HPV VACCIN. Sven-Eric Olsson KK Danderyd

HPV VACCIN Sven-Eric Olsson KK Danderyd

2 Gammal etiologi Tidig och hög sexuell aktivitet Tidig förlossning Icke omskuren man - smegma Cervicit Socioekonomiska faktorer Herpes typ 2 Cancer - Charlie

3 Ny etiologi HPV - virus (ss typ 16 o 18) Co-faktorer (rökning, p-piller m.m.)

4 Frekvens 470.000 fall av cx-cancer/år i världen 450 i Sverige 80 % i u-länder Ca 800.000 SMEAR/år i Sverige 30.000 cellförändringar/år i Sverige 8.000 koniseringar

5 Utveckling Skärpa diagnostiken - vilka förändringar är farligast - HPVtypning Nå dem som inte kommit till screening - hemtest? Prevention - vaccin

HPV types in cervical cancer HPV genotype 16 53.5 53.5% 17.2 6.7 18 45 31 33 52 58 35 59 56 51 39 68 73 82 X Other 2.9 2.6 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 1.2 4.4 0 10 20 30 40 50 60 70 80 90 100 Cancer cases attributed to the most frequent HPV genotypes (%) 70.7% 77.4% 80.3% Vaccine types Munoz N et al. Int J Cancer 2004; 111: 278 85. 6

Assembly of Human Papillomavirus Virus-Like Particles (VLP) Structural model of PapillomaVirus VLP L1 protein (55 to 57 kd) 5 x L1 L1 capsomere (~280 kd) 72 capsomeres Virus-Like Particle (~20,000 kd) 7 (Atomic force microscopy image of a single VLP) (Atomic force microscopic picture: Merck Research Laboratories) 1. Kirnbauer et al. Proc Natl Acad Sci USA 1992;89:12180 12184. 2. Kirnbauer et al. J Virol 1993;67:6929 6936. 3. Syrjänen and Syrjänen. Papillomavirus infections in human pathology. Wiley & Sons, Chichester; 2000. p.11 51.4. Brown et al. Virology 1996;222:43 50.

Spectrum of Changes in Cervical Squamous Epithelium Caused by HPV Infection 1 Normal Cervix HPV Infection / CIN 1 CIN 2 / CIN 3 / Cervical Cancer CIN = cervical intraepithelial neoplasia 1. Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555-1564. Copyright 2003 Massachusetts Medical Society. All rights reserved. Adapted with permission. 8

Histolopathology: Cervical Intraepithelial Neoplasia 1 CIN 1: Mild dysplasia; includes condyloma (anogenital warts) 2 CIN 2: Moderate dysplasia 2 CIN 3: Severe dysplasia; CIS; FIGO stage 0 2,3 Normal CIN 1 CIN 2 CIN 3 Basal cell layer All figures reprinted with permission from Frappart, et al. Histopathology and Cytopathology of the Uterine Cervix. Digital Atlas, Lyon, France: IARC Press, 2004. Cytology findings confirmed by histology 4 1. Frappart L, et al (eds). Lyon, France: International Agency for Research on Cancer; 2004. 2. Bonnez W. In: Richman DD, et al (eds). Washington, DC: American Society for Microbiology Press; 2002:557-596. 3. Canadian Cancer Society. Cervical Cancer: What you need to know. Available at: http://www.cancer.ca/vgn/images/portal/ cit_86751114/ 63/40/151140772cw_library_wyntk_cervical_en.pdf. Accessed March 13, 2006. 4. Wright TC Jr, et al, for the ASCCP-Sponsored Consensus Congress. JAMA. 2002;287:2120-2129. 9

10 Fas 1 studier Immunisering mot kapselproteinet L1 av HPV16 virus

HPV 16 Vaccine Anti-HPV 16 GMTs Geometric Mean Titer (mmu/ml) 1000 100 10 GMT + 95% CI following natural HPV 16 infection 10 mcg 20 mcg 40 mcg 80 mcg 0 3 7 Time (Months) 11 12 18

The adjuvant system AS04 provides an increased antibody response Same vaccine composition, with Aluminium or the adjuvant system AS04 Titres d anticorps (EU/ml) 1000 400 300 200 100 0 * anti-v5 HPV16 1000 AS04 * 400 * Al(OH) 3 * 300 * * * * * * 200 ** * * * 100 * * * * 0 0 8 16 24 32 40 48 0 8 16 24 32 40 48 * anti-j4 HPV18 vaccination Wilcoxon s non Parametric Time (months) vaccination Giannini SL, Hanon E, Moris P, et al. Vaccine 2006;24: 5937-5949

