The promise of HPV vaccines for Cervical (and other genital cancer) prevention

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1 The promise of HPV vaccines for Cervical (and other genital cancer) prevention CONTROVERSIES IN OBSTETRICS GYNECOLOGY & INFERTILITY Barcelona March 27 F. Xavier Bosch Catalan Institute of Oncology

2 CURRENT HPV VACCINES MSD / SPMSD GSK HPV 16 HPV 6,11,16 & 18 HPV 16 / 18 VLP L1 of four HPV types Yeast expressed Adjuvant aluminum Licensed in 26 in over 4 countries VLP L1 of HPV 16 and 18 Baculovirus expressed in insect cells AS4 adjuvant : Aluminum salts and monophosphoryl lipid A In evaluation

3 SAFETY OF HPV VACCINES IN THE VACCINE vs. PLACEBO trials Local side effects Mild systemic effects Low / nil attrition rates due to side effects No evidence of side effects in pregnancies / lactation No evidence of onset of autoimmune diseases No suspected side effects reported or under evaluation (within the limits of a 4-5 year follow up of a few tens of thousand women)

4 INMUGENICITY OF 3 doses of MSD TETRAVALENT VACCINE VLPs of HPVs 6,11,16 & 18 at month 7 Geometric Mean Titer (mmu/ml) Placebo 2/4/4/2 g 4/4/4/4 g 8/8/4/8 g Natural infection (GMTs, 95% CI) HPV 6 HPV 11 HPV 16 HPV 18

5 Geometric Mean Titer (mmu/ml) Placebo recipients who were HPV 16 Sero (+)/PCR(-) at day 1. ATP analyses 1 HPV 16-Antibody titers At 48 months of follow up Vaccination Months since enrollment Vaccine recipients Placebo recipients (Mao et al., Obstet & Gynecol, 26)

6 TYPE SPECIFIC HPV ANTIBODY TITERS INDUCED BY THE AS4 ADJUVANT AS COMPARED TO ALUMINUM IN A 4-YEAR FOLLOW UP NEUTRALIZING ANTIBODIES Anti-V5 (HPV 16) Anti-J4 (HPV 18) GMT (EU/ml) * * * * * * * * * * * * TIME (MONTHS) AS4 Al(OH)3

7 EFFICACY OF MERCK S VACCINE vs. PLACEBO AGAINST CERVICAL LESIONS CIN 2/3 AT 24 MONTHS. VPH TYPES : 6, 11, 16, 18 END POINT NUMBER OF WOMEN NUMBER OF EVENTS EVENT RATE NUMBER OF WOMEN NUMBER OF EVENTS EVENT RATE EFFICACY (CI 95%) CIN ,2 1 (72-1) CIN ,2 1 (74-1) VPH ,3 1 (75-1) VPH ,1 1 (42-1) KOUTSKY ET AL NEJM 22

8 MERCK TRIAL VACCINE vs. PLACEBO: EFFICACY AGAINST CERVICAL LESIONS Types 6, 11, 16, 18 CIN 2/3 at 24 MONTHS. Statistical analyses Number of women Number of cases Rate per womanyears Number of women Number of cases Rate per woman -years Efficacy 95% CI Per protocol (76-1) Intention to treat < (83-1) Skjeldestad FE. Future II Steering Committee Abstract 25

9 !" # $ Per-protocol* efficacy data after 3 doses (, 2 and 6 months) Efficacy measured from month 7 Endpoint HPV 6, 11, 16, 18-related CIN 2/3 or AIS GARDASIL n 8487 Cases Placebo n 846 Cases 53 Observed efficacy % (CI) 1% (93, 1) CIN % (89, 1) CIN 3/AIS % (88, 1) Median duration of follow-up = 4, 3 or 2 years depending on study after completion of vaccination schedule *Per-protocol population included subjects who were HPV vaccine-type naïve at the start of the study, received all three doses of the vaccine on schedule, remained HPV vaccine-type naïve until all three doses had been given and adhered to the protocol with respect to factors which could impact on the immune response of the vaccine (e.g. immunosuppressive therapy) 2 1. Ault K on behalf of the Gardasil TM Phase III Steering Committee. Prophylactic use of quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine reduces cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS) risk. European Cancer Conference. 2 November 25. Paris, France. 2. SPMSD data on file, 25.

10 % # $ Per-protocol* efficacy data after 3 doses (, 2 and 6 months) Efficacy measured from month 7 Endpoint GARDASIL Placebo Observed efficacy % (CI) n Cases n Cases HPV 6, 11, 16, 18-related genital warts % (93.7, 1) Median duration of follow-up = 3 or 2 years depending on study after completion of vaccination schedule *Per-protocol population included subjects who were HPV vaccine-type naïve at the start of the study, received all three doses of the vaccine on schedule, remained HPV vaccine-type naïve until all three doses had been given and adhered to the protocol with respect to factors which could impact on the immune response of the vaccine (e.g. immunosuppressive therapy) 2 1. Gardasil Summary of Product Characteristics. 2. SPMSD data on file, 25.

