Cervical Cancer a Global Problem

Cervical Cancer The long road from discovery global eradication

TRI, The University of Queensland Brisbane, Australia Cervical Cancer A global problem

The global burden of HPV associated cancer – 330,000 deaths/year Source: Globocan 2008 : IARC and WHO : 2015 Cervical Cancer elimination The beginning Giornale per servire ai progressi della patologia e della terapeutica Domenico Antonio Rigoni-Stern(1842)

Rigoni-Stern and Medical Statistics A Nineteenth-Century Approach to Cancer Research JOSEPH SCOTTO AND JOHN C. BAILAR, III Journal of the History of Medicine : January 1969 Giornale per servire ai progressi della patologia e della terapeutica (1842) Domenico Antonio Rigoni-Stern

STATISTICAL DATA RELATIVE TO THE DISEASE OF CANCER WHICH SERVE AS THE “….why“TheBASIS FORincidence SOMEeven BRIEF isREMARKS breastof MADE uterine BY DR. cancer RIGONI -STERNcancer ONthe THE 23RD mostis OFnot “ cancersSEPTEMBER are AT THE more SUBSESSION frequent OF SURGERY in OF THEnuns FOURTH than CONGRESS in other OF ITALIAN womenfrequentincreasedSCIENTISTS at a ratio cancer through of about among the 5 to licentious 1.”nuns? Could it be “thetheirpractices frequency habits of of arewomen; the toocancers tight?however, of the Or, uterus the perhaps, isrisk is inverselythegreater long related -amongsustained, to thatwomen of bent the who cancersposition are excessivelyof theassumed breast” whilesensitive saying morally prayers and with nervously forearms irritable” resting on knees and compressing the breasts.”

Rigoni-Stern and Medical Statistics A Nineteenth-Century Approach to Cancer Research JOSEPH SCOTTO AND JOHN C. BAILAR, III Journal of the History of Medicine : January 1969 A great step forward Georgios Papanikolaou Screening for cervical cancer First description in 1928 “Diagnosis of Uterine Cancer Georgios Nikolaou by the Vaginal Smear”(1943) Papanikolaou 1883-1962

Quinn M et al BMJ 1999; 318 904- 908 The swinging sixties Sexual activity and cervical cancer

American Journal of Public Health Volume 57(5); 1967 May “Epidemiology of cancer of the cervix. 3 Sexual characteristics of a cervical cancer population” I D Rotkin https://www.ncbi.nlm.nih.gov/pmc/journals/259

A substudy of97 patients with cervical cancer and 97 matching controls:

…..a considerable excess of patients with first coitus on the ground, compared to a heavy excess of controls with first coitus in a hotel or motel. The progressive 70’s : Is infection to blame ? • Cancer Res. 1974 May;34(5):1111-7. Epidemiological studies relating genital herpetic infection to cervical carcinoma

“The high frequency of herpes simplex virus type 2 (HSV-2) antibodies in young women (21 years or younger) with cervical carcinoma in situ and in women with dysplasia or carcinoma in situ, matched for various sexual attributes to control women, provide support for a causal relation.” Harald Zur Hausen : the age of enlightenment

Condylomata Acuminata and Human Genital Cancer, Cancer Res. 1976 Feb;36(2 pt 2):794. The condyloma agent has been entirely neglected thus far in all epidemiological and serological studies relating not only to cervical and penile, but also to vulvar and perianal, carcinomas. This is particularly unusual in view of the localization of genital warts, their mode of venereal transmission, the number of reports on malignant transition, and the presence of an agent belonging to a well- characterized group of oncogenic DNA viruses.

Boshart, Michael, Lutz Gissman, Hans Ikenberg, Andreas Kleinheinz, Wolfram Scheurlen, and Harald zur Hausen. "A New Type of Papillomavirus DNA, Its Presence in Genital Cancer Biopsies and in Cell Lines Derived from Cervical Cancer." The EMBO Journal 3 (1984): 1151– 1157. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC557488 /pdf/emboj00309-0223 .pdf Transformation of cells by HPV

Watts SL, Phelps WC, Ostrow RS, Zachow KR, Faras AJ (1984) Cellular transformation by human papillomavirus DNA in vitro. Science 225:634–636.

