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Prevention of Cancer Cervix by Vaccination Dr Hemant S Damle Professor Dept.of Obs/Gyn SKN Medical College Pune.

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Presentation on theme: "Prevention of Cancer Cervix by Vaccination Dr Hemant S Damle Professor Dept.of Obs/Gyn SKN Medical College Pune."— Presentation transcript:

1 Prevention of Cancer Cervix by Vaccination Dr Hemant S Damle Professor Dept.of Obs/Gyn SKN Medical College Pune.

2 Dr Harald zur Hausen

3 Nobel in Medicine 2008 Dr Harald zur Hausen for his discovery of "human papilloma viruses causing cervical cancer“ Discovery of human papilloma virus causing cervical cancer Against the prevailing view during the 1970s, Harald zur Hausen postulated a role for human papilloma virus (HPV) in cervical cancer. He assumed that the tumour cells, if they contained an oncogenic virus, should harbour viral DNA integrated into their genomes. The HPV genes promoting cell proliferation should therefore be detectable by specifically searching tumor cells for such viral DNA. Harald zur Hausen pursued this idea for over 10 years by searching for different HPV types, a search made difficult by the fact that only parts of the viral DNA were integrated into the host genome. He found novel HPV-DNA in cervix cancer biopsies, and thus discovered the new, tumourigenic HPV16 type in In 1984, he cloned HPV16 and 18 from patients with cervical cancer. The HPV types 16 and 18 were consistently found in about 70% of cervical cancer biopsies throughout the world.

4 0.5 million 10 million 30 million 300 million HPV infection - no abnormality 30 million Genital Warts Low-grade Intra-epithelial Lesions High-grade Intra-epithelial Lesions Cervical Cancer vulval, anal, vaginal oral cancer WORLDWIDE ESTIMATES ON THE BURDEN OF HPV & RELATED GENITAL DISEASES IN WOMEN UK /11

5 ESTIMATED HPV CONTRIBUTION TO CANCER Source: WHO/ICO Information Centre on HPV and Cervical Cancer, second edition 2009 ( ). Estimates are based on 4 reviews: Bosch et al, 2002; Kreimer et al, 2005; De Vuyst et al, 2008; Miralles-Guri et al, > 99% 84.3% 69.9% 47.0% 40.4% 35.6% 23,5% HPV DNA detection : 95% CI for the proportion 5% of all cancers are HPV associated UK /11

6 Importance of the HPV discovery The global public health burden attributable to human papilloma viruses is considerable. More than 5% of all cancers worldwide are caused by persistent infection with this virus. Infection by the human papilloma virus is the most common sexually transmitted agent, afflicting 50-80% of the population. Of the more than 100 HPV types known, about 40 infect the genital tract, and 15 of these put women at high risk for cervical cancer. In addition, HPV is found in some vulval, penile, oral and other cancers. Human papilloma virus can be detected in 99.7% of women with histologically confirmed cervical cancer, affecting some 500,000 women per year.

7 India ~134,000 World ~ 529,000 India ~25% of new Cervical Cancer cases in world India ~ 73,000 World ~ 274,000 India ~25% Rest of World - 75% India ~ 27% of deaths due to Cervical Cancer in world Rest of World - 73% India - 27% Cervical Cancer – Disease Burden IncidenceMortality India ~27% Rest of World - 73% HPV and Cervical Cancer in the World Report. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Available at:

8 Ten Most Frequent HPV Types of Cervical Cancer India Southern Asia WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report [Accessed on 5 th July,2010]. Available at www. who. int/ hpvcentre = 82.5% = 11.7%

9 Development History of Vaccine The research that led to the development of the vaccine began in the 1980s by groups at the University of Rochester, Georgetown University, and the USNational Cancer Institute (NCI). In 1991, Australian investigators at The University of Queensland found a way to form non-infectious virus-like particles(VLP), which could also strongly activate the immune system. However, these VLPs assembled poorly and did not have the same structure as infectious HPV. In 1993, a laboratory at the US National Cancer Institute was able to generate HPV16 VLPs that were morphologically correct. These VLPs were the basis for the HPV16 component of the Gardasil vaccine. [12] Upon commercialization of the vaccine, controversy involving intellectual property arose between the various groups that played a role in developing the vaccine.University of RochesterGeorgetown UniversityNational Cancer InstituteThe University of Queenslandvirus-like particles [12]

