinogenesis, Mutagenesis, Impairment of FertilityGARDASIL has not been evaluated for the potential to cause carcinogenicity orgenotoxicity. GARDASIL administered to female rats at a dose of 120 mcg total protein, whichcorresponds to approximately 300-fold excess relative to the projected humandose, had no effects on mating performance, fertility, or embryonic/fetalsurvival. 14CLINICAL STUDIESCIN 2/3 and AIS are the immediate and necessary precursors of squamous cellcarcinoma and adenocarcinoma of the cervix, respectively. Their detection andremoval has been shown to prevent cancer; thus, they serve as surrogate markersfor prevention of cervical cancer.

In the clinical studies, cases of CIN 2/3 andAIS were the efficacy endpoints to assess prevention of cervical cancer. Inaddition, cases of vulvar and vaginal intraepithelial neoplasia (VIN 2/3 andVaIN 2/3) were the efficacy endpoints to assess prevention of HPV-related vulvarand vaginal cancers, and observations of external genital lesions were theefficacy endpoints for the prevention of genital warts. Efficacy was assessed in 4 AAHS-controlled, double-blind, randomized Phase IIand III clinical studies. The first Phase II study evaluated the HPV 16component of GARDASIL (Protocol 005 or Study 1, N 2391) and the secondevaluated all components of GARDASIL (Protocol 007 or Study 2, N 551). ThePhase III studies evaluated GARDASIL in 5442 (Study 3 or Protocol 013 FUTUREI) and 12,157 (Study 4 or Protocol 015 FUTURE II) subjects.