Cervical Cancer 8/20/2008. New genital HPV infections are commonest amongst young adults. Development of antibody to HPV capsids after HPV infection

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Preventing cervical cancer from bench to bedside and beyond Ian Frazer Diamantina Institute, The University of Queensland, Brisbane, Australia Cervical Cancer Second

8% attributable to HPV infection Two HPV types (16 and 18) responsible for >7% of cancers HPV Infection is very common (>3%) only rarely leads to cancer (<2%) 15 year lag

Women by Age in US <1 1-14 15-19 2-24 24-29 3-

tonsillar Cancer Age group HPV+ve HPV -ve 3 39 3 1 4 49 23 6 5 59 59 32 23 6 69 23 46 7 79 16 25 8 89 2 3 Human papillomavirus as a risk factor for the increase in

1 Preventing cervical cancer from bench to bedside and beyond Ian Frazer Diamantina Institute, The University of Queensland, Brisbane, Australia Cervical Cancer Second commonest cause of cancer in women worldwide.25m deaths/year >99.8% attributable to HPV infection Two HPV types (16 and 18) responsible for >7% of cancers HPV Infection is very common (>3%) only rarely leads to cancer (<2%) 15 year lag period between infection and cancer Cervical Cancer : the HPV connection 4 main groups: % % % % + HPV X 85.% % % % % % % nital Warts on-years Rate of New Ge per 1 Perso New genital HPV infections are commonest amongst young adults Incidence of New Genital Warts in Women by Age in US < Age (years) Insinga RP. Clin Inf Dis. 23;36: High risk HPVs and Tonsillar Cancer.3.6 S MR 1 2 S MR MALES FEMALES HPV in tonsillar Cancer Age group HPV+ve HPV -ve Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer Lalle Hammarstedt, David Lindquist, Hanna Dahlstrand, Mircea Romanitan, Liselotte Dahlgren, Jeanna Joneberg, Nomi Creson, Johan Lindholm, Weimin Ye, Tina Dalianis and Eva Munck-Wikland Int. J. Cancer: 119, (26) Development of antibody to HPV capsids after HPV infection Proportion of wom men seroconverted HPV 6 HPV 16 HPV Months since first HPV DNA detected Capsid specific antibody is: - not a diagnostic test for HPV - not a marker for likely regression Carter JJ et al J Infect Dis 2, 181,

Serum antibody to VLP conformational determinants conveys protection s to prevent HPV infection Zur Hausen Serum from dogs from group 6 (control) and 4 (immunised), transferred to groups of naïve

OUTCOME: Group 6: 4/4 with warts; Group 4: /4 with warts Cancer associated Human (~198) -Some HPVs cause cancer - Virus can t be grown in the lab Jian Zhou Virus Like particles 1 (~199) - L1

. Proc.Natl.Acad.Sci.U.S.A 92 (25):11553-11557, 1995. 1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991.

2 Serum antibody to VLP conformational determinants conveys protection s to prevent HPV infection Zur Hausen Serum from dogs from group 6 (control) and 4 (immunised), transferred to groups of naïve animals, challenged with COPV. OUTCOME: Group 6: 4/4 with warts; Group 4: /4 with warts Cancer associated Human (~198) -Some HPVs cause cancer - Virus can t be grown in the lab Jian Zhou Virus Like particles 1 (~199) - L1 recombinant DNA - Self assembly to VLPs - VLPs highly immunogenic J. A. Suzich, S. J. Ghim, F. J. Palmer-Hill, W. I. White, J. K. Tamura, J. A. Bell, J. A. Newsome, A. B. Jenson, and R. Schlegel.. Proc.Natl.Acad.Sci.U.S.A 92 (25): , :J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1): , Clinical Lesion Virus L1 gene L1 + Expression Vector Eukaryotic Cell Gene expression s to prevent HPV infection Zur Hausen Expression Vector Gene cloning Virus Like particle purification Cancer associated Human (~198) -Some HPVs cause cancer - Virus can t be grown in the lab Jian Zhou Virus Like particles 1 (~199) - L1 recombinant DNA - Self assembly to VLPs - VLPs highly immunogenic HPV vaccines (~25) -Conventional vaccines - VLPs+ adjuvant - Neutralising Antibody Clinical trial validation ALUM Addition of adjuvant 1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1): , Protection > 5yrs - Safe Disclosure of conflict of interest HPV vaccines One technology two products Dr Ian Frazer and the University of Queensland benefit financially from commercial sale of the prophylactic HPV vaccines discussed in this talk Gardasil Manufacturer Merck (CSL) GSK Cervarix HPV types 6,11,16,18 16,18 Adjuvant Proprietary Alum Alum OH +MPL (ASO4) Administration,2,6 months,1,6 months Manufacture Yeast SF9 cells/baculovirus 2