10 Clinical trials Merck & Co. conducted a Phase III study named Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE II). This clinical trial was a randomized double-blind study with one controlled placebo group and one vaccination group. Over 12,000 women aged 16–26 from thirteen countries participated in the study. Each woman was injected with either Gardasil or a placebo on day 1, month 2, and month 6. In total, 6,082 women were given Gardasil and 6,075 received the placebo. [13] Subjects in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group. [13] double-blind studyplacebo [13] On February 27, 2006, the independent Data and Safety Monitoring Board recommended the clinical trials be terminated on ethical grounds, so that young women on placebo could receive Gardasil. [14] Merck tested the vaccine in several hundred 11- and 12-year-old girls. [15] [14] [15]

11 Cervarix Human Papillomavirus vaccine (Types 16, 18) (Recombinant, adjuvanted, adsorbed) is supplied in a pre-filled syringe for intramuscular injection in the deltoid at 0, 1, 6 months. GlaxoSmithKline Statement on UK HPV Immunisation Programme Posted GlaxoSmithKline (GSK) did not participate in the UK’s Human Papillomavirus (HPV) 2011 vaccine tender process. A recent health economics paper published in the British Medical Journal by Jit et al, concluded that the quadrivalent vaccine may have an advantage over Cervarix in reducing healthcare costs and the QALYs lost,

12 Gardasil is a prophylactic HPV vaccine, meaning that it is designed to prevent HPV infections. For maximum effect, it is recommended that girls receive the vaccine prior to becoming sexually active. However, women who were already infected with one or more of the four HPV types targeted by the vaccine (6, 11, 16, or 18) were protected from clinical disease caused by the remaining HPV types in the vaccine.

13 In addition, protection against HPV 6 and HPV 11 is expected to eliminate 90% of the cases of genital warts. Gardasil also protects against vulvar and vaginal cancers caused by HPV types 16 and 18. [9]vulvarvaginal cancers [9] In December 2010, Gardasil was approved by the FDA for prevention of anal cancer and associated precancerous lesions due to human papillomavirus (HPV) types 6, 11, 16, and 18 in people ages 9 through 26 years. [16][16][17 ] [16][17 ]

14 HPV infections, especially HPV 16, contribute to some head and neck cancer (HPV is found in an estimated 26-35% of head and neck squamous cell carcinoma). [18] In principle, HPV vaccines may help reduce incidence of such cancers caused by HPV, but this has not been demonstrated. [19]head and neck cancer [18] [19] Merck was denied FDA approval to market Gardasil to women aged 27 to 45. Although it was found to be safe and effective in the prevention of genital warts, it was not effective in the prevention of cervical cancer in that age group. [20] [20]

15 Use in males Gardasil is also effective in males, providing protection against genital warts, anal cancer, and some potentially precancerous lesions caused by some HPV types. [5][5][17][5][17][21][5][17][21][22] An ongoing study of 4,065 males demonstrated the efficacy of Gardasil in males who did not have HPV infection prior to vaccination. [8] The vaccination is expected to protect against penile cancer and anal cancer caused by included HPV types, and research in this area is still [when?] underway. [8]genital wartsanal cancerprecancerous lesions [5][17][21][22] [8]penile canceranal cancerwhen? [8] In December 2008, Merck asked the U.S. Food and Drug Administration (FDA) for permission to market the vaccine in the United States for males between ages 9 to 26, [23] and the FDA approved the request on October 16, [5][5][24][5][24][25][5][24][25][26][5][24][25][26][27][5][24][25][26][27][28] In the UK, HPV vaccines are already [when?] licensed for males aged 9 to 15 and for females aged 9 to 26. [29]U.S. Food and Drug Administration [23] [5][24][25][26][27][28]UKwhen? [29]

16 HPV Type 16 is also associated with oropharyngeal squamous-cell carcinoma, a form of throat cancer.

17 Biotechnology The HPV major capsid protein, L1, can spontaneously self- assemble into virus-like particles (VLPs) that resemble authentic HPV virions. Gardasil contains recombinant VLPs assembled from the L1 proteins of HPV types 6, 11, 16 and 18.capsidvirus-like particlesvirionsrecombinant Since VLPs lack the viral DNA, they cannot induce cancer.DNA They do, however, trigger an antibody response that protects vaccine recipients from becoming infected with the HPV types represented in the vaccine. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs.antibodyfermentationsSaccharomyces cerevisiae