Pirisi L, Yasumoto S, Feller M, Doniger J, DiPaolo JA (1987) Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA. J Virol 61:1061–1066. Bedell MA, Jones KH, Laimins LA (1987) The E6–E7 region of human papillomavirus type 18 is sufficient for transformation of NIH 3T3 and rat-1 cells. J Virol 61:3635–3640. Dürst M, Dzarlieva-Petrusevska RT, Boukamp P, Fusenig NE, Gissmann L (1987) Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 DNA. Oncogene 1:251–256. Kaur P, McDougall JK, Cone R (1989) Immortalization of primary human epithelial cells by cloned cervical carcinoma DNA containing human papillomavirus type 16 E6/E7 open reading frames. J Gen Virol 70:1261–1266. Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R (1989) The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63:4417–4421 Halbert CL, Demers GW, Galloway DA (1991) The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol 65:473–478. The beginning of the end Treating HPV infections : a challenge

Preventing them is more sensible Papillomavirus vaccine development First learn the natural history Zur of the disease

Hausen HPV 16

Cancer associated Human

Papillomaviruses Fraction infected Residual infection (~1980) Months since onset of Sexual activity - High risk HPV infection is common - Two common (16,18) and several rarer types - >95% resolve spontaneously –median 1.5yrs - 2% progress to cancer over 15 years - Unexpectedly, detection of pre-cancer is possible 1- 2 years post infection Harriet Richardson, Gail Kelsall, Pierre Tellier, Helene Voyer, Michal Abrahamowicz, Alex Ferenczy, Francois Coutlee, and Eduardo L. Franco Cancer Epidemiology, Biomarkers & Prevention Vol. 12, 485–490, June 2003 Vaccines to prevent HPV infection

Zur Hausen

Jian Zhou Cancer associated Human Virus Like particles1 Papillomaviruses (~1990) (~1980) - L1 recombinant DNA -Some HPVs cause cancer - Self assembly to VLPs - Virus can’t be grown in the lab - VLPs highly immunogenic

1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991. VLP vaccine citations Virus Clinical Lesion 200

Atg Atg L1 L1 gene Eukaryotic Cell + 150Expression Vector Gene expression

Expression Patenting enabled by: Vector 100 1)Eukaryotic Expression Gene cloning 2) 2nd ATG start site 3) DNA from infection Citations/year Virus Like particle purification 50 not cancer

1993 1998 2003 2008 2013 Year ALUM Clinical trial validation Vaccine Addition of adjuvant Expression systems with better yield Vaccines to prevent HPV infection

Ed Scolnick

Harald Zur Hausen Jian Zhou Kathrin Jansen Cancer associated Human Virus Like particles1 HPV vaccines Papillomaviruses (~1990) (~2005) (~1980) - L1 recombinant DNA -Conventional vaccines -Some HPVs cause cancer - Self assembly to VLPs - VLPs+ adjuvant - Virus can’t be grown in the lab - VLPs highly immunogenic - Neutralising Antibody

- Protection > 5yrs

- Safe 1:J. Zhou, X. Y. Sun, D. J. Stenzel, and I. H. Frazer. Virology 185 (1):251-257, 1991. The vaccine needed many people and a hard end point to prove efficacy

Vaccine Study Vaccine No of subjects End-points efficacy

Vaccine Control % ( confidence limits) Koutsky 6/11/16/18 6087 6080 CIN 2/3 AIS 98 (86-100) Ault 6/11/16/18 10291 10292 CIN 2/3 AIS 99 (93-100) 2241 2258 CIN 2/3 AIS 100 (94-100) Garland 6/11/16/18 2261 2279 GW VIN VAIN 100 (94-100) 7811 7785 VIN2/3 VAIN 100 (72-100) Joura 6/11/16/18 2/3 CIN2,3 93 (89-98) Parvonen* 16/18 9319 9325

Adapted from J. A. Kahn and R. D. Caveat Burk. Papillomavirus vaccines in prevention of premalignancy perspective. Lancet 369 (9580):2135-2137, 2007. - in HPV naïve subjects, - disease caused by vaccine HPV types *: Phase III bivalent vaccine data from 25th IPV Malmo 2009 Nine steps to translate HPV research into practical outcomes • Define the problem – HPV and cancer Zur Hausen • Develop the science –recombinant VLPS Jian Zhou • Find commercial partners Merck/GSK • Scale up the manufacture Merck/GSK • Complete safety and efficacy trials Many groups • Educate the profession, govt, the public Ongoing • Confirm field efficacy • Improve the product – 9 valent vaccines, 2 dose regimens • Encourage deployment globally • Develop effective immunotherapy Genital warts have disappeared in young vaccinated women in Australia

H.Ali, B.Donovan, H. Wand, T Read, D.Regan, A. Grulich, C Fairley, R. Guy, BMJ 2013;346:f2032 doi: 10.1136/bmj.f2032 Genital Warts have also disappeared in their unvaccinated male partners

H.Ali, B.Donovan, H. Wand, T Read, D.Regan, A. Grulich, C Fairley, R. Guy, BMJ 2013;346:f2032 doi: 10.1136/bmj.f2032 HPV VLP vaccines are not therapeutic! We need something else for those already infected

