Cervical Cancer Vaccine - Do we need it in India

Cervical Cancer Vaccine – Do WE need it?

Dr Gaurav Gupta, (Ex PGI)Practising Pediatrician,Charak Clinics, MohaliMember AAP, IAP.

Points to be discussed

• HPV – Natural History & Epidemiology

• Cervical Cancer – the Indian Context

• Preventing Cervical Cancer – other options

• Need for vaccination against Cervical Cancer

• Vaccine Efficacy & Safety

• Vaccine – the Indian experience

• IAP / FOGSI recommendations

Cervical Cancer & HPV – Epidemiology & Natural History

•500,000 women diagnosed per year1

•270,000 deaths per year1

– >1 million new cases of cervical cancer each year, 20502

•1 out of 4 women who die due to Cervical Cancer in the world is an Indian3

Global Burden of Cervical Cancer

1. Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase; Lyon, 2004;

2. Parkin DM, et al. Eur J Cancer 2001; 37(Suppl 8):S4-S66.3. GLOBOCAN 2008

In India, over 72000 women die every year due to Cervical Cancer

• Every year 134000 Indian women are diagnosed with Cervical cancer and around 72000 die from the disease

• Cervical cancer ranks No. 1 among cancers in Indian women, that’s even more than Breast Cancer

GLOBOCAN 2008 Cancer Incidence, Mortality andPrevalence India

Attributable to HPV

SiteTotal

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

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

HPV infection is a necessary cause for Cervical Cancer

In India 4 HPV Types: HPV 16, 18, 31 and 45 are responsible for>90% >90% Squamous Cell Carcinoma2

>95% >95% Adenocarcinoma2

100 HPV Types Have Been Identified1

30 HPV Types are Transmitted by Genital skin to skin Contact

15 HPV Types are Oncogenic

Human Papillomavirus (HPV)

1.Munoz N et al. N Engl J Med 2003; 348(6):518-527 2. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre).

Human Papillomavirus and Related Cancers in India. Summary Report 2010.

Adenocarcinoma of the cervix- An Emerging concern

• HPV 16, 18, 45 and 31 are responsible for >95% of Adenocarcinoma in India1,2

• Adenocarcinoma is difficult to detect difficult to detect with routine screening methods1

• Incidence increasing Incidence increasing (20–25% of all cervical cancers3,4

• More aggressive More aggressive and occurs in younger women3,4

1. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary

Report 2010. 2. Bhatla N et al. Vaccine 2008; 26(23):2811-2817.

3. Bosch FX, et al. Vaccine 2008; 26S:K1–K16; 4.Castellsague X, et al. JNCI 2006; 98:303–315.

Adenocarcinoma: may beinaccessible to the cervical

smear brush

Squamous cell carcinoma:usually accessible to the

cervical smear brush

Normal epithelium

Basement membrane

Basal (stem) cells

Parabasal cells

Squamous layer

Mature squamous

layer

Infected epithelium

Cervical canal

HPV Lifecycle in the Cervix

Frazer IH. Nat Rev Immunol 2004; 4:46–54.g

Invasivecarcinoma

Time YearsMonths

Normal epithelium

High-grade squamous intraepithelial lesion (HSIL)

CIN2 CIN3

Low-grade squamous intraepithelial lesion (ASCUS/LSIL)

HPV infectionkoilocytosis

CIN1

Regression

* With increasing probability of viral DNA integrationCIN=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

Progression*

Progression of Cervical Disease

• HPV infections are very common and up to 80% of women will acquire an HPV infection in their lifetime5–7

• The risk of oncogenic HPV infection is high even after first intercourse and continues throughout a woman’s sexually active lifetime2–4

• Although new infections decrease with age, risk of their persistence increases with age8

• The cumulative risk of acquiring cervical HPV infection in women with only one sexual partner is 46% (3 years after first sexual encounter)1

Every woman is at risk of Cervical Cancer

1. Collins S, et al. Br J Obstet Gynaecol 2002; 109:96–98; 2. Schiffman M, et al. J Natl Cancer Inst 2003; 31:14–19;3. Sellors JW, et al. CMAJ 2003; 168:421–425; 4. Dunne EF, et al. JAMA 2007; 297:813–819;

5. Brown DR, et al. J Infect Dis 2005; 191:182–192; 6. Koutsky L, et al. Am J Med 1997; 102:3–8;7. Bosch FX, et al. J Natl Cancer Inst Monogr 2003; 31:3–13; 8. Castle PE, et al. J Infect Dis 2005; 19:1808–1816.