18 The National Cancer Institute says, "Studies have shown that both Gardasil and Cervaix and prevent nearly 100 percent of the precancerous cervical cell changes caused by the types of HPV targeted by the vaccine for up to 4 years after vaccination among women who were not infected at the time of vaccination." [34]National Cancer Institute [34] Gardasil has been shown to be partially effective (approximately 38%) in preventing cervical cancer caused by ten other high-risk HPV types. [35] [35] Antibody levels at month 3 (1 month postdose 2) are substantially higher than at month 24 (18 months postdose 3), suggesting that protection is achieved by month 3 and perhaps earlier. [10][10][36] This does not imply that the third dose can be skipped. [10][36]

19 Public health advantages One unknown property of the vaccines now being researched is the persistence of their protective effects. Since the Gardasil vaccine has been administered for only a few years now, it is unknown whether it will provide life-long immunity to recipients. In coming decades, further study will answer this question. Whether the effects are temporary or life-long, widespread vaccination could have a substantial public health impact. 270,000 women died of cervical cancer worldwide in [49] Acting FDA Administrator Dr. Andrew von Eschenbach said the vaccine will have "a dramatic effect" on the health of women around the world. [50] Even in the United States, where screening programs are routine, the National Cancer Institute estimated that 9,700 women would develop cervical cancer in 2006, and 3,700 would die. [51] [49]Andrew von Eschenbach [50]National Cancer Institute [51]

20 Gardasil®Gardasil® [HPV (Human Papillomavirus) Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] 2006 June 8th - US FDA approves use in females aged 9 to 26 yearsUS FDA approves use in females aged 9 to 26 years 2008 September 12th - US FDA approves use to prevent vulvar and vaginal cancerUS FDA approves use to prevent vulvar and vaginal cancer 2009 October 16th - US FDA approves use to prevent genital warts in males aged 9 to 26 yearsUS FDA approves use to prevent genital warts in males aged 9 to 26 years 2010 December 22nd - US FDA approves use to prevent anal cancer in males andfemales aged 9 to 26 yearsUS FDA approves use to prevent anal cancer in males andfemales aged 9 to 26 years 2011 April 5th - US FDA approves use in women 27 through 45 years of ageUS FDA approves use in women 27 through 45 years of age

21 Phase III Randomised Control Trials (RCTs) End of Study: Per Protocol Efficacy Populations VaccineQuadrivalentBivalent Mean Follow up42 months34.9months Prophylactic Efficacy% CI HPV16/18 CIN2/3 98 (94,100) 93 (80,98) HPV16/18 AIS 100 (31,100)Not reported HPV 16/18 VIN3/VaIN3 100 (83,100)Not reported HPV6/11/16/18 VIN1/VaIN1 100 (86,100)Not a target EGL 99 (97,100)Not a target Kjaer etal Cancer Prev Res :868 Paavonen etal 2009 Lancet 371:314 Dillner et al BMJ 341:3493 Palefsky IPV Montreal 2010

22 The HPV vaccination program is listed on the National Immunisation Program (NIP) Schedule and funded under the Immunise Australia Program. From 2007 to 2009 there was a time- limited catch-up program, for girls aged 14 to 26 years of age delivered through schools, general practices and community immunisation services.

23 Legislation was passed by the Australian Government in 2007 to enable the HPV Register to receive data from all states and territories. Legislation The HPV Register plays an essential role in monitoring and evaluating the program by recording information about HPV vaccine doses administered in Australia.

24 School Based Program Girls years (catch-up) GP Based Young women years (catch-up) Girls years who miss doses at school July ’07 - Dec ’09 (catch up) April ’07 - Dec ’08 (catch-up) 29 Nov 2006: “The Commonwealth Government will fund the cervical cancer vaccine, QHPV Vaccine ®, for girls and women aged 12 to 26 from 2007.” Girls 12 – 13 years (ongoing) Reference: Dept of Health and Ageing 2007 Ongoing adolescent program aimed at 12 year old girls Australia HPV Immunization program

25 FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease; CIN = cervical intraepithelial neoplasia; EGL = external genital lesions. 1. Mao C et al. Obstet Gynecol. 2006;107:18– Villa LL et al. Lancet Oncol. 2005;6:271– Garland SM et al. New Engl J Med. 2007;356:1928– The FUTURE II Study Group. New Engl J Med. 2007;356:1915– Block SL et al. Pediatrics. 2006;118:2135– Reisinger KS et al. Pediatr Infect Dis J. 2007;26:201–209. Jan 2003 Jan 2004 Jan 2005 Jan 2009 Jan 2006 Jan 2008 Jan 2007 Jan 2010 Ph III―FUTURE II (P015) CIN 2/3 15- to 26-year-old women (N=12,167) 4 Duration of Efficacy Registry Study Nordic Region Jan 1998 May 2000 Phase II/III Program for Quadrivalent Human Papillomavirus Vaccine Long term follow up was extension of phase III clinical trial