HPV 16/18-Related Cervical Cancer Efficacy Quadrivalent vaccine Mean 36 Months of Follow-Up Subjects = Women, without prior infection with vaccine HPV types Efficacy = Prevention of disease caused by

3 HPV 16/18-Related Cervical Cancer Efficacy Quadrivalent vaccine Mean 36 Months of Follow-Up Subjects = Women, without prior infection with vaccine HPV types Efficacy = Prevention of disease caused by vaccine HPV types High grade anogenital lesion (CIN, AIN) Cases Cases (N=9342) (N=94) Efficacy 95% CI (92, 1) HPV vaccine Phase III trial outcomes Study 1 2 No of subjects End-points efficacy Control % (confidence limits) Koutsky 6/11/16/ CIN 2/3 AIS 98 (86-1) Ault 6/11/16/ CIN 2/3 AIS 99 (93-1) Garland 6/11/16/18 Joura 6/11/16/18 Harper 16/ Parvonen 16/ CIN 2/3 AIS 1 (94-1) GW VIN VAIN 1 (94-1) VIN2/3 VAIN 2/3 CIN CIN2,3 CIN CIN2,3 1 (72-1) 1 (42-1) 1 (-8-1) 89 (59-99) 9 (53-99) Adapted from J. A. Kahn and R. D. Burk. Papillomavirus vaccines in perspective. Lancet 369 (958): , 27. Efficacy Against HPV 6/11/16/18- Related External Genital Lesions Mean 32 Months of Follow-Up Cases (N = 7899) Cases (N = 7897) Efficacy CI EGL , 1 Cross protection against HPV associated CIN 2/3 CIN 2/3 CASES N= 4675 %Efficacy (95% CI) caused by N= 4616 any HPV (24,62) types 52 1 (93,1) Non vaccine types (6, 6) Non vaccine A9 (HPV16 like) (1, 68) Non vaccine A7 (HPV18 like) (-35, 8) Protection over time against CIN2/3 -all HPV types Percent t CIN 2/3 1 cerv /1 vical treatment avoided women/year Months A 7% reduction in cervical pre-cancer is observed with vaccination Despite some cross protection there is still residual disease due to non vaccine HPV types Source : ACIP website 28/3/3 3

HPV VACCINE FAQs Are there vaccine specific side effects?

reported possibly associated events (June 8) Pain 83.9% 75.4% 48.6% Mostly nonserious -fainting 11 (one broken nose) Swelling 25.4% 15.8% 7.3% Urticaria (5) Anaphylaxis (28) Erythema 24.6% 18.4% 12.

6% Systemic AEs (1 to 15 days Postvaccination) 1244 Pregnancies in vaccine group (N=5,88) (N=3,79) 1272 Pregnancies in placebo group Fever 1.3% 8.6% Nausea 3.6% adverse events in vaccine 4.

