1. Human Papilloma Virus (HPV) Vaccine

2.  HPV infection conveys risk of anogenital warts and local symptoms like itch and pain  High risks include cervical cancer, anogenital cancer or precancer  Cervix infection may lead to low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL)

3. The progression of human papillomavirus (HPV)-infected cells to low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL), carcinoma in situ and invasive cancer is determined by failing control mechanisms. These include an intracellular control that is presumably exerted by cyclin-dependent kinase inhibitors, a paracrine signalling cascade and a decreasing immunological control. The paracrine control is triggered by macrophages and cytokines, such as tumour necrosis factor-α and is underlined by loss of synthesis of interferon-β HPV Infection

4. How common are HPV infections? Prevalent HPV infections in the United States exceed 20 million and 5.5 million cases of new HPV infections are acquired annually. (Cates 1999) 75% of sexually active men and women have been exposed to HPV at some point in their lives (Koutsky, Galloway et al. 1988)

5. Males and females appear to be equally affected HPV prevalence among adolescent girls and young adult women range from 28%-82% ( Burk, Ho et al. 1996; Brown, Shew et al. 2005 ) Prevalence rates among adolescent and young adult males range between 29%- 48% ( Kataoka, Claesson et al. 1991; Svare, Kjaer et al. 2002 )

7. Age (years) Prevalence (%) 14 to 19 24.5% 20 to 24 44.8% 25 to 29 27.4% 30 to 39 27.5% 40 to 49 25.2% 50 to 59 19.6% 14 to 59 26.8% HPV Prevalence by Age

8. Human Papillomavir us

9. Sexual relationship represents the most efficient method of infection, although HPV can be transmitted though any skin-to-skin contact. Within ~36 months, the cumulative incidence of HPV infection among female college students who were HPV negative at time of enrollment reached 50%. (Winer, Lee et al. 2003) Months from first intercourse Cumulative incidence of HPV-infection (%)

10. The 40 types of HPV viruses which infect epithelial tissues include both “high-risk” and “low-risk” types based upon the type of disease outcomes resulting from infection. (e.g., “high risk” infections generally lead to cancers and pre-cancers)

11. High-risk HPV infections (e.g., HPV-16, -18, -31, -33, etc.) manifest as pap smear abnormalities – low grade squamous interepithelial lesions (LSIL), high grade squamous interepithelial lesions (HSIL), cervical cancers and other malignancies of the anogenital region. (Cox 1995; Munoz, Bosch et al. 2003) Infection with low-risk HPV types (e.g., HPV-6, -11, etc.) manifest as low grade pap smear abnormalities, genital warts, and recurrent respiratory papillomatosis (RRP), where obstructive papillomas form on the larynx and vocal cords

14. Thin Prep Pap smear with group of normal cervical cells on left and HPV-infected cells on right. Enlarged (x2 or x3) nuclei and hyperchromasia (property of tumour cells to stain more deep)

15. The vaccines are non-infectious Nearly all participants in clinical trials of HPV vaccines have demonstrated seroconversion with antibody levels several- fold higher than those observed following natural infection. (Harper, Franco et al. 2004; Sattler and Investigators. 2005; Skjeldestad and Committee 2005; Villa, Costa et al. 2005) Minimal antibody levels considered to provide protection against each of the HPV subtypes have not yet been established. Moreover, antibody levels are HPV type– specific and assay-specific, and it is not possible to compare antibody levels across or within trials

16. Licensed & Candidate Prophylactic HPV Vaccines Vaccine/Manufacturer HPV Types FDA Filing FDA Decision ACIP Vote QuadrivalentMerck6/11/16/18 Dec 2005 June2006June 2006 2006 BivalentGSK16/18 Dec 2006 2007?2007?

17. Clinical trials of the quadrivalent HPV vaccine (Gardasil®, Merck & Co., Inc., Whitehouse Station, NJ), which protects against HPV-16, -18, -6, and -11, and from clinical trials of a bivalent HPV vaccine (Cervarix™, GlaxoSmithKline, London, UK), which protects against HPV 16 and 18, show efficacy within the range of 90% to 100% across studies and clinical outcomes. Gardasil® was FDA-approved in June 2006 while an application for Cervarix™ was submitted in March 2007.