26 Start of Vacci nation 0%0% 2%2% 4%4% 6%6% 8%8% 10 % 12 % H1 2007H2 2007H1 2008H2 2008H H Female Australian residents eligible for free HPV vaccination Cases of Genital Warts in Australian Females <27yrs Cases of genital warts among first-time users of sexual health services, 2004–09 Ref: Basil Donovan et al, Published online November 9, 2010 DOI: /S (10) % reductio n 59% reduction 95% CI 54–61; ptrend<0·0001 During vaccine era, a decline of 59% in women<26 yr with genital warts was noted. H % reduction

27 Cases of Genital Warts in Australian Males <27yrs Cases of genital warts among first-time users of sexual health services, 2004–09 Ref: Basil Donovan et al, Published online November 9, 2010 DOI: /S (10) Start of Vacci nation 0% 2% 4% 6% 8% 10 % 12 % 14 % H1 2007H2 2007H1 2008H2 2008H1 2009H Heterosexual men 18% reducti on 28% Reduction (CI 24–33) ptrend<0·00 01 The proportion of heterosexual men diagnosed with genital warts declined in the vaccine period by 28%. H % reduction

28 Per-Protocol Efficacy Population Cohort 1 (N=2,650) Number of Cases Incidence Rate per 100 Person-Years at Risk Vaccine Effectiveness † n(%) HPV 16/18-Related 1, By HPV Type HPV 16-Related HPV 18-Related 1, By Lesion Type CIN 2 1, CIN 3 or Worse 1, CIN 3 1, AIS 1, Cervical Cancer 1, † Vaccine effectiveness measures the relative reduction of the disease incidence in vaccine recipients compared to the baseline incidence rate of per 100 person-years established from the incidence rate in an unvaccinated cohort and under the assumption vaccine effectiveness is 90%. Not enough follow-up time was accrued in any time interval since Day 1 to draw conclusions from the results of the analysis. Data on File Effectiveness Against HPV 16/18-Related CIN 2 or Worse Kjaer SK, An evaluation of the long-term effectiveness, immunogenicity and safety of the quadrivalent vaccine in previously vaccinated women, Presented at Eurogin 2011

29 Conclusions – Nordic Study Extensive monitoring of QHPV Vaccine is ongoing in Nordic countries as an extension of FUTURE 2 study. No breakthrough cases of HPV 16/18 related CIN 2 or worse. QHPV Vaccine shows a trend of continued protection in women who were vaccinated up to 7 years previously. QHPV Vaccine continues to be generally safe and well tolerated up to 7 years following vaccination. Kjaer SK, An evaluation of the long-term effectiveness, immunogenicity and safety of the quadrivalent vaccine in previously vaccinated women, Presented at Eurogin 2011

30 As of 17 June 2010, a total of 1,534 suspected adverse reactions have been reported in Australia following vaccination with Gardasil. The great majority have been mild and common problems such as soreness, swelling, or redness at the injection site. Most of the adverse reactions that have been reported are well recognised and listed in the Gardasil Product Information. Common adverse events reported to date are listed below

31 Suspected adverse reaction Number of reports (% of total reports for Gardasil) Injection site reaction 294 (19.1%) Headache 316 (20.5%) Dizziness 214 (13.9%) Nausea 237 (15.4%) Fatigue and lethargy 152 (10%) Fever 148 (9.6%) Fainting 134 (8.7%) General feeling of being unwell 123 (8.0%) Vomiting 123 (8.0%) Total 1534 = 100%

32 As of 17 June 2010, there had been 16 reports of anaphylaxis and 133 reports of urticarial reactions (hives) in Australia following Gardasil injection. All cases reported to the TGA to date have either been treated appropriately or have resolved without treatment. The current estimated rate of anaphylaxis based on doses distributed in Australia is 2.6 per million. The rates for other vaccines given to children and adolescents range from 0 to 3.5 per million doses in international studies. 1