4 HPV VACCINE FAQs Are there vaccine specific side effects? (Data for Quadrivalent vaccine) controlled trials Injection Site (1 to 5 days Postvaccination) Post Marketing surveillance 22,, doses over 12 months (Aluminum) (Saline) (N=5,88) (N=3,47) (N=32) 7526 reported possibly associated events (June 8) Pain 83.9% 75.4% 48.6% Mostly nonserious -fainting 11 (one broken nose) Swelling 25.4% 15.8% 7.3% Urticaria (5) Anaphylaxis (28) Erythema 24.6% 18.4% 12.1% Some serious events 3 cases Guillain Barre?expected fqy Pruritus 3.1% 2.8%.6% Systemic AEs (1 to 15 days Postvaccination) 1244 Pregnancies in vaccine group (N=5,88) (N=3,79) 1272 Pregnancies in placebo group Fever 1.3% 8.6% Nausea 3.6% adverse events in vaccine 4.2% group and placebo 4.1% group Dizziness 15 (vaccine) and 16 (placebo) congenital 2.8% abnormalities 2.6% What about pregnancy safety? Neutralizing Antibodies By Age at Enrollment 1 Neutralizing anti-hpv 6 GMTs at month 7 T with 95% U/mL Serum clia GM CI, mmu Block SL, Nolan T, Sattler C, et al. 26 Immunogenicity Bridge Efficacy Program Up to 1% clinical protection Adolescent Males + Females Females Only Age at Enrollment (Years) Month 7 Anti-HPV Neutralizing GMTs By Age Category Per-Protocol Immunogenicity Population* Anti-HPV 6 Anti-HPV Anti-HPV 16 Anti-HPV NOTE: non-logarithmic axes. *Subjects who were not general protocol violators, received all three doses within acceptable day ranges, were seronegative at day 1 and PCR negative day 1-month 7 for all relevant HPV types, and had a month 7 serum sample collected within an acceptable day range. Subjects years of age are from prior analyses and are included for comparison Primary Efficacy Results (young and younger women) Combined Incidence of HPV 6/11/16/18-Related Persistent Infection or Cervical/Vulvar/Vaginal Disease Per Protocol Efficacy Population Population Efficacy 95% CI P-value P19 Mid-Adult Women % 74, 98 <.11 P7 Young-Adult % 78, 1 <.1 Women P19: 24- to 45-Year- Women; mean of 1.65 years follow-up P7: 16- to 23-Year- Women; mean of 2.33 years follow-up* Antibody Titer Geometric Mean A (Log Scale) Anti HPV-16 Antibody over 5 years. 1 ) ** * Time Since Vaccination 1 (Months) Natural infection) Protection persists at 5 Years HPV 6, 11, 16, or 18-Related Persistent Infection N Cases N Cases Efficacy (%) 95% CI 235 2* Disease CIN 1, 2, or < 1 Vulvar/vaginal neoplasias or genital warts < 1 Per Protocol efficacy against vaccine HPV types. 4

5 Papillomavirus Prophylactic s Where Next? Determine from ongoing studies Duration of protection Scandinavian Cohort study Efficacy in men Significance of cross protection Efficacy in older women Studies underway Consider broader spectrum vaccines Challenge how do you prove efficacy, if you need 25, subjects to do it, and have no approved surrogate marker deployment Licenced in over 8 countries Mostly for males and females USA, Malaysia, Canada females only Government sponsored univesal immunisation programs (routine + catch-up) in: Australia (Quadrivalent) (Girls ) Commenced April 27 through schools and GPs - 8% coverage in schools in most states Germany, Italy, France (Q), Canada(Q), Great Britain (B) (Girls ) to commence in 28 Developing world initiatives Gates Foundation, Merck/GSK, WHO collaborating on delivery to countries with GDP < US$1 Field trials delivery strategies (eg Vanuatu) underway Deploying vaccines in the developing world >1% of healthy Vanuatu Women over 3 have CIN3 No screening program feasible one part time gynae for.2m people >5% of 12 year old girls no longer attend school Challenge how to fund and how to deliver vaccine. Conclusions s to prevent cervical cancer are here! They can prevent, with best results from early universal immunisation Up to 7% of cervical cancer in an unscreened population The majority of abnormal pap smears in screened populations >9% of genital warts quadrivalent vaccine only (nb: no efficacy data for males yet) They are not therapeutic for existing infection, therefore full public health benefit requires universal administration to pre-teen girls individual women of any age may benefit. Vaccination should not alter participation in existing cervical cancer screening programs We cannot claim a job well done till vaccine is delivered in the developing world. 5

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