Learning Objective  To understand the rationale for prophylactic human papillomavirus (HPV) vaccination with GARDASIL™. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1

Cervical Cancer Mortality/100,000 3 Cervical Cancer Incidene/100, Cervical Cancer Occurs Despite Established Screening Programs Example of Europe 1. Anttila A, Ronco G, Clifford G, et al. Br J Cancer. 2004;91:935– van Ballegooijen M, van den Akker-van Marle E, Patnick J, et al. Eur J Cancer. 2000;36:2177– Ferlay J, Bray F, Pisani P, Parkin DM. Lyon, France: IARC Press; 2004.CountryRecommendation % Regularly Screened Age Range (Years) Interval (Years) Finland 1 30–60593 England 1 25–643–53–583 Sweden 1 23–60383 Belgium 2 25–64378 The Netherlands 1 30–60577 Denmark 1 23–59375 France 1 25–65369 Italy 1 25–64353–74 Germany 1 20–85150 Spain 2 25–

Targeting High Disease Burden With GARDASIL™ TypeWomenMen 6/11  >90% of genital warts 2  ~10% of low-grade cervical lesions 3  Recurrent respiratory papillomatosis (RRP)*,4  Transmission to men 5  >90% of genital warts 2  Transmission to women 9  RRP*,4 16/18  ~70% of cervical cancer 3  ~50% of high-grade cervical lesions 6  ~25% of low-grade cervical lesions 3  ~70% of high-grade vulvar/vaginal lesions 7  Oropharyngeal cancer †,8  Other cancers †,8  Transmission to men 5  ~60% of anal cancer 10  Penile cancer †,8  Oropharyngeal cancer †,8  Other cancers †,8  Transmission to women 9  Targeting HPV types 6, 11, 16, and 18 with GARDASIL is expected to substantially reduce the burden of HPV-related diseases Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:271– Gissmann L, Wolnik L, Ikenberg H, et al. Proc Natl Acad Sci USA. 1983;80:560– Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. Cancer Epidemiol Biomarkers Prev. 2005;14:1157– Kashima HK, Mounts P, Shah K. Obstet Gynecol Clin North Am. 1996;23:699– Dunne EF, Nielson CM, Stone KM, et al. J Infect Dis. 2006;194:1044– Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003;89:101– GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 8. Parkin DM. Int J Cancer. 2006;118:3030– Castellsagué X, Bosch FX, Muñoz N. Salud Publica Mex. 2003;45(suppl 3):S345– Frisch M, Glimelius B, van den Brule AJC, et al. N Engl J Med. 1997;337:1350–1358. *GARDASIL TM is not indicated for RRP; † Undetermined proportion GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 3

HPV Types 6, 11, 16, and 18 in Cervical Cancer and Other Anogenital Diseases Prevalence of HPV Type 1. Clifford GM, Rana RK, Franceschi S, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:1157– Clifford GM, Smith JS, Aguado T, et al. Br J Cancer. 2003;89:101– Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518– Clifford GM, Smith JS, Plummer M, et al. Br J Cancer. 2003;88:63– Gissmann L, Wolnik L, Ikenberg H, et al. Proc Natl Acad Sci USA. 1983;80:560– ,3,4 5 4

GARDASIL™: The First Cervical Cancer Vaccine  HPV types 6, 11, 16, 18 1  Recombinant vaccine (does not contain live virus) 1  Manufactured in Saccharomyces cerevisiae 1 – Yeast-derived vaccines given to millions of children and adults 2  Proprietary aluminum adjuvant 225 μg per dose 1  Each 0.5-mL injection volume contains HPV types 6/11/16/18 (20/40/40/20 μg, respectively) 1  Intramuscular administration 1  0-, 2-, 6-month dosing regimen 1 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1. GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 2. Unger ER, Barr E. Human papillomavirus and cervical cancer [conference summary]. Emerg Infect Dis [serial on the Internet] Nov [Cited October 19, 2006]. Available from Accessed April 26,

Central/South America Northern Africa North America/ Europe South Asia HPV Type 52 Others *A pooled analysis and multicenter case control study (N = 3607) Muñoz N, Bosch FX, Castellsagué X, et al. Int J Cancer. 2004;111:278–285. Worldwide Prevalence of HPV Types in Cervical Cancer *

HPV and Anogenital Warts  HPV types 6 and 11 responsible for >90% of anogenital warts 1  Estimated lifetime risk of developing genital warts ~10% 2,3  External genital warts are very contagious. 4  Infectivity >75% 1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319– Franco EL, Villa LL, Richardson H, et al. In: Franco EL, Monsonego J, eds. Oxford, UK: Blackwell Science; 1997:14– Tortolero-Luna G. Hematol Oncol Clin North Am. 1999;13:245–257, x. 4. Soper DE. In: Berek JS, ed. Novak’s Gynecology. 13th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:453–470. Images top left and top right: Reprinted with permission from NZ DermNet ( 7