33 As of February 2009, 40 million doses of Gardasil had been distributed worldwide. [38] The vaccine was tested in thousands of females (ages 9 to 26). [39] [38] [39] The Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) consider the vaccine to be safe. It does not contain mercury, thiomersal or live virus or dead virus, only virus-like particles, which cannot reproduce in the human body. [39]Food and Drug AdministrationCenters for Disease Control and Preventionmercurythiomersal [39]

34 The FDA and the CDC say that the vaccine has only minor side effects, such as soreness around the injection area. [39] [39] Fainting is more common among adolescents receiving the Gardasil vaccine than in other kinds of vaccinations. Patients should remain seated for 15 minutes after they receive the HPV vaccine. [33] [33] There have been reports that the shot is more painful than other common vaccines, and the manufacturer Merck partly attributes this to the virus-like particles within the vaccine. [40] [40] General side effects of the shot may include joint and muscle pain, fatigue, physical weakness and general malaise. [33][33][41] [33][41]

35 GARDASIL ® GARDASIL is indicated in females aged 9 through 45 years for the prevention of cervical, vulvar, vaginal and anal cancer, precancerous or dysplastic lesions, genital warts, and infection caused by Human Papillomavirus (HPV) Types 6, 11, 16, and 18 (which are included in the vaccine).

36 PATH’s HPV vaccine project in India Started in Gujarat and Andhra Of the more than 23,000 girls vaccinated in India, three were hospitalized after vaccination as a cautionary measure. All three were released soon afterward, following observation. Project stopped.

37 GARDASIL is also indicated in males 9 through 26 years of age for the prevention of anal cancer, precancerous or dysplastic lesions, external genital lesions and infection caused by HPV Types 6, 11, 16, and 18.

38 AdministrationGardasil is given in three 0.5 milliliter injections over six months. The second injection is two months after the first, and the third injection is four months after the second shot was administered

39 Gardasil vaccination program at SKNMC Pune. Total 3 doses Total cost Rs 2200/- (MRP of each dose is Rs 2800 so less than 1/3 cost.) Registration Starts from 16 March2012 till 19 March First Dose in Last wk of March 2012 Second dose in Last wk of May 2012 Third Dose in Last wk of Sep 2012.

40 58 Female ( Student,staff) completed 3 doses No major adverse reaction. Total Vaccination done till date is 110 +

41 IAP Recommendations – Immunization Schedule Consensus Recommendations on Immunization, Indian Academy of Pediatrics Committee On Immunization (IAPCOI). Indian Pediatrics 2008; (45)

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45 New Vaccine V503 [HPV (Human Papillomavirus) Nonavalent (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) Vaccine, Recombinant] - to be released in V503 October 12th - Broad Spectrum HPV (Human Papillomavirus) Vaccine Study in 16-to 26-Year-Old Women (V )Broad Spectrum HPV (Human Papillomavirus) Vaccine Study in 16-to 26-Year-Old Women (V ) 2009 July 21st - A Study of V503 in Preadolescents and Adolescents (V )A Study of V503 in Preadolescents and Adolescents (V ) 2010 May 11th - The Phase III trial is ongoing and Merck anticipates filing a Biologics License Application (BLA) in 2012The Phase III trial is ongoing and Merck anticipates filing a Biologics License Application (BLA) in July - Merck is recruiting for Phase III clinical trials of a nine-valent vaccineMerck is recruiting for Phase III clinical trials of a nine-valent vaccine

46 NCI is also collaborating with other researchers on second-generation preventive vaccines and on therapeutic HPV vaccines, which would prevent the development of cancer among women previously infected with HPV. The ideal vaccine strategy would combine a preventive and therapeutic vaccine.therapeutic

47 Another prevention strategy that is being explored is topical microbicides. Carrageenan, a compound that is extracted from a type of seaweed and used widely in foods and other products, has been found to inhibit HPV infection in laboratory studies. Clinical trials are under way to test whether a topical microbicide that contains carrageenan can prevent genital HPV infection.microbicides

48 Secondary Prevention Microencapsulation of DNA vaccine can prevent DNA degradation by nucleases for efficient delivery. Amolmigene bepiplasmid (ZYC101A), a DNA vaccine comprised of plasmid DNA encoding HPV 16/18 E6/E7 proteins encapsulated in poly(glycolide-lactide) biopolymer, has advanced to Phase II/III clinical trials and is undergoing investigation in CIN 2/3 patients

49 Thank you Dr Hemant Damle. E Mail (Pl send queries,comments by )


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