11 % &'( $) $*+ (!" (!",% # - Type-specific per-protocol populations GARDASIL (N = 975) Placebo (N = 9,75) n Cases n Cases Efficacy 95% CI HPV 16 or 18- related VIN 2/3 7,771 7, (42, 1) HPV 16 or 18- related VaIN 2/3 7,771 7, (31, 1) N = number of subjects who received 1 vaccination n = number of subjects in the per-protocol analysis population *Data presented at ICACT Joura E., February 7 th 27

12 GARDASIL EFFICACY RESULTS SUBSEQUENT ANALYSES. % / ' 1 2 ' '+' ' ' 3 4 # " # 5$ 4 # / # 6- HPV 6, 11, 16 OR 18-RELATED Persistent infection or disease Persistent infection Disease* CIN 1 3 Condyloma GARDASIL (N = 277) N CASES 2 2 PLACEBO (N = 275) 95.8% Vaccine administered on a -, 2- and 6-month dosing schedule. *Disease = cervical intraepithelial neoplasia and external genital lesions. **A subset of 241 subjects (114 GARDASIL and 127 placebo) had follow-up through 5 years post-dose 1. N CASES EFFICAC Y 95.6% 1% 1% 1% 1. Villa LL, Costa RLR, Petta CA et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like 95% CI (83.8, 99.5) (83.3, 99.5) (12.4, 1) (<, 1) (<, 1)

13 &&.778,.(. 9,&. &'(.. :.79. :.89.(.,;. <,& = > <9?. DISEASE RELATED TO TYPES 6,11,16,18 (PRIMARY ENDPOINT) CASES IN THE GARDASIL GROUP CASES IN THE PLACEBO GROUP GARDASIL PER PROTOCOL EFFICACY ANALYSIS * PRE-CANCEROUS CERVICAL LESIONS (CIN ** 2/3), CERVICAL CANCER in situ or worse (n=1,599) 21 1% 95% CI [81,1] 1 PRE-CANCEROUS (CIN* * 2/3) & POTENTIALLY PRE-CANCEROUS CERVICAL LESIONS (CIN ** 1) (n=4,498) 37 2, 3 1% 97.5% CI [87,1] PRE-CANCEROUS VULVAR LESIONS (n=15,796) 8 1% 95% CI [41.4,1] 3 PRE-CANCEROUS VAGINAL LESIONS (n=15,796) 3 7 1% 95% CI [31.4,1] 3 GENITAL WARTS (n=4,54) 29 1% 95% CI [86.4,1] % (95% CI [87.2, 98.7]) in the Combined Analysis 98.9% (95% CI [93.7, 1]) in the Combined Analysis of several clinical studies In women already exposed to one or more vaccine virus types, GARDASIL was still up to 1% (95% CI [55, 1]) efficacious against CIN 1 3 and genital warts caused by the remaining vaccine types to which the women had not been exposed 3 1% (95% CI [12.4, 1]) efficacy against clinical disease through up to 5 years after onset of vaccination *3 doses of vaccine or placebo at months, 2 and 6; follow up 2 to 4 years since the start of the vaccination; efficacy results were assessed from month 7. **Cervical Intraepithelial Neoplasia. ***Endpoint was combined incidence of HPV 16/18-related CIN 2/3 or worse. [1] Ault K on behalf of the Gardasil TM Phase III Steering Committee. Prophylactic use of quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine reduces cervical intraepithelial neoplasia (CIN) 2/3 and adenocarcinoma in situ (AIS). European Cancer Conference (ECCO). 2 November 25, Paris France. [2] Ferris D for FUTURE I investigators. Efficacy of a prophylactic quadrivalent human papillomavirus (HPV) (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine for the prevention of pre-cancerous cervical dysplasia and external genital lesions (EGL). Interscience Conference on

14 GSK TRIAL: VACCINE vs. PLACEBO EFFICACY AGAINST CIN1+ RELATED to HPV Types 16 & 18 HPV TYPE NR. OF WOMEN NR. OF CIN1+ HPV 16 OR 18 NR. OF WOMEN NR. OF CIN1+ HPV 16 OR 18 EFFICACY (95% CI) 16 / % (42.4-1%) *ITT cohort HARPER ET AL., THE LANCET 26

15 Endpoints for Extended Follow Up Study HPV 16 and 18 Immunogenicity Seropositivity Geometric Mean Titers HPV Vaccine Safety HPV 16/18 Efficacy Incident infection Persistent infection (6 and 12 months) Abnormal cytology and CIN lesions Incident infection: HPV 45, 31, 33, 52, 58 Any HR HPV type Independent of HPV status

16 Sustained Seropositivity And High Antibody Levels up to 4.5 Years log (ELU/ml) HPV % 1% % seropositive 99.7% 99% 99% 1% Vaccine HPV 16 IgG Placebo HPV 16 IgG 1% 1% 1 Natural Infection 17x 1 6% % 17% % % 1% 1% 12% 11% 12% 1 month month 7 month 12 month 18[M25-M32][M33-M38][M39-M44][M45-M5][M51-M53] Months follow up time Initial Study Extended Follow Up