18.  Both vaccines are based on self assembled L1 particles  Cervix contains aluminum hydroxide and MPL as adjuvants  Merck vaccine contains only aluminum hydrophosphate sulphate as adjuvant  No preservative  Used through intramuscular injection

19. Quadrivalent HPV Vaccine HPV L1 major capsid protein of the virus is antigen used for immunization HPV L1 major capsid protein of the virus is antigen used for immunization Expression of L1 protein uses recombinant technology Expression of L1 protein uses recombinant technology L1 proteins self-assemble into virus-like particles (VLP) L1 proteins self-assemble into virus-like particles (VLP) HPV VLP

20. Quadrivalent HPV Vaccine FDA Licensure – June 8, 2006 Indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18: Indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18: –Cervical cancer –Genital warts (condyloma acuminata) –Cervical, vaginal and vulvar precancerous or dysplastic lesions

21. Efficacy for Prevention of Clinical HPV Disease Due to HPV 6/11/16/18 EndpointVaccine N Cases Placebo Efficacy Efficacy HPV 16/18 related CIN2/3 8487 0 8460 53 100 100 HPV 6/11/16/18 related CIN 7858 4 7861 83 95 95 HPV 6/11/16/18 related Genital warts 7897 1 7899 91 99 99 CIN = Cervical Intraepithelial Neoplasia

22. Local symptoms: Injection site reactions such as pain, swelling, and redness Systemic symptoms: Fatigue, headache, rash, upset stomach, and temperature elevation HPV preventive vaccines are well tolerated (Harper, Franco et al. 2004; Sattler and Investigators. 2005; Skjeldestad and Committee 2005; Villa, Costa et al. 2005; 2007; Ault 2007; Garland, Hernandez-Avila et al. 2007; Paavonen, Jenkins et al. 2007)

23. At this point it is not known if, or when, booster doses for these HPV vaccines might be needed Follow-up data extending out to about five years show continued efficacy and immunogenicity for both the quadrivalent HPV vaccine (Villa, Ault et al. 2006) and for the bivalent HPV vaccine (Harper, Franco et al. 2006) Studies monitoring long term effectiveness remain underway

24. The quadrivalent HPV vaccine (Gardasil®, Merck) is approved for administration to girls and women ages 9 to 26 years as a 3 dose series

25. Recommendations from the Advisory Committee on Immunization Practices (ACIP) include routine use of the quadrivalent HPV vaccine (HPV-6,-11,-16,-18; Gardasil®) among girls at the 11-12 year visit; girls as young as age 9 years can be included as part of a systematic approach to vaccination (Markowitz, Dunne et al. 2007).

26. The HPV preventive vaccine should also be offered to all girls and women ages 13-26 years as part of a catch-up vaccination strategy (Markowitz, Dunne et al. 2007) Preventive HPV vaccines will have optimal efficacy among persons who have not yet been exposed to HPV

27. The ACIP recommends use of the HPV vaccine among women: -with a history of abnormal pap smears -known to be HPV-positive to high risk HPV DNA -lactating -immunocompromised (although the immune response and effectiveness are uncertain)

28. The HPV vaccines rely upon a 3 dose series, administered over a period of 6 months. Immune theory and available data suggest a prime with the first dose, a boost with the second dose, and higher longer term titers from the third dose. PrimeBoostHigher, longer term titers baseline2 months6 months Schedule:

29. The HPV vaccines are an adjunct to a comprehensive cervical cancer control program. Clinicians should emphasize to patients who receive the HPV vaccine that regular pap smear screening for cervical cancer early detection should continue at the recommended intervals. (Saslow, Runowicz et al. 2002)

30. Non-compliance with recommended pap screening is a risk factor for invasive cervical cancer The maximal public health benefits of the preventive HPV vaccine will not be realized until vaccine recipients reach the ages of peak incidence for cervical, vaginal and vulvar malignancies, generally ages 50 years and older

31. The emotional impact of HPV infections includes feeling of anxiety, rejection, shame, loss of sexual interest and fears about cancer. (Anhang, Goodman et al. 2004) Most HPV infections are transient and will clear on their own; generally these infections are asymptomatic Chronic and persistent infection with high-risk HPV is associated with the development of malignancies and precursor lesions At this time, there is no strategy to identify patients at risk of developing persistent HPV infection

32. Second Generation Prophylactic vaccines  Upper respiratory tract delivery of purified VLPs in young women  50ug aqueous dose without adjuvant  Responses were similar when compared with intramuscular route and when delivered via a cold ultrasound nebulizer

33.  3 other alternative vaccines 1. Based on L1 capsomeres (pentameric subunits of VLPs) 2. Live recombinant bacteria ( Solmonella typi vaccine strain TY21a) 3. L2 based vaccines

34.  HPV induced proliferating diseases are attractive targets for immuno- therapeutic interventions  Oncoproteins like E6 and E7 exhibit continuous expression and are also non self antigens Q: what stage of HPV induced neoplasia should be targeted by therapeutic vaccines?  Prime concern is prevention of cancer  However it has also proved to the most difficult target  Therapeutic vaccines have thus had only moderate success in clinical trials