AS04:GSK s Novel Adjuvant System MPL : Detoxified LPS, obtained from Salmonella minnesota MPL adsorbed to Aluminum hydroxide = AS04 3-O-desacyl-4 -monophosphoryl lipid A

14 How Do We Show Cancer Efficacy? 0 to 1 Year 0 to 5 Years Up to 20 Years Initial HPV Infection Persistent Infection CIN 1 CIN 2/3 Cervical Cancer Cleared HPV Infection

15 Pathology Panel Adjudication panel of up to 5 pathologists with expertise in gynaecologic pathology, particularly cervical pathology

16 FUTURE II Interim Analysis Efficacy Findings Per-Protocol Efficacy Population Mean 17 Months After Completion of the Vaccination Regimen Endpoint HPV 16/18-related CIN 2/3+ GARDASIL Cases (N=5,301) Placebo Cases (N=5,258) Vaccin e Efficac y Confidence Interval P-value 0 21 100% 76%,100% p<0.00 1 HPV 16-related CIN 2/3+ 0 16 100% 75%,100% HPV 18-related CIN 2/3+ 0 8 100% 42%,100% HPV 16/18-related CIN 2 0 15 100% 72%,100% HPV 16/18-related CIN 3/AIS 0 16 100% 74%,100% Subjects are counted once per row. Subjects may be counted in >1 row.

Mekanismer bakom skydd Humoral immunitet (IgG, oklart om IgA) Cellulär immunitet (T-lymfocyter) mest för terapeutiska vacciner 17

HPV Infection Causes Benign and Malignant Tumors of the Genital Tract Epithelium Cervical Surface Shedding of virus-laden cells L1 Produced E6 and E7 shut off Virus assembled Normal Epithelium Cervical Intraepithelial Neoplasia Viral DNA in nucleus of infected basal cells; E6 and E7 produced 18

19 Long-Term Persistence of Anti-HPV 16 clia Responses 10000 Geometric Mean Titer With 95% CI - mmu/ml (Log Scale) 1000 100 10 ** * Vaccination GARDASIL (Sero (-) at Day 1 and PCR (-) to HPV 16 through Month 60) Placebo (Sero (+) at Day 1 and PCR (-) to HPV 16 at Day 1) 0 7 12 18 24 30 36 54 60 Time Since Vaccination 1 (Months)

20 Anti-HPV 16 responses to a Month 60 antigen challenge of GARDASIL Seropositivity threshold (20 mmu/ml) 1 month post-challenge 95% CI 1 week post-challenge Pre- challenge (Month 60) 0 2000 4000 6000 8000 10000 Anti-HPV 16 GMT (mmu/ml)

Hepatit B vaccin Likartad produktion som HPV-vaccin Starkt immunologiskt minne kvar efter 10 år och troligen inget behov av booster. Naturlig booster under livet Zanetti et al 2005 21

Serum clia GMT with 95% CI, mmu/ml 1600 1500 1300 1100 900 700 500 Impact of Age at Enrollment on Month 7 Anti-HPV 6 GMTs (PPI Population Gardasil ) Immunogenicity Bridge 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at Enrollment (Years) Number of Subjects Evaluable (n) Age 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 n 68 129 166 141 166 148 109 85 137 440 511 624 576 564 400 22 Efficacy Program

Gardasil Tetravalent (6/11/16/18) Injiceras 0-2-6 mån 98% - 100 % skyddseffekt mot CIN 2+ beroende på HPV 16/18 hos osmittade 40 ug HPV VLP 16 20 ug HPV VLP 18 23

Cervarix Bivalent (16/18) 90% - 100 % skyddseffekt mot CIN 2+ beroende på HPV 16/18 hos osmittade. 20 ug HPV VLP 16/18 Kanske registrerat sep -07 24

Biverkningar Mestadels lokala (rodnad, ömhet) Några generella (feber, muskelvärk, huvudvärk) 25

Skillnad mellan vaccinerade och ovaccinerade under 3 år Sexdebut vid 15 år 5 % smittas med HPV 16/18 varje år = 25 % av 20 åringar smittade Om man vaccineras kommer inte fler i den gruppen att bli nysmittade men den gamla smittan finns kvar Bland de ovaccinerade smittas ytterligare 5% varje år. 1 år efter vaccination är inte skillnaden mellan grupperna så stor, men blir större för varje år som går

VACCINERADE OVACCINERADE ÅR 1 VACCINATION ÅR 2 ÅR 3

HPV 16/18-Related Cervical, Vulvar, Vaginal Cancer Efficacy (Via Surrogates) Per-Protocol Efficacy Population - Protocols 007, 013, 015 HPV 16/18- Related Analysis GARDASIL Placebo % Efficacy 95% CI CIN 2/3 or AIS Licensure (2005) 0 41 100 91, 100 Update 1 73 99 92, 100 VIN 2/3 or VaIN 2/3 Licensure (2005) 0 10 100 56, 100 Update 0 15 100 72, 100

