Gardasil®’s

VLPs are produced in baker’s yeast (Saccharomyces cerevisiae) expressing L1 [11]. Each VLP type is produced and purified separately and the different types are mixed during final formulation. Both vaccines must be refrigerated, but not frozen. Delivery of both vaccines is via three intramuscular injections in the deltoid area over a 6-month period, but the recommended timing of the second dose differs slightly ( Table 1). Like other protein subunit vaccines, the two HPV VLP vaccines are formulated with adjuvants to increase their immunogenicity. Gardasil® contains a simple aluminum salts adjuvant (aluminum hydroxyphosphate sulfate), whereas Cervarix® Stem Cell Compound Library contains a more complex adjuvant system, designated AS04,

consisting of monophosphoryl lipid A (MPL) and an aluminum salt (aluminum phosphate) [12]. MPL is a detoxified Crizotinib nmr form of bacterial lipopolysaccharide and is a toll-like receptor (TLR)-4 agonist. TLRs are an evolutionarily conserved class of host sensors of microbial constituents that activate innate and adaptive immune responses to invading microbes. It is noteworthy that AS04 is the first TLR agonist-containing prophylactic vaccine adjuvant to be licensed by the United States (U.S.) Food and Drug Administration (FDA). Neither vaccine contains a preservative. Phase III efficacy trials of the VLP vaccines in young women were primarily designed to demonstrate efficacy in preventing incident vaccine-related HPV infection and the preneoplastic lesions caused by incident persistent infections related to vaccine HPV types. Initiation heptaminol of these trials was predicated on successful completions of a series of preceding studies including development of industrial scale manufacturing processes, validation of type-restricted measures of antibody responses to the VLPs,

and promising safety, immunogenicity and preliminary efficacy results in preclinical and early phase I/II trials [10] and [13]. Two phase III studies, FUTURE I [14] and FUTURE II [15], evaluated Gardasil® and two, PATRICIA [16] and the Costa Rica HPV Vaccine Trial (CVT) [17], evaluated Cervarix®. All of the trials were relatively large (5,500–18,500 vaccinees), blinded, randomized and controlled trials of young women (mean age 20, range 15–26) (Table 2). The CVT was a U.S. government sponsored community-based trial, centered in the Guanacaste province of Costa Rica [17], whereas the other trials were company-sponsored and multi-centric, involving multiple trial sites in Europe, North, Central and South America, and Asia Pacific, including Australia. With the exception of the CVT and the Finnish subjects in PATRICIA, there was a restriction on the number of lifetime sexual partners. This restriction was used to limit the number of women with prevalent infections and/or prevalent genital lesions at enrollment, in keeping with the primary goal of evaluating immunoprophylaxis.