Gardasil is a non-infectious quadrivalent recombinant vaccine, which delivers the major capsid (L1) protein of human papillomavirus (HPV) types 6, 11, 16 and 18 in highly purified virus-like particles, in combination wth an aluminum-containing vaccine adjuvant.
Gardasil is specifically indicated for the prevention of conditions caused by HPV types 6, 11, 16 and 18 infections. These include cervical cancer, genital warts (condyloma acuminata), and precancerous or dysplastic lesions (including cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grades 1 and 2/3, vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3, and vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3).
Gardasil is supplies as a white, cloudy liquid for intramuscular injection. The recommended dosing regimen is 3 single injections of 0.5 ml of the vaccine, at day 0, 2 months after the first dose, and 6 months after the first dose.
Approval of Gardasil for the prevention of cervical cancer, AIS, and CIN 2/3 related to HPV-6, -11, -16 and -18 infections was based on 4 placebo-controlled, double-blind, randomized trials, including two phase II trials (Protocol 005, n=2391; and Protocol 007, n=551) and two phase III trials, Protocols 013 and 015, also dubbed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease) I & II (n=5442, n=12157, respectively); these studies treated a total of 20,541 women ages 16-26 at the time of enrollment. In all 4 trials, subjects received treatment on day 0, and 2 and 6 months thereafter. Protocol 005 investigated only the HPV-16 portion of the vaccine, while Protocol 007 and FUTURE I&II evaluated the full quadrivalent vaccine. Subjects were not prescreened for HPV status. All four trials were designed to investigate the prophylactic efficacy of the vaccine in preventing cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts. Among subjects receiving the full treatment regimen, combined data from the four trials indicated 0 new cases of HPV-16 or -18 related CIN 2/3 or AIS, vs. 53 cases for placebo (100% efficacy); 4 new cases of HPV-6, -11, -16, or -18 related CIN (CIN 1, CIN 2/3) or AIS, vs. 83 for placebo (95.2% efficacy); and 1 case of HPV-6, -11, -16, or -18 related genital warts, vs. 91 for placebo (98.9% efficacy). The vaccine is designed as a prophylactic vaccine, and efficacy was not established in protecting subjects from disease caused by pre-existing HPV infection. The vaccine was efficacious in protecting subjects who were previously infected with 1 or more vaccine-related strains from disease associated with remaining strains (those for which they were negative at outset).
Predicted General Population Impact
In addition to the prophylactic efficacy established in the four trials, data were analyzed for the vaccine's predicted impact on the rates of HPV-related diseases in the general patient population, based on current infection rates, predicted treatment-regimen compliance, and population demographics. Gardasil was predicted to produce a 39.0% reduction in HPV-16 or -18 related CIN 2/3 or AIS (98.8% prophylactic efficacy); a 69.1% reduction in HPV-16 or -18 related VIN 2/3 and VaIN 2/3 (100.0% prophylactic efficacy); a 46.4% reduction in HPV-6, -11, -16, -18 related CIN (CIN 1, CIN 2/3) or AIS (93.7% prophylactic efficacy); and a 68.5% reduction in HPV-6, -11, -16, -18 related genital warts (93.4% prophylactic efficacy).
Ongoing Study Commitments
1. The long-term burden of HPV disease including the incidence
of HPV 6/11/16/18-related cervical disease;
2. The long-term burden of HPV disease caused by types other than HPV 6/11/16/18;
3. The overall incidence of cervical HPV disease;
4. The incidence of HPV-related cancers and pre-cancers (CIN 2/3, AIS and cervical cancer; VIN 2/3 and vulvar cancer; and VaIN 2/3 and vaginal cancer);
5. The interaction between administration of Gardasil and pregnancy outcomes, especially congenital anomalies, by linking the vaccination registry with the Medical Birth Registry.
The size and age range of the population studied will depend on
the final vaccination guidelines implemented by the Norwegian
Government. Although at this time no other governments in the
Nordic region have committed to similar population studies, Merck
will notify CBER of any other collaborations if they occur.
Final Study Protocol Submission: Contingent on Norwegian Government’s response
Enrollment Completion: 6 years after study initiation
Study Completion: 7 years after study initiation
Final Study Report: 8 years after study initiation
1. The Nordic Long-Term Follow-up Study:
Interim reports of effectiveness (i.e., incident breakthrough cases of CIN 2/3, AIS and cervical cancer; VIN 2/3 and vulvar cancer; and VaIN 2/3 and vaginal cancer) and immunogenicity results will be submitted in 2009, 2011, 2013, and 2015. Final Study Report: December 31, 2018
2. Protocol 018 (Adolescent Sentinel Cohort):
- Periodic reports beginning with Month 24 immunogenicity and long-term safety data: starting no later than March 30, 2007.
- Publication of one year Post-dose 3 data: January 30, 2007.
- A Biologics License Supplement (BLS) for 1.5 year Post-dose 3 data: June 30, 2007.
- A Biologics License Supplement (BLS) for 2.5 year Post-dose 3 data: December 31, 2007.
- A Biologics License Supplement (BLS) for 5.5 year Post-dose 3 data: December 31, 2010.
3. Protocol 007:
Publication of five-year immunogenicity data submitted: December 31, 2006.
4. Protocol 005:
Publication of seven and one half year immunogenicity data submitted: December 31, 2007.
Adverse events associated with the use of Gardasil may include, but are not limited to, the following:
In addition, a small portion of patients (0.475%; n=102/21464) experienced all-cause serious adverse experiences, which included headache, gastroenteritis, appendicitis, and pelvic inflammatory disease.
Gardasil delivers HPV-6, -11, -16 and -18 L1 protein, conferring protection against these HPV strains, presumably through induction of humoral immune response. These strains are responsible for the majority of cases of cervical cancer, AIS, CIN and VIN, and for a number of cases of VaIN and genital warts.
Villa LL, Ault KA, Giuliano AR, Costa RL, Petta CA, Andrade RP, Brown DR, Ferenczy A, Harper DM, Koutsky LA, Kurman RJ, Lehtinen M, Malm C, Olsson SE, Ronnett BM, Skjeldestad FE, Steinwall M, Stoler MH, Wheeler CM, Taddeo FJ, Yu J, Lupinacci L, Railkar R, Marchese R, Esser MT, Bryan J, Jansen KU, Sings HL, Tamms GM, Saah AJ, Barr E. Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18. Vaccine 2006 Jul 7;24(27-28):5571-83. Epub 2006 May 15
Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. Journal of Clinical Investigation 2006 May;116(5):1167-73
Stanley M. Immune responses to human papillomavirus. Vaccine 2005 Sep 19; Epud ahead of print
Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA, Malm C, Lehtinen M, Skjeldestad FE, Olsson SE, Steinwall M, Brown DR, Kurman RJ, Ronnett BM, Stoler MH, Ferenczy A, Harper DM, Tamms GM, Yu J, Lupinacci L, Railkar R, Taddeo FJ, Jansen KU, Esser MT, Sings HL, Saah AJ, Barr E. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncology 2005 May;6(5):271-8
For additional information regarding Gardasil or cervical cancer and precancerous lesions caused by HPV infections, please visit the Gardasil web page.