HPV and HPV Vaccine: The Current State of the Research

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1 HPV and HPV Vaccine: The Current State of the Research Robert A. Bednarczyk, PhD May 31, 2018 University of Calgary The O Brien Institute for Public Health and The Department of Community Health Sciences

2 Human Papillomavirus and HPV Vaccines

3 Human Papillomavirus Ubiquitous epithelial virus Most HPV infections are cleared by the immune system in 1-2 years /reports/can.pdf

4 HPV is not like other STI Epithelial tropism allows for greater means of transmission than just penetrative sexual intercourse Liu Z, Rashid T, and Nyitray AG. Sexual Health 2016;13:10-21

5 Potential other sources of HPV transmission Digital-anogenital Non-penetrative genital-genital Shared clothing/towels Ingestion/inhalation following laser ablation therapy Fomites Reusable specula Transvaginal/transrectal ultrasound probe (even after disinfection) Sex toys (HPV DNA detected 24h after cleaning) Liu Z, Rashid T, and Nyitray AG. Sexual Health 2016;13:10-21

6 HPV-related disease Necessary, but not sufficient, cause of a broad range of diseases Epithelial warts Anogenital and oropharyngeal cancers Laryngeal papillomas Persistent infection required for disease processes Allows time for HPV gene expression Moody and Laimins. Nature Reviews Cancer 2010;10:

7 HPV-related Disease - Cervical Cancer 4 th most common cancer in females globally 13 th most common cancer in females in Canada 3 rd most common cancer in females aged in Canada Figure 3 of Schiffman M, et al. Lancet 2007;370:

8 Other HPV-Related Diseases Cancer Anal Vulvar Vaginal Oropharyngeal Penile Warts Cutaneous and genital mucosal warts Laryngeal papillomas Wart-like growths in respiratory tract Most common in infants born to mothers with active genital wart outbreak then among mothers without active wart outbreak 6.9/1,000 vs 0.03/1,000 Shah KV. J Infect Dis 2013;209(9):

9 Estimates of HPV-related disease in Canada Cancer Female Male Total Cervical 1,408 Anal Vulvar 409 Vaginal 124 Penile 132 Oropharyngeal OP (70% HPV) Total 2, ,397 Genital warts* 20,681 21,194 41,875 *Extrapolated from annual incidence rates from three provinces (~115/100,000) as reported in:

10 Cervical cancer over time Current recommendation for cervical screening in Canada cytology screening every three years in women aged Cervical cancer rates have stayed steady in year old Canadian women, but dramatic decreases seen in older women published-guidelines/cervical-cancer/ orts/can.pdf

11 HPV Vaccines Virus-like particle (VLP) vaccine Similar manufacturing process as recombinant HepB vaccine HPV type-specificity based on L1 protein specific to that type

12 HPV Vaccines In 2006, the first HPV vaccine was licensed for use in Canada VLP vaccine provoking immune response against HPV 6, 11, 16, 18 98% efficacy against HPV-caused cancer/pre-cancer and genital warts In 2015, 9HPV licensed and recommended for use in Canada HPV types 16 & 18 cause most HPV-associated cancers (~70%) Types 31, 33, 45, 52, & 58 cause ~20% of HPV-associated cancers HPV types 6 & 11 cause most HPV-associated warts (~90%)

13 HPV vaccine series completion, by province

14 HOW WELL DOES HPV VACCINE WORK?

15 Clinical trial efficacy - females Markowitz LE, et al. MMWR Morbid Mortal Wkly Rep 2014;63(RR-5):1-36.

16 Clinical trial efficacy - males Markowitz LE, et al. MMWR Morbid Mortal Wkly Rep 2014;63(RR-5):1-36.

17 Cochrane Review of HPV Vaccine Efficacy

18 Real world vaccine effectiveness Genital warts are a good model for early effectiveness HPV4 coverage in year old Australians: Dose 1: 83% Dose 2: 80% Dose 3: 73% Ali H, et al. BMJ 2013;346:f2032. Fig 1 Proportion of Australian born women diagnosed as having genital warts at first visit, by age group,

19 Real-world herd immunity Fig 3 Proportion of Australian born heterosexual men diagnosed as having genital warts at first visit, by age group, Fig 5 Proportion of Australian born women aged under 21 years, heterosexual men aged under 21 years, and men who have sex with men who tested positive for chlamydia Ali H, et al. BMJ 2013;346:f2032. at first visit,

20 HOW CAN HPV VACCINE BE EFFECTIVE AT PREVENTING CANCER IF TRIALS ASSESSED PRE- CANCERS?

21 Gardasil is NOT a cancer vaccine. It is simply a vaccine for two strains of human papillomaviruses (HPVs) that in some instances can lead to cancer in some women (Gardasil's other two HPV strains are for genital warts, which don't cause cancer). According to Merck's package insert on Gardasil, the end-point in its clinical trials for the vaccine's efficacy, or effectiveness, was NOT cancer, but instead was the presence, or non-presence, of vaccine-relevant pre-cancerous lesions (CIN 2/3). There is absolutely no proof, and no clinical trials that show Gardasil protects against cancer in the long-term.

22 Bednarczyk RA, et al. Why is it appropriate to recommendation human papillomavirus vaccination as cervical cancer prevention? Am J Obstet Gynecol 2016.