17 Sustained Seropositivity And High Antibody Levels up to 4.5 years log (ELU/ml) 1 1 1% 1% HPV 18 % seropositive 99.7% 99% 99% 99% Vaccine HPV 18 IgG Placebo HPV 18 IgG 1% 1% 1 Natural Infection 14X 1 1% % 17% % % 7% 12% 16% 13% 9% 1 month month 7 month 12 month 18 [M25-M32] [M33-M38] [M39-M44] [M45-M5] [M51-M53] Initial Study Extended Follow Up Months follow up time

18 Sustained Protection of HPV 16/18 Associated Endpoints up to 4.5 years Vaccine efficacy (%) ATP ATP ITT ITT Incident Infection 6M Persistent Infection 12M Persistent Infection Abnormal Cytology Combined Study Initial Study CIN Harper et al. Lancet. 26, 367:

19 POTENTIAL FOR ADDITIONAL BENEFITS ON CERVICAL CANCER OF A 16 & 18 VACCINE Cross-protection against infections with non HPV 16 or 18 types : reported Cross-protection against lesions related to non HPV 16 or 18 types : to be confirmed Protection against other HPV 16/18 cancers : suggested but still to be confirmed

20 GSK TRIAL: VACCINE vs. PLACEBO EFFICACY AGAINST INCIDENT CERVICAL INFECTIONS By Types 45 & 31 HPV TYPE Number of women Number of HPV incident infections Number of women Number of HPV incident infections Efficacy (95% CI) % ( ) % ( ) *ITT analysis HARPER ET AL., THE LANCET 26

21 '.?8 :9,98, ;.,,&, 9; '9,.,,,9 &;? ''9?(;,8'. GARDASIL TOTAL lgg GEOMETRIC MEAN END POINT TITRES AGAINST DIFFERENT HPV TYPES ACCORDING TO TIME (n=1) 1, 2... HPV 16 HPV 18 HPV 45 HPV 31 HPV 58 HPV 52 Antibody response to types 31, 45, 52, 58 (cross reactivity) 2 Antibodies neutralise HPV type 31 and 45 pseudovirions (in vitro cross neutralisation) 2 Dose 1 st 2 nd 3 rd months The relevance of this phenomenon, however, to protect from subsequent disease has not been established. Clinical studies are under way to investigate the prevention of disease due to virus types closely related to the vaccine types (cross protection) 1. SPMSD data on file, Smith JF, Brownlow M, Brown M et al. Gardasil antibodies cross-neutralize infection of vaccine type-related HPV types. International PapillomavirusConference, 3 September 26, Prague, Czech Republic. 3. Clifford GM, Smith JS, Plummer M et al. Human papillomavirus types in invasive cervical cancer worldwide: A meta-analysis. Br J Cancer 23;88:63 73.

22 THEORETICAL IMPACT OF AN HPV 16/18 VACCINE FOR THE PREVENTION OF CERVICAL CANCER (proportion of cases avoided) SS AFR. N. AFR. ASIA C.S.A EU/NA TOTAL HPV 16 & HPV 16 & 18 + CROSS PROTECTION Vaccine efficacy: CIN1+HPV 16/18 = 1% Incident infection HPV 31 = ~54%; HPV 45 = ~94% HARPER ET AL., THE LANCET 26, 367:

23 OTHER GENITAL CANCERS: ESTIMATES OF THE HPV TYPE-SPECIFIC FRACTIONS SITE Attributed HPV (%) PENIS ? Some? VULVA, Wb, VULVA SQ Some Some? Some? VAGINA Some Some HPV 35 / 59? ANUS Some Some??

24 OTHER FINDINGS OF INTEREST & GAPS IN KNOWLEDGE NO THERAPEUTIC EFFECT OBSERVED. No accelerated regression rates of HPV 16 or 18 positive women at the time of vaccination HIV POSITIVE SUBJECTS RESPOND TO VACCINE AS A FUNCTION OF THEIR IMMUNE STATUS AT VACCINATION MALES SHOW IMMUNE RESPONSE BUT STILL. NO EVIDENCE ON PROPHILACTIC EFFECTS LIMITED EVIDENCE ON INTERACTION WITH OTHER VACCINES NO EVIDENCE ON INFANT VACCINATION..

25 A SHIFT TO HPV-BASED CERVICAL CANCER PREVENTION HPV PRECANCER CANCER AGE Pap Smears/Cytology Vaccinate HPV DNA HPV DNA ADAPTED FROM SCHIFFMAN ET AL. NEJM,25

26 Thank you for your attention

Prophylactic HPV Vaccines. Margaret Stanley Department of Pathology Cambridge

Prophylactic HPV Vaccines. Margaret Stanley Department of Pathology Cambridge Prophylactic HPV Vaccines Margaret Stanley Department of Pathology Cambridge 8kb double stranded DNA viruses, absolutely host and tissue specific, Can t grow virus in tissue culture Classified by genotype