1. Human Papillomavirus (HPV) Vaccines: Addressing Safety & Efficacy – Promoting Adolescent Immunization James H. Conway, MD FAAP Professor of Pediatrics Division of Pediatric Infectious Disease University of Wisconsin – School of Medicine & Public Health Wisconsin Chapter – American Academy of Pediatrics

2. Disclosure Statement I disclose the following relationships with commercial interests: –Research/Grant Support:, Sanofi-Pasteur Pediatric Vaccines, Centers for Disease Control, American Academy of Pediatrics –Consultant/Advisory Board: Merck Vaccines I do not intend to reference unlabeled or unapproved uses of drugs or products in my presentation.

3. Objectives 3 Review the adolescent vaccine platform Review currently available vaccines Explore the efficacy of these vaccines –HOW DOES IT WORK? –DOES IT WORK? Transmission in USA –DOES MY PATIENT/KID NEED IT? Addressing Safety Concerns –IS IT SAFE? Conclusions

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5. A Brief History of Adolescent Immunizations 1996 ACIP, AAP, AAFP & AMA first recommended a health-care visit at 11-12 years Before 2005 immunizations for adolescents only administered for ‘catch up’ or ‘special circumstances’ 2006 NIS first collected immunization information for adolescents 13-17 years old 2006-2007 Creating the Adolescent Platform MMWR August 31, 2007. 56(34);885-888.

6. Few Adolescents Would Visit Physicians’ Offices for Preventive Care Only 8% of all reported physician visits by 11- to 18-year-old patients were coded as “preventive” Surveillance Data Inc, March 2004.

7. 77 Clinical Snapshot: How Many Adolescents Visited Physicians’ Offices in 2003? Of 32.8 million adolescents ages 11–18 years, approximately 26.6 million visited a physician in 2003 1 1. US Census Bureau, accessed August 2005

8. 88 Opportunities to Immunize Adolescents Are Missed Schaffer SJ, et al. Arch Pediatr Adolesc Med. 2001;155:566. When Physicians Check Immunization Status…

9. US National Immunization Survey Vaccination Coverage Among Adolescents 13 to 17 Years 9 a The Healthy People 2010 objective is 90% vaccination coverage among adolescents 13 to 15 years. b Any new universally recommended vaccine for adolescents should be at a 90% coverage level within 5 years of the recommendation. Recommendations were published for MCV4 in 2005, for Tdap in 2006, and for HPV in 2007. http://www.healthypeople.gov/Document/HTML/Volume1/14Immunization.htm Centers for Disease Control and Prevention. Vaccination coverage among adolescents aged 13-17 years-United States, 2007. Morb Mortal Wkly Rep. 2008;57(40);1110-1103. 2010 Target Coverage, % HepB a MMR a Td/Tdap a,b Varicella a MCV4 b HPV b Not specified in 2010 goals

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12. HPV vaccines and vaccine immunogenicity HOW DOES IT WORK? 12

13. Human Papillomavirus (HPV) >100 types identified 2 30–40 anogenital 2,3 –15–20 oncogenic 4 HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers. 5 –Nononcogenic † types include: 6, 11, 40, 42, 43, 44, 54 4 HPV 6 and 11 are most often associated with external anogenital warts. 3 Nonenveloped double-stranded DNA virus 1 1. Howley PM. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 4 th ed. Philadelphia, Pa: Lippincott-Raven; 2001:2197–2229. Reprinted with the permission of Lippincott-Raven. 2. Schiffman M, Castle PE. Arch Pathol Lab Med. 2003;127:930–934. 3. Wiley DJ, Douglas J, Beutner K, et al. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 4. Muñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med. 2003;348:518–527. 5. Clifford GM, Smith JS, Aguado T, Franceschi S. Br J Cancer. 2003:89;101–105.

