1. HPV Vaccines: What We Know and What We Should Expect Laura Koutsky, PhD Professor of Epidemiology University of Washington Seattle, WA

2. Summary of Cervical Cancer Prevention Options Current optionsCurrent options –Abstinence –Lifelong mutual monogamy –Screening (followed by diagnosis and treatment) HPV DNA or Pap testingHPV DNA or Pap testing Both HPV DNA and Pap testingBoth HPV DNA and Pap testing Future optionsFuture options –Screening or triage by more accurate and less costly biomarkers (e.g., p16 INK4a protein, DNA methylation markers) –Prophylactic and therapeutic vaccines

3. HPV L1 VLP Vaccine Synthesis Yeast Cell L1 gene on HPV DNA L1 gene inserted into genome of yeast cell Yeast cell DNA mRNA tRNA rRNA Transcription Translation Capsid proteins Empty viral capsids Elicits immune response in host

4. HPV L1 Virus-Like Particle (protein from the L1 gene of HPV)

5. Results from Two Randomized Clinical Trials of Young Women (~15 to 25 Years of Age) using HPV 16 or HPV 16 and 18 L1 VLP Vaccines Merck GSK Vaccine Placebo VE (95% CI) Vaccine Placebo VE (95% CI) 768 765 401 397 Endpoint: Persistent HPV 16 0 41 100 (90,100) HPV 16 or 18 0 10 100 (20,100) HPV16-CIN 0 9 Merck Vaccine: HPV16 L1 VLP expressed in yeast (NEJM 2002;347:1645-51) GSK Vaccine: HPV16 & 18 L1 VLP expressed in baculovirus system (presented at EUROGIN Meeting in Paris April, 2003)

6. Results from Two Randomized Clinical Trials of HPV L1 VLP Vaccines (cont.) Both Merck and GSK trials showed: –High efficacy for preventing HPV infection –High levels of immunogenicity >99% of vaccinees seroconverted Antibody titers considerably higher than observed in natural infection –Generally safe and tolerable

7. Anti-HPV 16 RIA Following Vaccination (Merck Trial) GMTs (mMU/mL) With 95% CIs HPV 16 10  g HPV 16 20  g HPV 16 40  g HPV 16 80  g Time (Months) Geometric Mean Titer (mMU/mL) 037121824 1 10 100 1000 GMT 95% CI Anti-HPV 16 in women with ongoing/previous HPV 16 infection High titers persist through month 36

8. Tolerability of Vaccination (Merck Trial) Subjects with follow-up With vaccine-related AEs Injection-site AEs Systemic AEs Discontinuations due to an AE With serious AEs With serious vaccine-related AEs HPV 16 Vaccine (N=1194) 1130 1011 975 470 4 0 (95) (90) (86) (42) (<1) (0) n(%) 1150 1007 947 500 5 3 0 (96) (88) (82) (44) (<1) (0) Placebo (N=1198) n(%)

9. Other HPV L1 VLP Vaccine Findings Cannot cause HPV infection –Vaccine only contains one protein from the virus (L1 protein) HPV L1 protein is not a human carcinogen HPV L1 VLPs appear to elicit both B cell and T cell responses HPV antibody responses to L1 VLPs appear to be mostly type-specific

10. Detection of HPV Types in Cervix Cancers from Different Regions of the World from Clifford Br J Cancer 2003;88:63 HPV Types

11. Ongoing HPV L1 Vaccine Trials Phase II trial of Merck tetravalent HPV 6, 11, 16, and 18 vaccine near completion –high antibody titers for each HPV type International phase III trial of Merck tetravalent HPV 6, 11, 16, and 18 vaccine has begun –Potential elimination of up to: 70% of invasive cervical cancers 60% of high grade cervical intraepithelial lesions 90% of genital warts and recurrent respiratory papillomatosis GSK Phase III trial of bivalent HPV 16 and 18 vaccine to begin soon

12. HPV L1 VLP Vaccine Research Prevention of CIN2-3 and anogenital warts Duration of protection Gender differences in vaccine efficacy Therapeutic potential of HPV VLP vaccines for post-infection protection Increasing number of HPV types prevented Potential for “replacement” lesions Cost–effective approaches to screening and vaccinating –increase screening interval –improve accuracy of screening test Reduction in incidence of cervical and other anogenital cancers, head and neck cancers and RRP

13. Future HPV Immunization Programs Implementation Issues Potential target populations –9 -12 years of age –Adolescents and young adults Protection in men –Data on HPV vaccine efficacy in men not yet available –Only vaccinating women might be a good option in some communities Societal acceptance of vaccines to prevent sexually transmitted infections –Awareness of HPV consequences and ubiquity –Anti-cancer vaccine

14. Potential Impact of HPV 6, 11, 16, and 18 Vaccine on STD Control Reduce number of genital wart visits –Later or less frequent detection of other STDs Reduce number of women requiring referral to colposcopy, biopsy and treatment Increase demand for information on HPV and HPV vaccines –Vaccine is prophylactic not therapeutic –Vaccine does not prevent all HPVs or other STDs/HIV –Pap screening still important

15. Take Home Messages A prophylactic vaccine to prevent HPV 6, 11, 16, and 18 infections and related-neoplasms is likely to be available within 4 to 6 years –The promise of such a vaccine will be realized only if immunization programs achieve wide coverage 2 nd generation vaccines that prevent infection by additional oncogenic HPV types are under development Screening to detect and treat lesions in women who were infected prior to vaccination or infected with HPV types not covered by the vaccine will continue –More accurate and less costly screening tests are being developed Public health experts must begin thinking about the use of prophylactic HPV vaccines in their communities

16. Collaborators University of Washington Akhila Balasubramanian Qinghua Feng Tiffany Harris (Albert Einstein) King Holmes James Hughes Jane Kuypers Nancy Kiviat Shu-Kuang Lee Connie Mao Leslie Miller Bethany Weaver Noel Weiss Rachel Winer Long Fu Xi Duke University Shalini Kulasingam Evan Myers Fred Hutchinson Cancer Research Center Denise Galloway Jody Carter Merck Research Laboratories Eliav Barr Kathrin Jansen University of New Mexico Cosette Wheeler