8. Castle PE, et al. J Infect Dis 2005;191:808–816;

HPV Clinical Features

• Most HPV infections are asymptomatic and result in no clinical disease

• Clinical manifestations of HPV infection include:

– anogenital warts (2-25.2% of STI clinic in India)

– recurrent respiratory papillomatosis

– cervical cancer precursors (cervical intraepithelial neoplasia)

– Cancer (cervical, anal, vaginal, vulvar, penile, and some head and neck cancer)

• Cervical Cancer – the Indian Context

CERVICAL CANCER

• Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2009:– New Cases: 11,270

– Deaths: 4,070

• India– New Cases: 1,32,000

– Deaths: 74,000

• In India Cervical cancer ranks No. 1 among cancers in women followed by breast cancer

• Every year 132000 Indian women are diagnosed with Cervical cancer and around 74000 die from the disease

Cervical Cancer is more common than Breast Cancer, in India

GLOBOCAN 2002 Cancer Incidence, Mortality andPrevalence India

• Preventing Cervical Cancer – other options

• Cervical screening (traditionally using the Pap smear and more recently by liquid-based cytology [LBC]) is used to detect existing cervical abnormalities and precancerous disease1

• Neither method offers primary prevention; HPV infection and development of cervical disease can still occur – Deaths from cervical cancer still occur in countries with

established screening programmes2

• Vaccination offers an important new management option in the primary prevention of cervical cancer

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Cervical Cancer Prevention

1. Sankaranarayanan R, et al. Int J Gynaecol Obstet 2005; 89(Suppl 2):S4–S12;2. WHO/ICO Information Centre on Human Papilloma Virus (HPV) and Cervical Cancer.

Available at: http://www.who.int/hpvcentre/statistics (accessed February 2010).

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Impact of HPV vaccination on screening practices

• In countries withoutwithout existing screening programmes– Modelling studies suggest that vaccination is likely to be the most

effective option to reduce the incidence of cervical cancer2,4

• In countries withwith established screening programmes – HPV vaccination + screening is predicted to be more effective and

cost-effective than screening alone for the prevention of cervical cancer and cervical pre-cancer1,2, 3

– Screening should continue in order to detect disease related to non-vaccine HPV types Screening intervals are likely to increase once widespread vaccination

occurs

1. Garnett GP, et al. Vaccine 2006; 24(Suppl 3):S178–S186; 2. Goldie SJ, et al. J Natl Cancer Inst 2004; 96:604–615;

3. Elbasha EH, et al. Emerg Infect Dis 2007; 13:28–41; 4. Goldie SJ, et al. Int J Cancer 2003; 106:896–904.

HPV AND WOMEN

Treatment for HPV related cervical abnormalities:• Colposcopys, cervical biospsies, cryotherapy, laser treatment,

LEEP.

New opinions often appear first as jokes and fancies, then as blasphemies and treason, then as questions open to discussion, and finally as established truths

»George Bernard Shaw

PREVENTION OF HPV

• Primary Prevention: Vaccination

• Secondary Prevention: Screening Program including regular PAP smear tests

Harald zur Hausen

Born March 11, 1936 (age 74)Germany

Nationality German

Known for Discovery that HPV can causecervical cancer

Notable awards 2008

Nobel Prize in Physiology or Medicine

The need for Vaccination against Cervical Cancer

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 response1-4

1. Parr EL et al. J Virol 1997;71(11):8109-15, 2. Nardelli-Haefliger D et al. J Natl Cancer Inst 2003;95(15):1128-37, 3. Schiller JT et al. Nat Rev Microbiol 2004;2(4):343-7, 4. Poncelet et al. ESPID, Porto, Portugal 2007; Abstract 37,

session ES2, 5. Stanley M. HPV Today 2007; 11: 1-16, 6. Einstein M, Cancer Immunol Immunother 2007; 57(4):443-51.