14. 14 CDC Pink Book. 12th ed. Washington DC: Public Health Foundation, 2012. Accelerating HPV Vaccine Uptake: Urgency for Action to Prevent Cancer. A Report to the President of the United States from the President’s Cancer Panel. Bethesda, MD: National Cancer Institute; 2014. Natural history of HPV infections: cervix Within 1 year 1-5 yearsUp to decades Initial HPV infection Persistent infection CIN 1 CIN 2/3 Cervical cancer Cleared HPV infection CIN – cervical intraepithelial neoplasia

15. Area of immature metaplasia between the original and current squamocolumnar junction (SCJ) 1Area of immature metaplasia between the original and current squamocolumnar junction (SCJ) 1 ~99% of HPV-related genital cancers arise within the transformation zone of the cervix. 1~99% of HPV-related genital cancers arise within the transformation zone of the cervix. 1 1. Castle PE. J Low Genit Tract Dis. 2004;8:224–230. 2. American Cancer Society. Prevention and early detection. Pap test. July 2006; Available at; http://www.cancer.org/docroot/PED/content/PED_2_3X_Pap_Test.asp?sitearea=PED The Cervical Transformation Zone

16. HPV Prophylactic Vaccines HPV Virus-Like Particle Recombinant L1 capsid proteins that form “virus-like” particles (VLP) Non-infectious and non-oncogenic Produce higher levels of neutralizing antibody than natural infection

17. HPV vaccines WHAT ARE THE OPTIONS? 17

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22. HPV efficacy: DOES IT WORK? 22

23. HPV Vaccine Duration of Immunity Studies suggest that vaccine protection is long- lasting; no evidence of waning immunity –Available evidence indicates protection for at least 8-10 years –Multiple cohort studies are in progress to monitor the duration of immunity Romanowski B. Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. Hum Vaccin. 2011 Feb;7(2):161-9.

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25. 91011121314151617181920212223 Age at Enrollment (Years) 500 700 900 1,100 1,300 1,500 1,600 Serum cLIA GMT with 95% CI, mMU/mL Efficacy ProgramImmunogenicity Bridge *Inclusive of 5 study protocols; all GMTs measured using cLIA. Adolescent Females (aged 9–17) Young Adult Females (aged 18–26) Anti-HPV Neutralizing Antibodies By Age [at month 7]

26. Neutralizing Antibody Titers to HPV16 by age (non-inferiority) 26

27. HPV vaccine immunogenicity (continued) Better antibody response is observed among preteens compared to older teens –Results of immunogenicity studies during VE trials –18 months post HPV4 series completion, anti-HPV antibodies in females aged 9-15 years were two- to three-fold higher than those observed in females aged 16-26 years 27 CDC Pink Book 2012. CDC. MMWR 2007:56: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr56e312a1.htm

28. HPV vaccine immunogenicity (continued) Duration of immunity –For both vaccines, subset of participants followed for >60 months with no evidence of waning immunity –Anti-HPV antibody titers decline over time after the third dose but plateau by 24 months –Vaccinated women given a challenge dose (revaccinated) 5 years after enrollment demonstrated increase in antibody titer consistent with immune memory –This available evidence suggests protection for at least 8- 10 years –Multiple cohort studies in progress to monitor duration of immunity 28 CDC Pink Book 2012. Romanowski B, et al. Human Vaccines 2011 Feb;7(2):161-9. CDC. MMWR 2007:56: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr56e312a1.htm

29. HPV vaccination: Measures of program impact 29

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31. Proportion of Australian-born women and heterosexual men diagnosed with genital warts at first visit, by age group, 2004-2011 31 Ali H, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. British Medical Journal 2013:346. Females (%)Heterosexual males (%)

32. Anogenital wart prevalence among females with private health insurance, by age, U.S., 2003-2010 32 Flagg E, et al. American Journal of Public Health 2013;103(8):1428-1435. (Data source: Truven Health Analytics MarketScan Commercial Claims and Encounters Database, United States, 2003–2010.) Markowitz L. HPV Vaccination Program and Impact Monitoring: http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-jun-2013/04-HPV-Markowitz.pdf

33. Prevalence of individual human papillomavirus (HPV) types among females aged 14–19 years, 2003–2006 and 2007–2010 Markowitz L E et al. J Infect Dis. 2013;infdis.jit192 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2013.