HPV 16/18-Related Cervical, Vulvar, Vaginal Cancer Efficacy (Via Surrogates) All Subjects, Including HPV-infected Women -Prot 007, 013, 015 HPV 16/18- Related Analysis GARDASIL Placebo % Efficacy 95% CI CIN 2/3 or AIS Licensure (2005) 117 178 34 16, 48 Update 137 232 41 27, 53 VIN 2/3 or VaIN 2/3 Licensure (2005) 8 26 69 30, 88 Update 9 31 71 37, 88

Time to HPV 16/18-Related CIN 2/3 or AIS All Subjects, Including HPV-infected Women -Prot 007, 013, 015 Graphs truncated at M36 (few subjects with follow-up at M42)

31 LÄKEMEDELSFÖRMÅNSNÄMNDEN Har 8/5-07 beslutat att Gardasil ska ingå i läkemedelsförmånen om det förskrivs till kvinnor 13-17 år gamla Unikt med att rabattera ett profylaktiskt vaccin Staten betalar och inte kommunerna som i skolvaccinationsprogrammet SoS utreder om Gardasil ska ingå i skolvaccinationsprogrammet

CROSS PROTECTION HPV 45 liknar i någon mån HPV 18 och HPV 31 liknar delvis HPV 16

A6 Species: HPV 56- Related Cancer-Causing HPV Species HPV Phylogenetic Tree A9 Species: HPV 16- Related A7 Species: HPV 18- Related A5 Species: HPV 51- Related

Studies GSK 001 & 007 during 4.5 years: Preliminary Data suggesting broad protection Independent of HPV DNA status Endpoint Vaccine N~500 Placebo N~500 Vaccine efficacy (%) (95% CI) p- values* Estimated prevalence of HPV-16/18 ASCUS 90 138 39.8 (20.9-54.4) <0.001 20-30% 1 LSIL 41 70 44.6 (17.4-63.3) 0.003 25-30% 1 CIN1+ 12 24 51.5 (-0.9-77.9) 0.042 25-30% 1 CIN2+ 3 11 73.3 (-1.0-95.2) 0.033 50% 2 Adapted from Harper et al. Lancet 2006; 367: 1247-55 ITT analysis, Conditional Exact method * p-values not used for inferential purposes 1 Clifford et al. Cancer Epidemiol Biomarkers Prev 2005; 14(5):1157-64 2 Muñoz et al. N Engl J Med 2003; 348:518-27

Studies GSK 001 & 007 during 4.5 years : Preliminary data suggesting cross-protection against HPV types 45 & 31 Incident infection with most common oncogenic types beyond 16 & 18 Vaccine Placebo HPV Type Event rate (rate per 100) (95% CI) Event rate (rate per 100) (95% CI) Vaccine Efficacy (%) (95% CI) N n Rate N n Rate HPV-45 528 1 0.1 (0.0-0.4) 518 17 1.2 (0.7-1.9) 94.2 (63.3-99.9) HPV-31 528 14 0.9 (0.5-1.6) 516 30 2.1 (1.4-3.0) 54.5 (11.5-77.7) Study not powered to evaluate cross protection against all individual types Harper et al. Lancet 2006; 367: 1247-55 Combined initial efficacy and extended follow up studies

DURATION AV HPV-VACCINATION Simulering där man använde alla tillgängliga serumdata från Gardasil. Durationen bedöms som mkt sannolik till 12 år och mkt trolig till livslång C.Fraser et al 2007 36

Monitorering av skyddseffekt De vaccinerade kohorterna från studierna i Norden följs upp via sina personnummer och: Cytologiregister Diagnosregister från sjukvården Cancerregistret Eventuellt blodprovskontroller 37

Effekt i ett oselekterat material En del är redan smittade med HPV 16 el 18 En del smittas av andra virus än HPV 16 o 18 En del förhindras att få cx-cancer pga HPV 16 eller 18 Lätta dysplasier uppkommer oftare av andra virustyper än HPV 16 och 18

39 FRÅGOR I SVERIGE Hur ska skolvaccinationsprogrammet se ut? Ska man vaccinera 20 åringar som betalar själva? HPV-test innan vaccination? Förändrad prevalens annan HPV typ dominerar? Hur länge håller vaccinationen Fortsätta att ta cellprov Ska pojkar vaccineras? Vaccinationsregister på SMI

Utveckling Fler virustyper i vaccinet Andra dosregimer i u-länder Effekt i andra åldersgrupper Effekt hos immunsupprimerade Effekt hos HIV-patienter Cytologiscreening hos vaccinerade