Vaccination induces higher antibodies in the blood and site of infection

•Vaccine induces higher antibody levels in the blood which means higher antibody levels at the site of infection4

•These Antibodies neutralize the virus & prevent entry into cells5,6

What makes a good cervical cancer vaccine?

• Antigens (virus-like particles) that closely mimic the virus structure

• Generation of neutralizing antibodies – the major basis of protection

• High levels of antibodies in the serum that can transude to the site of infection

• Induce long lasting protection

What makes a good cervical cancer vaccine?

1. Antigens which closely mimic the virus

2. Adjuvants for the generation of high levels of neutralizing antibodies

HPV-containing double stranded

DNA

‘Empty’ non-infectious virus-like particle (VLP)

mimics the virus

The adjuvant concept

• Adjuvants enhance the specific immune response to vaccine antigens1

– Efficient antigen delivery – depot effect

– Mimic danger signals & stimulate innate immunity through pro-inflammatory cytokines

• Adjuvants currently used in Cervical Cancer vaccines:

– Aluminium salts (Gardasil®)

– AS04 (Monophosphoryl-Lipid A + Al(OH)3) (CervarixTM)

Vaccines, 5th edition, 2008 Stanley Plotkin

Composition of the two licenced HPV vaccines

+HPV 16 VLPs HPV 18 VLPs

Oncogenic Antigens AS04

+Aluminium

saltMPL(Immuno

Stimulant)

CervarixTM

+HPV 16 VLPs HPV 18 VLPs HPV 6 VLPs HPV 11 VLPs

Oncogenic Antigens Adjuvant

Gardasil®

Non- Oncogenic Antigens

Aluminium salt

High and Lasting levels of Antibodies and Memory B cells

Highly purified antigens Strong immunogens

Enhanced immune responseAS04

AS04: Novel adjuvant system in Cervarix™

Aluminium salt

MPL (ImmunoStimulant)

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.

+

Twenty years from now you will be more disappointed by the things that you didn't do than by the ones you did do. Explore. Dream. Discover.

Mark Twain

1. Higher antibody titres were detected in the serum in those women who recieved Cervarix compared to those who recieved Gardasil

2. Higher antibody titres were detected at the Cervix in those women who recieved Cervarix compared to those who recieved Gardasil

3. The memory B-cell responses were also higher with Cervarix than Gardasil for both antigens

Summary: Comparison of the immunogenicity of Cervarix™ and Gardasil®

Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F, et al. Comparison of the immunogenicity and safety of Cervarix() and Gardasil((R)) human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin 2009 Oct 14;5(10).

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Cervarix™: 100% efficacy against HPV 16/18 year after year

HPV 16/18-related

CIN2+

Cervarix® Control Vaccine efficacy

n n % 95% CI

Initial efficacy study 2.3 years1 0 3 NA* NA*

Combined analysis of initial efficacy study and extended follow-up

4.5 years2 0 5 100.0 -7.7–100.0

5.5 years3 0 7 100.0 32.7–100.0

6.4 years4,5 0 9 100.0 51.3–10.00

7.3 years6 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.