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36. 36 PEDIATRICS Volume 135, number 5, May 2015  Ontario, Canada – 260,493 girls  Population based cohort comparing before/after HPV program  HPV vaccines in Grades 8-9 (88% completed series)  Outcomes in Grades 10-12  Reduced incidence of dysplasia by 5.7 per 1000 girls  Relative reduction of 44%

37. 37 HPV Vaccine Safety

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39. HPV vaccines: safety More than 60 million doses of HPV vaccine distributed in the U.S. since 2006 and more than 200 million doses worldwide. –Most common adverse events reported are local reactions at the site of injection (20-90%) and fever (10-13%). –No new safety concerns identified during post-licensure vaccine safety surveillance among vaccine recipients. –Among 7.9% of reports coded as “serious,” most frequently cited include: headache, nausea, vomiting, fatigue, dizziness, syncope, and generalized weakness. Syncope continues to be a frequently reported adverse event among adolescents in general. 39 Markowitz L. HPV Vaccination Program and Impact Monitoring: http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-jun-2013/04-HPV-Markowitz.pdf CDC Pink Book. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al., eds. 12th ed., second printing. Washington DC: Public Health Foundation, 2012.

40. Trends in total and serious female HPV4 vaccine reports to VAERS 40 CDC, unpublished data Markowitz L. HPV Vaccination Program and Impact Monitoring: http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-jun-2013/04-HPV-Markowitz.pdf

43. DOES EVERY KID NEED IT? 43

45. Estimated Prevalence of HPV infection

46. Rapid acquisition of HPV following sexual debut 46 Winer RL, et al. American Journal of Epidemiology 2003;157:218-226. Partridge M, et al. The Journal of Infectious Diseases 2007;196 (8): 1128-1136. CDC. You Are the Key to HPV Cancer Prevention. PowerPoint Presentation. September 9, 2013. Partridge et al. Male university students aged 18-23 years (N=240) Winer et al. Female university students aged 18-20 years (N=603)

47. 100 80 60 40 20 Suggests minimal exposure to HPV at 9 to 11 years of age 12–13 years old 14–15 years old 16–17 years old <11 years old The Most Effective Time to Vaccinate Is Before Exposure 1 1. Centers for Disease Control and Prevention. MMWR 2002;51(No. RR-6):1–80. 2. Hoff T et al. National Survey of Adolescents and Young Adults: Sexual Health Knowledge, Attitudes and Experiences. Henry J. Kaiser Family Foundation;2003:14. Cohorts That Have Had Intercourse, % Age at First Intercourse Behavior reported in an independent study These data suggest minimal risk of exposure to HPV in 9- to 11-year-olds. In an analysis of 1,552 adolescents and young adults, the subset (n=1,014) featured in this chart reported having engaged in sexual intercourse. 2

48. WI Youth Risk Behavior 2,843 students in 53 public schools Response rate 68% 77% white Grades: 25% each from grades 9-12 Sexual debut less than age 13 = 3% –(was 7% 1993) Sex ever = 35% –(was 47% 1993) 48

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51. *Mantle-Haenszel estimates adjusted for age only 1. La Vecchia C, Franceschi S, DeCarli A, et al. Cancer. 1986;58:935–941. Relative risks for CIN and invasive cancer increase with decreasing age of first sexual intercourse Age at First Intercourse (Years) (n=206)(n=327)

52. DOES IT CHANGE SEXUAL BEHAVIOR? 52

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58. Prevent HPV-related cancers, cancer precursor lesions and genital warts Emphasize HPV vaccination as a standard and routine part of adolescent health care. Eliminate missed opportunities to vaccinate. –Take advantage of the adolescent immunization visit and every other potential visit. Do not delay vaccination. –Start the conversation regarding HPV vaccination during the first adolescent visit. Share a personal story and welcome questions from parents, especially about HPV vaccine safety. 58

59. Giving a Strong Recommendation Parents trust their health provider’s opinion more than anyone else's when it comes to immunizations. If we were to give HPV vaccine when other adolescent vaccines are given, our rates would be close to 90% and 4,400 cases of cervical cancer would be prevented. 59

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62. Thank you 62