Immunised At 14 No exposure Good protection

Immunised At 17 Prior exposure Poor protection

Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. Dorota M Gertig, , Julia ML Brotherton, Alison C Budd, Kelly Drennan Genevieve Chappell and A Marion Saville BMC Medicine 2013, 11:227 doi:10.1186/1741-7015-11-227 ENABLING GLOBAL USE There is disparity between HPV vaccine programs and cervical cancer prevalence

http://www.indexmundi.com/blog/wp-content/uploads/2013/05/HPV-vaccine-infographic.jpg Vaccine delivery logistics in Vanuatu: staffing, and a cold chain

Vanuatu ->50 islands ~250,000 people ~25 doctors -91 parliamentarians! -1 vaccine fridge -0 reliable electricity

500 well women over 30 Bx result Number Cancer 5 CIN 3 17 CIN 1 23 Education in Vanuatu: parents, children, staff, and government

Parents and Kids under the Banyan Tree- north Efate When vaccine is available, vaccination programs in subsistence economies can be as successful as Australia

State Age Dose 1 Dose 1 immunised receiving Coverage (%) Dose 2 (%) Dose 3 (%) Australia 12-18 (Opt out) ~ 90% 96 86 Australia 18-25 (Opt in) ~80% 82 50 Vanuatu 10-12 (Opt out) ~80% 98 93

~80% coverage for bivalent HPV vaccine for 10-12 year olds in 2008, and 2013 Vaccine through Australian Cervical Cancer Foundation: delivery by government 25 Vaccine success in Bhutan Government champions are needed The benefits of royal sponsorship HPV vaccine delivery to 12 year-olds, Bhutan, 2010–2014

YEAR Approach Pop’n 3rd Dose(%)

2010 School 6706 100 2011 Health-center 7805 59 2012 Health-center 7203 67 2013 Health-center 7231 68 2014 School 7575 94

. T. Dorji et al. / Vaccine 33 (2015) 3726–3730 HPV associated cancer control through immunisation 10 years on -how are we doing? • >200 million doses of vaccine delivered 25,000,000 people alive today who will die of an HPV induced cancer Theoretical benefit from vaccine delivered 2 million lives saved

Likely practical benefit 10,000 who will avoid an HPV cancer related death because of vaccine already delivered Efficacy of the HPV vaccine with reduced dose number Prevention of infection 5 years after immunisation One versus two versus three doses

Three doses: n=11,110 HPV: 11,217 control Two doses : n= 611 HPV : 574 control One dose : n = 292 HPV: 251 control

Lancet Oncol. 2015 Jul; 16(7): 775–786 Efficacy of Fewer than Three Doses of an HPV-16/18 AS04 adjuvanted Vaccine: Combined Analysis of Data from the Costa Rica Vaccine Trial and the PATRICIA Trial Aimee R Kreimer et al HPV vaccines –the current issues • What age to immunise? • Where to immunise? • How many doses- 1, 2, or 3? • Is “HPV16 and 18” enough? • Girls only, or boys as well? • Given the efficacy of herd immunity, maybe a single dose mass immunisation program would be the most cost effective?

Cervical cancer eradication?

The projected timeframe until cervical cancer elimination in Australia: a modelling study Michaela T Hall, Kate T Simms, Jie- Bin Lew, Megan A Smith, Julia ML Brotherton, Marion Saville, Ian H Frazer, Karen Canfell http://dx.doi.org/ 10.1016/ S2468- 2667(18)30183-X A case for worldwide routine HPV vaccination

POLIO HPV Lifetime risk of 50% 50% catching the infection (pre- vaccine) Lifetime risk of 1% (paralytic polio) 2% (surgery to the cervix to serious disease given prevent cancer) infection Lifetime risk of 0.1% 0.8% death given infection (no intervention) Annualised death 1952 USA(worst year) 2005 USA (avge year) rate pre vaccine, 3,145 died and 21,269 were 3,924 women died and 11,999 post screening left with mild to disabling diagnosed with cervical cancer paralysis Efficacy of vaccine >95% (3 doses) >97% (3 doses) Safety of vaccine 1:100,000 (vaccine induced 1:1,000,000 (severe allergy to paralytic polio) vaccine) 1996 13th HPV conference A life in HPV research? 2006 Acknowledgements Frazer Lab, Diamantina Institute, TRI, Brisbane • Former members : Dr Robert Tindle, Dr Seyed Jazayeri, Dr Ritu Chakraborty, Dr Christina Gosmann, Dr Steve Mattarollo, Dr Rached De Klyuver, Dr Antje Blumenthal, and many others Lambert Lab, McArdle Ins FUNDING • NHMRC Australia • NCI, NIH • Cancer Council Australia • Australian Cancer Research Foundation

• Postdocs: Kelvin Tuong, Katharina Noske, MeiHua Yu, Janin ChandraGarnett Passe Rodney • PhD students: Paula Kuo, Annika Krueger, Abate Bashaw, Siok MinhTehWilliams, Chenhao Zhou • ScientistsMemorial: Stacey Foundation Cole, Lynn Tolley , Tracey Doan, Sarah Hanson