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 VaccineAdverse Reactions

• Local reactions commonest

(pain, swelling)

• Syncope – Give vaccine in sitting / lying down position, and observe for 15 minutes after vaccination

• No serious adverse reactions reported

*similar to reports in placebo recipients (9%)

HPV vaccines: Safety and approval

• WHO’s Global Advisory Committee on Vaccine Safety (GACVS) concluded that the HPV vaccines had good safety profiles1

• U.S. Food and Drug Administration (FDA) approved Cervarix™ on 15 October 20092

1. http://www.who.int/wer/2009/wer8415.pdf. (Accessed Feb 2010) 2. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/

ucm186959.htm. (Accessed Feb 2010)

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women

HPV Vaccine Study of Cervarix™ in India

Bhatla N et al. J. Obstet. Gynaecol. Res. Vol. 36, No. 1: 123–132, February 2010

Study Design

• 354 women recruited in 4 centres in India- PGIMER, Chandigarh

- All-India Institute of Medical Sciences, New Delhi- Chittananjan National Cancer Institute, Kolkata- Tata Memorial Hospital, Mumbai

• Women aged 18-35• Doses given 0,1,6 months• Double-blind, 1:1 randomization Vaccine: Placebo

(aluminum hydroxide)• ELISA testing of sera + safety & reactogenicity at 7

months


Results

• 100% Seroconversion / seropositivity of vaccine group

• No difference for safety of vaccine vs. placebo• Commonest solicited Adverse Events:

- Injection site pain, redness, swelling – all of which resolved

• The AS04-adjuvanted HPV-16/18 cervical cancer vaccine (Cervarix™) was highly immunogenic and generally well-tolerated.


Potential impact of HPV Vaccination

• HPV vaccination is the primary prevention strategy against cervical cancer

• HPV vaccination is predicted to have a major impact on the burden of cervical cancer, especially in settings without optimal screening programs

1. Paavonen J et al. Final Phase III Efficacy Analysis Of Cervarix™ In Young Women Abstract presented at the 25th International Papillomavirus conference, Malmo, Sweden, 8-14 May 2009 2. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in India. Summary Report 2010.

• Cervical cancer causes significant morbidity/ mortality

• HPV vaccine to be offered to all appropriate females who

can afford the vaccine

• Vaccine should be given prior to sexual debut

FOGSI & IAP Recommendations

www.fogsi.org/hpv vaccine

• Age for initiation of vaccination is 10- 12 years.

– Catch up vaccination is permitted up to the age of 26 years for quadrivalent & 45 yrs for bivalent vaccine

• 3 doses at 0, 2 and 6 months with quadrivalent vaccine

• 3 doses 0, 1 and 6 months with bivalent vaccine

• No need for Booster doses

FOGSI & IAP Recommendations– Vaccine Schedule


• Sexually active women and women with previous abnormal cervical cytology can receive the HPV vaccine

• Benefits may be limited to the protection against infection of HPV genotypes with which they have not been infected

FOGSI Recommendations:Vaccination of Sexually Active

Women


• The vaccine can be given to patients with previous CIN, but the benefits may be limited to the protection against infection of HPV genotypes (and related CIN) with which they have not been infected

• The HPV vaccine is not therapeutic. It does not treat existing HPV infection or cervical intraepithelial neoplasia (cervical pre-cancers)

FOGSI Recommendations:Women With Previous CIN


– Not recommended for use in pregnancy

– If patient becomes pregnant - Delay remaining doses till delivery

– If vaccinated during pregnancy - No intervention (MTP) needed

– Lactating women can receive the HPV vaccine and still continue breastfeeding as it is a vaccine without live viral DNA

FOGSI & IAP Recommendations:Pregnancy & Lactation


• Vaccinated women should be screened as per the standard guideline

• Screen positive women may be vaccinated after counseling

• Screening/ HPV test is not required prior to vaccination

FOGSI & IAP Recommendations:Vaccination & Screening


• Vaccination: One of greatest public health achievements in the world

• With the exception of clean drinking water, vaccines are the most effective intervention in reducing and preventing the return of infectious disease1

• 26 diseases are now vaccine preventable2

Value of vaccination Today

1 - European Vaccine Manufacturer’s paper 20032 - International Federation of Pharmaceutical Manufacturing Associations. May 2003

Let’s add Cervical Cancer to this list!

Health & Medicine

Cervical Cancer Vaccine - Do we need it in India