23 IS THE HPV VACCINE SAFE OR TESTED ENOUGH?

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25 HPV vaccine safety clinical trials Clinical trials (N = 10s of thousands) Local and systemic reactions similar between HPV4 and placebo Most common: headache, fever, nausea, dizziness; injection side pain, bruising, erythema, pruritus, and swelling Autoimmune disease incidence similar in HPV4 and placebo recipients (2.3% in females, 1.5% in males)

26 HPV vaccine safety post-licensure 600,558 doses of HPV4 evaluated through the Vaccine Safety Datalink Outcomes Guillain-Barré Syndrome Stroke Venous thromboembolism Appendicitis Seizure Syncope Allergic reaction Anaphylaxis Gee J, et al. Vaccine 2011;29(46): No statistically significant associations between HPV4 receipt and outcome

27 HPV vaccines are safe and tested! Two assessments at Kaiser Permanente California 346,972 HPV doses evaluated Study 1: General safety assessment Syncope on day of vaccination and skin infections w/in 2 weeks No other safety signals detected Study 2: 16 pre-specified autoimmune conditions No confirmed signals for monitored conditions Klein NP, et al. Arch Pediatr Adolesc Med 2012;166: Chao C, et al. J Intern Med 2012;271:

28 HPV vaccines are safe and tested! Denmark and Sweden Health Registry 2 studies 997,585 adolescent girls aged years Evaluated 23 autoimmune conditions, 5 neurologic conditions, and VTE Three significantly elevated risks identified Bechet s syndrome, Raynaud s Disease, Type 1 diabetes 3,126,790 adult women aged years Evaluated 45 autoimmune and neurological conditions One significantly elevated risk identified when controlling for multiple comparisons Celiac disease No consistent patterns in AE development, and unmasking was a plausible explanation for these findings Arnheim-Dahlsrom L, et al. BMJ 2013;347:f5906.

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30 290,000 girls eligible for HPV vaccine between 2007 and 2013 in Ontario

31 Self-controlled case series design Each person s unexposed time acts as their own control, to account for unmeasured confounding and inter-person variation

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33 ADVERSE EVENT REPORTING

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35 HPV IS A SEXUALLY TRANSMITTED VIRUS DOESN T VACCINATION CONDONE SEX?

36 11-12 years is too young to vaccinate? Because HPV is a sexually transmitted virus, concerns have been raised about the recommended age of vaccination Concerns often expressed about what message will this send

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38 11-12 years is too young to vaccinate? Parent It s like blaming a kid before they even get a chance to do anything. Provider I d honestly say it s rare that I spend more than 20 seconds on it at 11 So few 11 year olds are physically mature to be sexually active that it s, I find it s almost sort of an awkward conversation. I rarely give it at 11 or 12. I most commonly give it in the like 8th, 8th to 10th grade range when sexual activity would put them at risk, rather than just an age. This is what I tell parents: it s very different than other vaccines because you can quantify your risk. Perkins RB, et al. Pediatrics 2014;doi: /peds

39 Repeated self-reported surveys indicated that inidivduals would not change their sexual activity profiles, but these never seemed to move public opinion.

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41 11-12 years is NOT too young to vaccinate! Cohort study of 1,398 girls Received HPV or other vaccines at years of age Followed for up to 3 years Monitored for pregnancy or STI testing/diagnosis or contraceptive counseling Unadjusted incidence rate and rate difference Outcome Test/Dx/ Counsel Diagnosis Only Bednarczyk et al. Pediatrics 2012;130: HPV vaccine exposed (N = 493) HPV vaccine unexposed (N = 905) HPV vaccine exposed versus HPV vaccine unexposed IRD (95% CI) airr (95% CI) IR (/100 py) IR (/100 py) (/100 py) (-0.03, 3.24) 1.29 (0.92, 1.80) (-0.35, 0.38) 1.11 (0.26, 4.64)

42 <7 Weeks

43 The power of advocacy and data Guichon JR, Mitchell I, Buffler P, Caplan. Prev Med 2013;57:

44 Smith LM, et al. CMAJ 2014; doi: /cmaj Jena AB, et al. JAMA Intern Med 2015;175: Bednarczyk RA. JAMA Intern Med 2015;175:624-5

45 IF WE VACCINATE EARLY, WILL HPV LAST LONG ENOUGH TO PREVENT CANCER?

46 Schwarz TF, et al. Human Vaccines 2011;7(9): HPV Antibody Persistence

47 Kjaer SK, et al. Clin Infect Dis Long-term follow-up

48 More Long-Term Follow-Up Luostarinen T, et al. Int J Cancer 2018;142:

49 ATTITUDES ON HPV VACCINATION

50 Parents of 9-10 year old girls in Quebec 683 (88%) had daughter vaccinated 91 (12%) did not accept vaccination Krawczyk et al. Human Vaccines & Immunotherapeutics. 2015;11(2):

51 Parents of 9-10 year old girls in Quebec Krawczyk et al. Human Vaccines & Immunotherapeutics. 2015;11(2):

52 News Article Comments 3073 comments from 1198 individuals on 71 articles in people expressed positive 404 people expressed negative 130 people expressed neutral pone pdf

53 Thank you! Any

54 SUPPLEMENTAL SLIDES

55 Immune response to vaccination Markowitz LE, et al. MMWR Morbid Mortal Wkly Rep 2014;63(RR-5):1-36.

56 Walker et al. MMWR 2017 HPV vaccine uptake and acceptability

57 Most HPV infections are cleared anyway Incident HPV infection is common after initiation of sexual activity 39% cumulative incidence by 2 years Median time to clearance: 8 months 70% resolved by 12 months 91% resolved by 24 months Winer RL, et al. Am J Epidemiol 2003;157: Ho GF, et al. NEJM 1998;338:423-8.

58 Resources Canadian resources CIRN publications: Canadian vaccine safety reporting: US-based resources Centers for Disease Control and Prevention: National HPV Vaccination Roundtable: Vaccine Safety Datalink publications: General resources Cervivor (cervical cancer survivor advocacy group): Someone You Love (HPV movie): Lady Ganga (Nilza s Story) advocacy video: