Cervical Cancer Vaccine - Do we need it in India
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Cervical Cancer Vaccine - Do we need it in India
- 1. Cervical Cancer Vaccine – Do WE need it? Dr Gaurav Gupta, (Ex PGI) Practising Pediatrician, Charak Clinics, Mohali Member AAP, IAP.
- 3. Cervical Cancer & HPV – Epidemiology & Natural History
- 6. HPV infection is a necessary cause for Cervical Cancer Adapted from Parkin DM & Bray F. Vaccine 2006; 24 (Suppl 3):S11. Walboomers JMM, et al. J Pathol 1999; 189: 12–19. * Global total HPV-attributable cancers in 2002 Attributable to HPV Site Total cancers % Cases Cervix 492,800 100 492,800 Vulva, vagina 40,000 40* 16,000 Anus 15,900 90* 14,300 Oropharynx 9,600 12* 1,100 Mouth 98,400 3* 2,900 Total 527,100
- 9. HPV Lifecycle in the Cervix Normal epithelium Basement membrane Basal (stem) cells Parabasal cells Squamous layer Mature squamous layer Infected epithelium Cervical canal Frazer IH. Nat Rev Immunol 2004; 4: 46–54.g
- 10. Progression of Cervical Disease Time Years Months Normal epithelium * With increasing probability of viral DNA integration CIN=cervical intraepithelial neoplasia; ASCUS=atypical squamous cells of undetermined significance Burd EM. Clin Microbiol Rev 2003; 16: 1–17; Solomon D, et al. JAMA 2002; 287: 2114–2119 Invasive carcinoma High-grade squamous intraepithelial lesion (HSIL) CIN2 CIN3 Low-grade squamous intraepithelial lesion (ASCUS/LSIL) HPV infection koilocytosis CIN1 Regression Progression*
- 27. The need for Vaccination against Cervical Cancer
- 28. 1.Stanley M. Vaccine 2006; 24: S106-13, 2.Tindle, Nat Rev Cancer 2002; 2, 59, 3.Stanley M. Vaccine 2006; 24: S16-22, 4. Stanley M. HPV Today 2007; 11: 1-16 No viremia Local immunosuppression No inflammation, no danger signals Natural HPV infection induces a weak immune response 1-4
- 34. Composition of the two licenced HPV vaccines Gardasil ® Non- Oncogenic Antigens Aluminium salt + HPV 16 VLPs HPV 18 VLPs Oncogenic Antigens AS04 + Aluminium salt MPL (Immuno Stimulant) Cervarix TM + HPV 16 VLPs HPV 18 VLPs HPV 6 VLPs HPV 11 VLPs Oncogenic Antigens Adjuvant
- 35. AS04: Novel adjuvant system in Cervarix™ High and Lasting levels of Antibodies and Memory B cells Highly purified antigens Enhanced immune response AS04 Aluminium salt MPL (Immuno Stimulant) AS04 Garcon N. Development and evaluation of AS04, a novel and improved adjuvant system containing MPL and aluminum salt. In: Immunopotentiators in modern vaccines, 2005; pp. 161–178. Edited by: Schijns V, O’Hagan D. London: Academic Press. + Strong immunogens
- 38. Cervarix™ : 100% efficacy against HPV 16/18 year after year 1. Harper D, et al. Lancet 2004; 364: 1757–1765; 2. Harper D, et al . Lancet 2006; 367: 1247–1255; 3. Gall S, et al. AACR 2007; Abstract; 4. Harper D, et al. SGO 2008 ; Abstract; 5. GlaxoSmithKline Vaccine HPV-007 Study Group . Lancet 2009; 374: 1975–1985; 6. Carvalho ND, et al . ESGO 2009; Abstract. HPV 16/18-related CIN2+ Cervarix ® Control Vaccine efficacy n n % 95% CI Initial efficacy study 2.3 years 1 0 3 NA* NA* Combined analysis of initial efficacy study and extended follow-up 4.5 years 2 0 5 100.0 -7.7–100.0 5.5 years 3 0 7 100.0 32.7–100.0 6.4 years 4,5 0 9 100.0 51.3–10.00 7.3 years 6 100.0 -129.9–100.0 * The initial efficacy study was not powered to calculate vaccine efficacy against histopathologically confirmed CIN. n = number of subjects reporting at least one event in each group. ITT analysis.
Editor's Notes
- Global incidence The incidence of cervical cancer varies widely around the world, with the highest incidence in developing countries. Incidence rates exceeding > 30 cases per 100 , 000 population occur in Latin America and Sub-Saharan Africa with lower incidences observed in Western Europe, North America and Japan. The incidence rates for each country are available from the International Agency for Research on Cancer (IARC) database. The main reason for these variations in incidence is the availability of screening programmes in developed countries but not in poorer developing countries. Screening can detect the early signs of cervical cancer, allowing for prompt treatment to prevent the development of invasive and potentially fatal cervical cancer. It is important to understand that these figures are not necessarily accurate everywhere. They are sourced from World Health Organization and IARC data , which varies in quality depending on country. Data from Finland, for example, will be perfect because they have good records systems and all cancers are routinely reported. In India, by contrast, very few centres report into data sources and, in some areas of Africa, incidence figures are an estimate only because of the lack of availability of cancer registries or other reporting mechanisms . Likewise, t he incidence in China is reported to be low but this may be because of under-reporting . Reference Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004 .