Necessary criteria Possible End Points HPV Infection CIN* 1 CIN 2/3 Required precursor for cervical cancer √—√ Prompts treatment——√ Reduction leads to cervical cancer reduction —— √ Clinical Program for GARDASIL™: Selection of Trial End Points 1–3 1. Pagliusi SR, Aguado T. Vaccine. 2004;23:569– GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 3. Lowy DR, Frazer IH. Chapter 16: Prophylactic human papillomavirus vaccines. J Natl Cancer Inst Monogr. 2003:111–116. CIN 2/3 are World Health Organization (WHO) – recommended surrogate end points for HPV vaccine trials. 1 Surrogate end points are required because it is unethical to wait for the development of cervical cancer. 3 8 *CIN = cervical intraepithelial neoplasia GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

GARDASIL™ Yields Higher Neutralizing Anti-HPV Antibodies in Baseline Seropositive Subjects GMT** (mMU/mL) Log 10 Scale ***PCR = polymerase chain reaction Villa LL, Ault KA, Giuliano AR, et al. Vaccine. 2006;24:5571– Month (n=14) (n=177) (n=15) (n=170) 9 *vaccination **GMT = geometric mean titer * * * Vaccine: naïve recipient Placebo: naïve recipient Vaccine: seropositive and PCR*** -negative recipient Placebo: seropositive and PCR-negative recipient

GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity In a double-blind, placebo-controlled, dose-ranging study of quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine HPV 6 *** HPV 11 *** Time Since Vaccination (Months) ,000 GMT with 95% CI mMU/mL (Log Scale) ** * HPV 18 *** HPV 16 Per-Protocol Subjects (GARDASIL) * vaccination GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Adapted from Olsson S-E et al. Vaccine. 2007;25:4931–

GARDASIL™ Demonstrated Immune Memory Antibodies were built up during the 3-dose vaccination series. When tested by antigen challenge, vaccinated subjects demonstrated classic immune memory—the hallmark of long-term protection. 1 Minimum protective level of antibodies is defined through breakthrough cases. Through five years, there were no breakthrough cases for GARDASIL, while there were continuing infections for placebo Time (months) VVVA Anti-HPV 16 response (GMT levels with 95% CI) Immune memory response was proven by antigen challenge 1 GARDASIL n=78 placebo n=70 12 Time Antigen challenge A Antigen challenge at month 60 Vaccination series for GARDASIL V Vaccination at day 0, month 2, and month 6 Antibody levels stabilized through at least five years… and counting Data on file, MSD. 11 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

HPV 6, 11, 16, or 18-related GARDASILPlacebo NCasesNCasesEfficacy 95% CI Persistent Infection 2352* %(83, 100) Disease %(12, 100) CIN 1, 2, or %(<0, 100) Vulvar/Vaginal Neoplasias or Genital Warts %(<0, 100) GARDASIL™: Durable Protection Through Five Years A total of 241 subjects were entered into the five-year extension phase of Protocol 007. *One case of confirmed persistent infection: HPV 18 DNA detected at months 12 and 18 only (not a case in the five-year extension). *One case of HPV 16 DNA detected at the last visit (month 36); not a subject in the five-year extension phase. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Villa LL, Costa R, Petta R, et al. Br J Cancer. 2006;95:1459–1466. Per-protocol efficacy population Subjects were naïve to HPV types 6, 11, 16, and/or 18 12

GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. GARDASIL™ TOLERABILITY  Vaccination was generally well tolerated. The most common adverse event was local discomfort at the injection site.  There were no discontinuations due to serious vaccine-related adverse events. 13

Select Information About GARDASIL TM  GARDASIL is a vaccine indicated in girls and women 9 to 26 years of age for the prevention of cervical cancer, precancerous or dysplastic lesions, and genital warts caused by HPV Types 6, 11, 16, and 18.  GARDASIL is contraindicated in individuals who are hypersensitive to the active substances or to any of the excipients of the vaccine.  GARDASIL does not substitute for routine cervical cancer screening, and women who receive GARDASIL should continue to undergo screening per standard of care.  Vaccination with GARDASIL may not result in protection in all vaccine recipients.  GARDASIL has not been shown to protect against diseases due to non- vaccine HPV types.  GARDASIL is not intended to be used for treatment of active genital warts; cervical cancer; CIN, VIN, or VaIN.  The vaccine-related adverse experiences that were observed among recipients of GARDASIL at a frequency of at least 1.0% and greater than placebo were pain, swelling, erythema, fever, nausea, pruritus, and dizziness.