- Message: Of all the HPV types that have been identified, only 4 account for approximately 80% of all cervical cancer cases. Transmission of HPV occurs by skin-to-skin contact HPVs infect the skin and mucous membranes, causing - Benign skin warts (papilloma) - Genital warts ( condyloma acuminata) - Precancerous cervical dyskaryoses - Cervical cancer – caused by “high risk” types of HPV Condoms reduce the risk of transmission, but do not prevent it Types HPV16 and HPV45 are closely related; Types HPV18 and 31 are closely related
- The HPV lifecycle is restricted to the cervical epithelium; there is no viraemia. The virus is thought to infect the basal cell layer of the epithelium via microabrasions. It then uses the host cell machinery to replicate viral DNA and express virally encoded proteins. The HPV genome encodes eight genes: six encode the ‘early’ or nonstructural proteins (E1, E2, E4, E5, E6, E7); two encode the ‘late’ or structural proteins (L1, L2). Finally, new virus particles are assembled in the upper layers of the epithelium and virus is released with the cells as they are shed from the epithelial surface. Reference Frazer IH. Nat Rev Immunol 2004; 4: 46–54.
- The process of cervical carcinogenesis is illustrated schematically here. After the cervix is infected with HPV, infection may cause mild Pap abnormalities and/or mild CIN, which usually clear spontaneously. Koilocytosis is a distinctive histological feature of HPV infection and is the appearance of halo or koilocytotic cells in the differentiated layers of the squamous epithelium. The koilocytes are squamous epithelial cells that contain an acentric, hyperchromatic nucleus that is displaced by a large perinuclear vacuole. 1 It has become clear that persistence of high-risk HPV is a key factor in the progression to precancerous lesions or high-grade dysplasia (CIN2/3) which has a greater likelihood of progression to invasion and cancer. 2,3 As shown, abnormal infected cells and CIN1 can also be termed low-grade squamous intraepithelial lesions (LSIL), while CIN2 and CIN3 can also be termed high-grade squamous intraepithelial lesions (HSIL). 3 The progressive development of cellular changes from HPV infection to cervical cancer generally takes 10–20 years, although , in very few cases , it may only take 1–2 years. 2 CIN1 changes can arise within 3 months of infection , CIN2 within 6 months and CIN3 within 1–2 years. References 1. Krawczyk E, et al, Am J Pathol 2008; 173: 682–688 2. Burd EM. Clin Microbiol Rev 2003; 16: 1–17. 3. Solomon D, et al. JAMA 2002; 287: 2114–2119.
- Secondary prevention of cervical cancer
- Impact of HPV vaccination on screening practices
- An overview of key points which will be covered in more detail later in this section is provided. Virus-like particles (VLPs) of HPV 16 and 18 were chosen because these HPV types are most frequently associated with cervical cancer worldwide. Capsid proteins self-assemble into VLPs which are highly immunogenic because they closely mimic the virus. When used together with an effective adjuvant system, they elicit a high and sustained immune response.
- An overview of key points which will be covered in more detail later in this section is provided. Virus-like particles (VLPs) of HPV 16 and 18 were chosen because these HPV types are most frequently associated with cervical cancer worldwide. Capsid proteins self-assemble into VLPs which are highly immunogenic because they closely mimic the virus. When used together with an effective adjuvant system, they elicit a high and sustained immune response.
- Comparison of antigen/adjuvant content of the two vaccines.
- This slide describes Cervarix’s innovative adjuvant, AS04. AS04 consists of monophosphoryl lipid A (MPL) adsorbed onto the antigen carrier aluminium hydroxide. MPL is a purified lipopolysaccharide from a bacterial wall and is a powerful stimulant of the immune system. The combination of the highly purified and immunogenic VLP antigens with the AS04 adjuvant system provides a strong vaccine immunogen leading to an immune response which is enhanced when compared with traditional adjuvants. Reference Garcon N. Development and evaluation of AS04, a novel and improved adjuvant system containing MPL and aluminum salt. In: Immunopotentiators in modern vaccines, 2005; pp. 161–178. Edited by: Schijns V, O’Hagan D. London: Academic Press.
- Cervarix ® : HPV 16/18 efficacy profile up to 7.3 years (Phase IIb, women aged 15–25 years) Up to 7.3 years, none of the subjects in the vaccine group developed HPV 16- or 18-related CIN2+ over the study period. References Harper D, et al. Lancet 2004; 364: 1757–1765. Harper D, et al . Lancet 2006; 367: 1247–1255. Gall S. AACR 2007; Abstract. Harper D, et al. Gynecol Oncol 2008; 110 (Suppl 1) : S11-S17 . GlaxoSmithKline Vaccine HPV-007 Study Group . Lancet 2009; 374: 1975–1985 . Carvalho ND, et al . ESGO 2009; Abstract.